Serum inter-alpha-trypsin inhibitor and matrix hyaluronan promote angiogenesis in fibrotic lung injury.

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Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S; Hollingsworth, John W; Jiang, Dianhua; Lancaster, Lisa H; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K; Noble, Paul W; Kimata, Koji; Schwartz, David A

2008-11-01

The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627).

ANGIOGENESIS INHIBITORS FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA

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Massimiliano Berretta

2016-11-01

Full Text Available Background: Angiogenesis inhibitors have become an important therapeutic approach in the treatment of hepatocellular carcinoma (HCC patients. The achievement of Sorafenib in prolonging overall survival of patients with HCC makes therapeutic inhibition of angiogenesis a fundamental element of the treatment of HCC. Considering the heterogeneous aspects of HCC and to enhance therapeutic efficacy, overcome drug resistance and reduce toxicity, the combination of antiangiogenic drugs with antiblastic chemotherapy (AC, radiotherapy or other targeted drugs have been evaluated. The issue is further complicated by the combination of antiangiogenesis with other AC or biologic drugs. To date, there is no planned approach to determine which patients are more responsive to a given type of antiangiogenic treatment. Conclusion: Large investments in the clinical research are essential to improve treatment response and minimize toxicities for patients with HCC. Future investigations will need to focus on utilizing patterns of genetic information to classify HCC into groups that display similar prognosis and treatment sensitivity, and combining targeted therapies with AC producing enhanced anti-tumor effect. In this review the current panel of available antiangiogenic therapies for the treatment of HCC have been analyzed. In addition current clinical trials are also reported herein.

Serum Inter–α-Trypsin Inhibitor and Matrix Hyaluronan Promote Angiogenesis in Fibrotic Lung Injury

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Garantziotis, Stavros; Zudaire, Enrique; Trempus, Carol S.; Hollingsworth, John W.; Jiang, Dianhua; Lancaster, Lisa H.; Richardson, Elizabeth; Zhuo, Lisheng; Cuttitta, Frank; Brown, Kevin K.; Noble, Paul W.; Kimata, Koji; Schwartz, David A.

2008-01-01

Rationale: The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-α-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury. Objectives: To determine whether IaI promotes HA-mediated angiogenesis in tissue injury. Methods: An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined. Measurements and Main Results: IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC. Conclusions: Our findings indicate that serum IaI interacts with HA, and promotes angiogenesis in lung injury. IaI appears to contribute to the vascular response to lung injury and may lead to aberrant angiogenesis. Clinical trial registered with www.clinicaltrials.gov (NCT00016627). PMID:18703791

Toxicity management of angiogenesis inhibitors: resolution of expert panel

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Pavel O. Rumiantsev

2017-12-01

Full Text Available On 22 June 2017 in St. Petersburg the expert panel was held on the topic “Management of toxicity of angiogenesis inhibitors”, which discussed current issues of systemic therapy of advanced differentiated thyroid cancer resistant to radioactive iodine therapy, advanced kidney cancer and questions of efficacy and safety of new target drugs in the treatment of these diseases. The reports and discussions of experts raised the following questions: 1. Own experience of using lenvatinib in patients with differentiated thyroid cancer refractory to therapy with radioactive iodine and kidney cancer. 2. Profile of efficacy and safety of modern targeted therapy with multikinase inhibitors. 3. Prophylaxis and management of predictable toxicity.

History of research on angiogenesis.

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Ribatti, Domenico

2014-01-01

Over the past 25 years, the number of Medline publications dealing with angiogenesis has increased in a nonlinear fashion, reflecting the interest among basic scientists and clinicians in this field. Under physiological conditions, angiogenesis is regulated by the local balance between endogenous stimulators and inhibitors of this process. In tumor growth, there is an imbalance between endogenous stimulator and inhibitor levels, leading to an 'angiogenic switch'. Starting with the hypothesis formulated by Judah Folkman that tumor growth is angiogenesis-dependent, this area of research has a solid scientific foundation and inhibition of angiogenesis is a major area of therapeutic development for the treatment of cancer. This paper offers an account of the most relevant discoveries in this field of biomedical research. Copyright © 2014 S. Karger AG, Basel.

[Angiogenesis and endometriose].

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Becker, C M; Bartley, J; Mechsner, S; Ebert, A D

2004-08-01

Endometriosis is considered a chronic disease of women during their reproductive phase, which resembles many signs of malignancy. So far, therapeutic options for endometriosis-associated pain and infertility are unsatisfactory and often lead to recurrence of disease after termination of treatment. Angiogenesis seems to play an important role in the pathogenesis of endometriosis. The use of angiogenesis inhibitors may add an important new tool to well-established treatment schedules. Therefore, it is very important to thoroughly investigate the role of angiogenesis in endometriosis with respect to the female reproductive system.

Reduction of Adipose Tissue Mass by the Angiogenesis Inhibitor ALS-L1023 from Melissa officinalis.

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Byung Young Park

Full Text Available It has been suggested that angiogenesis modulates adipogenesis and obesity. This study was undertaken to determine whether ALS-L1023 (ALS prepared by a two-step organic solvent fractionation from Melissa leaves, which exhibits antiangiogenic activity, can regulate adipose tissue growth. The effects of ALS on angiogenesis and extracellular matrix remodeling were measured using in vitro assays. The effects of ALS on adipose tissue growth were investigated in high fat diet-induced obese mice. ALS inhibited VEGF- and bFGF-induced endothelial cell proliferation and suppressed matrix metalloproteinase (MMP activity in vitro. Compared to obese control mice, administration of ALS to obese mice reduced body weight gain, adipose tissue mass and adipocyte size without affecting appetite. ALS treatment decreased blood vessel density and MMP activity in adipose tissues. ALS reduced the mRNA levels of angiogenic factors (VEGF-A and FGF-2 and MMPs (MMP-2 and MMP-9, whereas ALS increased the mRNA levels of angiogenic inhibitors (TSP-1, TIMP-1, and TIMP-2 in adipose tissues. The protein levels of VEGF, MMP-2 and MMP-9 were also decreased by ALS in adipose tissue. Metabolic changes in plasma lipids, liver triglycerides, and hepatic expression of fatty acid oxidation genes occurred during ALS-induced weight loss. These results suggest that ALS, which has antiangiogenic and MMP inhibitory activities, reduces adipose tissue mass in nutritionally obese mice, demonstrating that adipose tissue growth can be regulated by angiogenesis inhibitors.

Lack of association between level of Plasminogen Activator Inhibitor-1 and estimates of tumor angiogenesis in early breast cancer

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Offersen, Birgitte Vrou; Riisbro, Rikke; Knoop, Ann

2007-01-01

Plasminogen Activator Inhibitor type-1 (PAI-1) is involved in tumor invasion and progression. High levels of PAI-1 are associated with poor prognosis in breast cancer, and PAI-1 has been shown to play a role in angiogenic processes. Since estimates of tumor angiogenesis may predict poor prognosis...... we studied the relationship between PAI-1 and estimates of angiogenesis in breast cancer. Tumor tissue specimens from 438 breast cancer patients were included. Median follow-up was 10.3 years. Protein levels of PAI-1 were measured using an ELISA. Angiogenesis scores were performed using a Chalkley.......009) were independent markers of death from breast cancer. This study confirms high PAI-1 or high Chalkley counts as markers of poor prognosis in breast cancer patients, and suggests that the prognostic impact of PAI-1 is independent of its supposed involvement in tumor angiogenesis. Udgivelsesdato: 2007...

Distribution and pharmacokinetic analysis of angiostatin radioiodine labeled with high stability

International Nuclear Information System (INIS)

Song, Sung Hee; Jung, Kyung-Ho; Paik, Jin-Young; Koh, Bong-Ho; Bae, Joon-Sang; Choe, Yearn Seong; Lee, Kyung-Han; Kim, Byung-Tae

2005-01-01

Objective: Radiotracers of anticancer agents provide important information on its in vivo handling. Angiostatin (AST) is a promising anticancer drug with potent antiangiogenic effects, but reported AST radiotracers suffer from poor in vivo stability. In this study, we synthesized an AST probe radioiodinated via the Bolton-Hunter reagent ( 125 I-BH-AST) and investigated its stability and biokinetics in mice. Methods: 125 I-BH-AST and conventional direct radioiodinated 125 I-AST were evaluated for human endothelial cell binding characteristics. In vivo stability of the radiotracers was compared by biodistribution studies in normal ICR mice. Angiostatin pharmacokinetics was analyzed by serial blood sampling after intravenous injection of 125 I-BH-AST with varying AST concentrations in mice. Results: Both 125 I-AST and 125 I-BH-AST retained selective endothelial binding as demonstrated by dose-dependent inhibition by nonradiolabeled AST. 125 I-BH-AST was substantially more stable in mice than 125 I-AST, with 28- and 7-fold lower 24-h thyroid and blood activities, respectively (15.5±1.5 vs. 430.9±32.2 and 0.1±0.0 vs. 0.8±0.0 %ID/g; both P 125 I-BH-AST, we found that 24-h AST accumulation was highest in the kidneys, followed by the liver and lungs. Kinetic analysis of 125 I-BH-AST revealed AST to have linear pharmacokinetics with a T 1/2 of 5.8±2.6 h, volume of distribution (V d ) of 6.8±1.3 ml and clearance of 0.8±0.1 ml/h. Conclusion: Radioiodine-labeled AST prepared by the BH method provides a radioprobe with superior stability and improved in vivo biokinetics that is useful for distribution and pharmacokinetic studies

In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

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Latham, Antony M; Kankanala, Jayakanth; Fearnley, Gareth W; Gage, Matthew C; Kearney, Mark T; Homer-Vanniasinkam, Shervanthi; Wheatcroft, Stephen B; Fishwick, Colin W G; Ponnambalam, Sreenivasan

2014-01-01

Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues. We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2) and cyclin-dependent kinase 1 (CDK1). This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A)-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis. We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

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Klenke, Frank Michael; Gebhard, Martha-Maria; Ewerbeck, Volker; Abdollahi, Amir; Huber, Peter E; Sckell, Axel

2006-01-01

The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. In 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases

Cancer gene therapy targeting angiogenesis: An updated Review

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Liu, Ching-Chiu; Shen, Zan; Kung, Hsiang-Fu; Lin, Marie CM

2006-01-01

Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971, scientists have made efforts exploring the possibilities in treating cancer by targeting angiogenesis. Inhibition of angiogenesis growth factors and administration of angiogenesis inhibitors are the basics of anti-angiogenesis therapy. Transfer of anti-angiogenesis genes has received attention recently not only because of the advancement of recombinant vectors, but also because of the localized and sustained expression of therapeutic gene product inside the tumor after gene transfer. This review provides the up-to-date information about the strategies and the vectors studied in the field of anti-angiogenesis cancer gene therapy. PMID:17109514

In silico design and biological evaluation of a dual specificity kinase inhibitor targeting cell cycle progression and angiogenesis.

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Antony M Latham

Full Text Available Protein kinases play a central role in tumor progression, regulating fundamental processes such as angiogenesis, proliferation and metastasis. Such enzymes are an increasingly important class of drug target with small molecule kinase inhibitors being a major focus in drug development. However, balancing drug specificity and efficacy is problematic with off-target effects and toxicity issues.We have utilized a rational in silico-based approach to demonstrate the design and study of a novel compound that acts as a dual inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2 and cyclin-dependent kinase 1 (CDK1. This compound acts by simultaneously inhibiting pro-angiogenic signal transduction and cell cycle progression in primary endothelial cells. JK-31 displays potent in vitro activity against recombinant VEGFR2 and CDK1/cyclin B proteins comparable to previously characterized inhibitors. Dual inhibition of the vascular endothelial growth factor A (VEGF-A-mediated signaling response and CDK1-mediated mitotic entry elicits anti-angiogenic activity both in an endothelial-fibroblast co-culture model and a murine ex vivo model of angiogenesis.We deduce that JK-31 reduces the growth of both human endothelial cells and human breast cancer cells in vitro. This novel synthetic molecule has broad implications for development of similar multi-kinase inhibitors with anti-angiogenic and anti-cancer properties. In silico design is an attractive and innovative method to aid such drug discovery.

Melatonin as an angiogenesis inhibitor to combat cancer: Mechanistic evidence.

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Goradel, Nasser Hashemi; Asghari, Mohammad Hossein; Moloudizargari, Milad; Negahdari, Babak; Haghi-Aminjan, Hamed; Abdollahi, Mohammad

2017-11-15

Melatonin, a pineal indolamine, participates in different body functions and is shown to possess diverse biological activities such as anti-tumor action. Angiogenesis inhibition is one of the mechanisms by which melatonin exerts its oncostatic effects. Increased angiogenesis is a major feature of tumor progression, thus angiogenesis inhibition is a critical step in cancer therapy. Melatonin employs a variety of mechanisms to target nutrients and oxygen supply to cancer cells. At the transcriptional level, hypoxia induced factor-1α (HIF-1α) and the genes under its control, such as vascular endothelial growth factor (VEGF) are the main targets of melatonin for inhibition of angiogenesis. Melatonin prevents translocation of HIF-1α into the nucleus thereby hindering VEGF expression and also prevents the formation of HIF-1α, phospho-STAT3 and CBP/p300 complex which is involved in the expression of angiogenesis-related genes. Angiostatic properties of melatonin could be also due to its ability to inhibit VEGFR2's activation and expression. Other angiostatic mechanisms of melatonin include the inhibition of endothelial cell migration, invasion, and tube formation. In the present study, we have reviewed the molecular anti-angiogenesis pathways mediated by melatonin and the responsible mechanisms in various types of cancers both in vitro and in vivo. Copyright © 2017 Elsevier Inc. All rights reserved.

Anti-tumor angiogenesis effect of aminopeptidase inhibitor bestatin against B16-BL6 melanoma cells orthotopically implanted into syngeneic mice.

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Aozuka, Yasushi; Koizumi, Keiichi; Saitoh, Yurika; Ueda, Yasuji; Sakurai, Hiroaki; Saiki, Ikuo

2004-12-08

We investigated the effect of bestatin, an inhibitor of aminopeptidase N (APN)/CD13 and aminopeptidase B, on the angiogenesis induced by B16-BL6 melanoma cells. Oral administration of bestatin (100-200 mg/kg/day) was found to significantly inhibit the melanoma cell-induced angiogenesis in a mouse dorsal air sac assay. Additionally, anti-APN/CD13 mAb (WM15), which neutralizes the aminopeptidase activity in tumor cells, as well as bestatin inhibited the tube-like formation of human umbilical vein endothelial cells (HUVECs) in vitro. Furthermore, the intraperitoneal administration of bestatin (50-100 mg/kg/day) after the orthotopic implantation of B16-BL6 melanoma cells into mice reduced the number of vessels oriented towards the established primary tumor mass on the dorsal side of mice. These findings suggest that bestatin is an active anti-angiogenic agent that may inhibit tumor angiogenesis in vivo and tube-like formation of endothelial cells in vitro through its inhibition of APN/CD13 activity.

Lister vaccine strain of vaccinia virus armed with the endostatin-angiostatin fusion gene: an oncolytic virus superior to dl1520 (ONYX-015) for human head and neck cancer.

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Tysome, James R; Wang, Pengju; Alusi, Ghassan; Briat, Arnaud; Gangeswaran, Rathi; Wang, Jiwei; Bhakta, Vipul; Fodor, Istvan; Lemoine, Nick R; Wang, Yaohe

2011-09-01

Oncolytic viral therapy represents a promising strategy for the treatment of head and neck squamous cell carcinoma (HNSCC), with dl1520 (ONYX-015) the most widely used oncolytic adenovirus in clinical trials. This study aimed to determine the effectiveness of the Lister vaccine strain of vaccinia virus as well as a vaccinia virus armed with the endostatin-angiostatin fusion gene (VVhEA) as a novel therapy for HNSCC and to compare them with dl1520. The potency and replication of the Lister strain and VVhEA and the expression and function of the fusion protein were determined in human HNSCC cells in vitro and in vivo. Finally, the efficacy of VVhEA was compared with dl1520 in vivo in a human HNSCC model. The Lister vaccine strain of vaccinia virus was more effective than the adenovirus against all HNSCC cell lines tested in vitro. Although the potency of VVhEA was attenuated in vitro, the expression and function of the endostatin-angiostatin fusion protein was confirmed in HNSCC models both in vitro and in vivo. This novel vaccinia virus (VVhEA) demonstrated superior antitumor potency in vivo compared with both dl1520 and the control vaccinia virus. This study suggests that the Lister strain vaccinia virus armed with an endostatin-angiostatin fusion gene may be a potential therapeutic agent for HNSCC.

Mature and progenitor endothelial cells perform angiogenesis also under protease inhibition: the amoeboid angiogenesis.

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Chillà, Anastasia; Margheri, Francesca; Biagioni, Alessio; Del Rosso, Mario; Fibbi, Gabriella; Laurenzana, Anna

2018-04-03

Controlling vascular growth is a challenging aim for the inhibition of tumor growth and metastasis. The amoeboid and mesenchymal types of invasiveness are two modes of migration interchangeable in cancer cells: the Rac-dependent mesenchymal migration requires the activity of proteases; the Rho-ROCK-dependent amoeboid motility is protease-independent and has never been described in endothelial cells. A cocktail of physiologic inhibitors (Ph-C) of serine-proteases, metallo-proteases and cysteine-proteases, mimicking the physiological environment that cells encounter during their migration within the angiogenesis sites was used to induce amoeboid style migration of Endothelial colony forming cells (ECFCs) and mature endothelial cells (ECs). To evaluate the mesenchymal-ameboid transition RhoA and Rac1 activation assays were performed along with immunofluorescence analysis of proteins involved in cytoskeleton organization. Cell invasion was studied in Boyden chambers and Matrigel plug assay for the in vivo angiogenesis. In the present study we showed in both ECFCs and ECs, a decrease of activated Rac1 and an increase of activated RhoA upon shifting of cells to the amoeboid conditions. In presence of Ph-C inhibitors both cell lines acquired a round morphology and Matrigel invasion was greatly enhanced with respect to that observed in the absence of protease inhibition. We also observed that the urokinase-plasminogen-activator (uPAR) receptor silencing and uPAR-integrin uncoupling with the M25 peptide abolished both mesenchymal and amoeboid angiogenesis of ECFCs and ECs in vitro and in vivo, indicating a role of the uPAR-integrin-actin axis in the regulation of amoeboid angiogenesis. Furthermore, under amoeboid conditions endothelial cells seem to be indifferent to VEGF stimulation, which induces an amoeboid signaling pattern also in mesenchymal conditions. Here we first provide a data set disclosing that endothelial cells can move and differentiate into vascular

Identification of brain-specific angiogenesis inhibitor 2 as an interaction partner of glutaminase interacting protein

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Zencir, Sevil; Ovee, Mohiuddin; Dobson, Melanie J.; Banerjee, Monimoy; Topcu, Zeki; Mohanty, Smita

2011-01-01

Highlights: → Brain-specific angiogenesis inhibitor 2 (BAI2) is a new partner protein for GIP. → BAI2 interaction with GIP was revealed by yeast two-hybrid assay. → Binding of BAI2 to GIP was characterized by NMR, CD and fluorescence. → BAI2 and GIP binding was mediated through the C-terminus of BAI2. -- Abstract: The vast majority of physiological processes in living cells are mediated by protein-protein interactions often specified by particular protein sequence motifs. PDZ domains, composed of 80-100 amino acid residues, are an important class of interaction motif. Among the PDZ-containing proteins, glutaminase interacting protein (GIP), also known as Tax Interacting Protein TIP-1, is unique in being composed almost exclusively of a single PDZ domain. GIP has important roles in cellular signaling, protein scaffolding and modulation of tumor growth and interacts with a number of physiological partner proteins, including Glutaminase L, β-Catenin, FAS, HTLV-1 Tax, HPV16 E6, Rhotekin and Kir 2.3. To identify the network of proteins that interact with GIP, a human fetal brain cDNA library was screened using a yeast two-hybrid assay with GIP as bait. We identified brain-specific angiogenesis inhibitor 2 (BAI2), a member of the adhesion-G protein-coupled receptors (GPCRs), as a new partner of GIP. BAI2 is expressed primarily in neurons, further expanding GIP cellular functions. The interaction between GIP and the carboxy-terminus of BAI2 was characterized using fluorescence, circular dichroism (CD) and nuclear magnetic resonance (NMR) spectroscopy assays. These biophysical analyses support the interaction identified in the yeast two-hybrid assay. This is the first study reporting BAI2 as an interaction partner of GIP.

CS2164, a novel multi-target inhibitor against tumor angiogenesis, mitosis and chronic inflammation with anti-tumor potency.

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Zhou, You; Shan, Song; Li, Zhi-Bin; Xin, Li-Jun; Pan, De-Si; Yang, Qian-Jiao; Liu, Ying-Ping; Yue, Xu-Peng; Liu, Xiao-Rong; Gao, Ji-Zhou; Zhang, Jin-Wen; Ning, Zhi-Qiang; Lu, Xian-Ping

2017-03-01

Although inhibitors targeting tumor angiogenic pathway have provided improvement for clinical treatment in patients with various solid tumors, the still very limited anti-cancer efficacy and acquired drug resistance demand new agents that may offer better clinical benefits. In the effort to find a small molecule potentially targeting several key pathways for tumor development, we designed, discovered and evaluated a novel multi-kinase inhibitor, CS2164. CS2164 inhibited the angiogenesis-related kinases (VEGFR2, VEGFR1, VEGFR3, PDGFRα and c-Kit), mitosis-related kinase Aurora B and chronic inflammation-related kinase CSF-1R in a high potency manner with the IC 50 at a single-digit nanomolar range. Consequently, CS2164 displayed anti-angiogenic activities through suppression of VEGFR/PDGFR phosphorylation, inhibition of ligand-dependent cell proliferation and capillary tube formation, and prevention of vasculature formation in tumor tissues. CS2164 also showed induction of G2/M cell cycle arrest and suppression of cell proliferation in tumor tissues through the inhibition of Aurora B-mediated H3 phosphorylation. Furthermore, CS2164 demonstrated the inhibitory effect on CSF-1R phosphorylation that led to the suppression of ligand-stimulated monocyte-to-macrophage differentiation and reduced CSF-1R + cells in tumor tissues. The in vivo animal efficacy studies revealed that CS2164 induced remarkable regression or complete inhibition of tumor growth at well-tolerated oral doses in several human tumor xenograft models. Collectively, these results indicate that CS2164 is a highly selective multi-kinase inhibitor with potent anti-tumor activities against tumor angiogenesis, mitosis and chronic inflammation, which may provide the rationale for further clinical assessment of CS2164 as a therapeutic agent in the treatment of cancer. © 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Correlation of matrix metalloproteinases and their inhibitors with hypoxia and angiogenesis in premenopausal patients with adenocarcinoma of the breast.

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Vinothini, Govindarajah; Aravindraja, Chairmandurai; Chitrathara, K; Nagini, Siddavaram

2011-08-01

The present study was designed to correlate the expression of proteins regulating invasion and angiogenesis in patients with adenocarcinoma of the breast. Seventy-five premenopausal breast cancer patients histologically categorized as grades I, II and III were chosen for the study. We analyzed the expression of MMP-2, and -9 and their inhibitors TIMP-2 and RECK together with HIF-1α and VEGF in tumor, adjacent tissues and serum samples by immunohistochemical and Western blot analysis. The breast tumors analyzed in the present study were characterized by increased expression of MMP-2, -9, HIF-1α and VEGF with differential expression patterns of TIMP-2 and downregulation of RECK. The simultaneous analysis of the expression of these molecular markers is important to understand the intricate network between key molecules involved in invasion and angiogenesis that eventually determines the clinical course of the disease. Copyright © 2011 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

Micronutrients attenuate progression of prostate cancer by elevating the endogenous inhibitor of angiogenesis, Platelet Factor-4

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Fleshner Neil E

2010-06-01

Full Text Available Abstract Background Longstanding evidence implicates an inadequate diet as a key factor in the onset and progression of prostate cancer. The purpose herein was to discover, validate and characterize functional biomarkers of dietary supplementation capable of suppressing the course of prostate cancer in vivo. Methods The Lady transgenic mouse model that spontaneously develops prostate cancer received a diet supplemented with a micronutrient cocktail of vitamin E, selenium and lycopene ad libitum. A proteomic analysis was conducted to screen for serum biomarkers of this dietary supplementation. Candidate peptides were validated and identified by sequencing and analyzed for their presence within the prostates of all mice by immunohistochemistry. Results Dietary supplementation with the combined micronutrients significantly induced the expression of the megakaryocyte-specific inhibitor of angiogenesis, platelet factor-4 (P = 0.0025. This observation was made predominantly in mice lacking tumors and any manifestations associated with progressive disease beyond 37 weeks of life, at which time no survivors remained in the control group (P Conclusion We present unprecedented data whereby these combined micronutrients effectively promotes tumor dormancy in early prostate cancer, following initiation mutations that may drive the angiogenesis-dependent response of the tumor, by inducing platelet factor-4 expression and concentrating it at the tumor endothelium through enhanced platelet binding.

Icariin stimulates angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways in human endothelial cells

International Nuclear Information System (INIS)

Chung, Byung-Hee; Kim, Jong-Dai; Kim, Chun-Ki; Kim, Jung Huan; Won, Moo-Ho; Lee, Han-Soo; Dong, Mi-Sook; Ha, Kwon-Soo; Kwon, Young-Geun; Kim, Young-Myeong

2008-01-01

We investigated the molecular effect and signal pathway of icariin, a major flavonoid of Epimedium koreanum Nakai, on angiogenesis. Icariin stimulated in vitro endothelial cell proliferation, migration, and tubulogenesis, which are typical phenomena of angiogenesis, as well as increased in vivo angiogenesis. Icariin activated the angiogenic signal modulators, ERK, phosphatidylinositol 3-kinase (PI3K), Akt, and endothelial nitric oxide synthase (eNOS), and increased NO production, without affecting VEGF expression, indicating that icariin may directly stimulate angiogenesis. Icariin-induced ERK activation and angiogenic events were significantly inhibited by the MEK inhibitor PD98059, without affecting Akt and eNOS phosphorylation. The PI3K inhibitor Wortmannin suppressed icariin-mediated angiogenesis and Akt and eNOS activation without affecting ERK phosphorylation. Moreover, the NOS inhibitor NMA partially reduced the angiogenic activity of icariin. These results suggest that icariin stimulated angiogenesis by activating the MEK/ERK- and PI3K/Akt/eNOS-dependent signal pathways and may be a useful drug for angiogenic therapy

The effectiveness of cyclooxygenase-2 inhibitors and evaluation of angiogenesis in the model of experimental colorectal cancer.

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Gungor, Hilal; Ilhan, Nevin; Eroksuz, Hatice

2018-06-01

Colorectal cancer (CRC) is an important cause of cancer-related deaths worldwide. Early diagnosis and treatment of CRCs are of importance for improving the survival. In the present study, we studied the effects of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced chemopreventive effects on tumor development incidence and angiogenesis in experimental CRC rats. 1,2-Dimethylhydrazine dihydrochloride (DMH) was used as cancer-inducing agent and two NSAIDs (celecoxib and diclofenac) were given orally as chemopreventive agents. Histopathological and immuno histochemical evaluations were performed in colorectal tissue samples, whereas angiogenesis parameters were studied in blood samples. Histopathological examination showed that adenocarcinoma (62.5%), dysplastic changes (31.25%) and inflammattory changes (6.25%) were detected in DMH group, whereas no pathological change was observed in control rats. In treatment groups, there was marked decrease in adenocarcinoma rate (30% and 10%, respectively). A significant increase was detected in MMP-2, MMP-9 levels and MMP-2/TIMP-2 ratio in DMH group as compared with controls and treatment groups. In immunohistochemical evaluations, there was an increase in intensity and extent of staining of MMP-2 and MMP-9 in DMH group as compared to controls and treatment groups. The decrease in celecoxib group was more prominent. Overall, it was concluded that NSAIDs, particularly cyclooxygenase-2 (COX-2) inhibitors, might have a protective effect on CRC development and slow down progression of tumor in a DMH-induced experimental cancer model. One of the possible mechanisms in the chemoprevention of colon cancer seems to be inhibition of angiogenesis by diclofenac and celecoxib. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Standardization of a method to study angiogenesis in a mouse model

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DAVID FEDER

2013-01-01

Full Text Available In the adult organism, angiogenesis is restricted to a few physiological conditions. On the other hand, uncontrolled angiogenesis have often been associated to angiogenesis-dependent pathologies. A variety of animal models have been described to provide more quantitative analysis of in vivo angiogenesis and to characterize pro- and antiangiogenic molecules. However, it is still necessary to establish a quantitative, reproducible and specific method for studies of angiogenesis factors and inhibitors. This work aimed to standardize a method for the study of angiogenesis and to investigate the effects of thalidomide on angiogenesis. Sponges of 0.5 x 0.5 x 0.5 cm were implanted in the back of mice groups, control and experimental (thalidomide 200 mg/K/day by gavage. After seven days, the sponges were removed. The dosage of hemoglobin in sponge and in circulation was performed and the ratio between the values was tested using nonparametric Mann-Whitney test. Results have shown that sponge-induced angiogenesis quantitated by ratio between hemoglobin content in serum and in sponge is a helpful model for in vivo studies on angiogenesis. Moreover, it was observed that sponge-induced angiogenesis can be suppressed by thalidomide, corroborating to the validity of the standardized method.

Angiogenesis is inhibitory for mammalian digit regeneration

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Yu, Ling; Yan, Mingquan; Simkin, Jennifer; Ketcham, Paulina D.; Leininger, Eric; Han, Manjong

2014-01-01

Abstract The regenerating mouse digit tip is a unique model for investigating blastema formation and epimorphic regeneration in mammals. The blastema is characteristically avascular and we previously reported that blastema expression of a known anti‐angiogenic factor gene, Pedf, correlated with a successful regenerative response (Yu, L., Han, M., Yan, M., Lee, E. C., Lee, J. & Muneoka, K. (2010). BMP signaling induces digit regeneration in neonatal mice. Development, 137, 551–559). Here we show that during regeneration Vegfa transcripts are not detected in the blastema but are expressed at the onset of differentiation. Treating the amputation wound with vascular endothelial growth factor enhances angiogenesis but inhibits regeneration. We next tested bone morphogenetic protein 9 (BMP9), another known mediator of angiogenesis, and found that BMP9 is also a potent inhibitor of digit tip regeneration. BMP9 induces Vegfa expression in the digit stump suggesting that regenerative failure is mediated by enhanced angiogenesis. Finally, we show that BMP9 inhibition of regeneration is completely rescued by treatment with pigment epithelium‐derived factor. These studies show that precocious angiogenesis is inhibitory for regeneration, and provide compelling evidence that the regulation of angiogenesis is a critical factor in designing therapies aimed at stimulating mammalian regeneration. PMID:27499862

Ethyl p-methoxycinnamate from Kaempferia galanga inhibits angiogenesis through tyrosine kinase

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Juni Ekowati

2015-04-01

Full Text Available Background Many tumors express on their receptor tyrosine kinases vascular endothelial growth factor activity associated with angiogenesis. Inhibition of angiogenesis through reduction of tyrosine kinase activity is a promising strategy for cancer therapy. The present study aimed to determine the mechanism and potency of ethyl p-methoxycinnamate (EPMC isolated from Kaempferia galanga as angiogenesis inhibitor. Methods A laboratory experimental study was conducted using chorio-allantoic membranes (CAMs of nine-day old chicken eggs induced by 60ng basic fibroblast growth factor (bFGF. Ethyl p-methoxycinnamate (EPMC potency was determined at dosages of 30, 60, 90 and 120 mg and compared with celecoxib 60 mg as reference drug and one negative bFGF-induced control group. Neovascularization and endothelial cell count in CAM blood vessels were evaluated. To predict the antiangiogenic mechanism of EPMC, a docking study was performed with the Molegro Virtual Docker program on tyrosine kinase as receptor (PDB 1XKK. Results Angiogenesis stimulation by bFGF was prevented significantly (p<0.05 by EPMC at dosages of 30, 60, 90 and 120 mg and this activity was dose dependent. Molecular docking showed interaction between EPMC functional groups and tyrosine kinase amino acids at Met766, Met793, Thr854, Thr790, Gln791 and Ala743. There was an association between EPMC antiangiogenic activity and docking study results. Conclusions Ethyl p-methoxycinnamate is a potential new angiogenesis inhibitor through interaction with tyrosine kinase. EPMC could be a promising therapeutic agent for treatment of angiogenesis-related diseases.

Apatinib Inhibits Angiogenesis Via Suppressing Akt/GSK3β/ANG Signaling Pathway in Anaplastic Thyroid Cancer

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Zhijian Jin

2017-12-01

Full Text Available Background/Aims: Anaplastic thyroid carcinoma (ATC is one of the most lethal human malignancies, and there is no efficient method to slow its process. Apatinib, a novel tyrosine kinase inhibitor (TKI, has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma patients. However, the effects of Apatinib in ATC are still unknown. Methods: In this study, we explored the effects and mechanisms of Apatinib on tumor growth and angiogenesis in vitro and in vitro in ATC cells. Angiogenesis antibodies array was utilized to detect the expression of angiogenesis-related genes after Apatinib treatment in ATC cells. In addition, we used Akt activator, Akt inhibitor and GSK3β inhibitor to further study the mechanism for how Apatinib suppressed angiogenesis. Results: Apatinib treatment could suppress the growth of ATC cells in a dose- and time-dependent manner via inducing apoptosis and blocking cell cycle progression at G0/G1 phase. Moreover, Apatinib treatment decreased the expression of angiogenin (ANG and inhibited angiogenesis of ATC cells in vitro and in vitro. We further confirmed that recombinant human ANG (rhANG significantly abrogated Apatinib-mediated anti-angiogenic ability in ATC cells. Additionally, Apatinib treatment decreased the level of p-Akt and p-GSK3β. Moreover, the Apatinib-mediated decrease of ANG and anti-angiogenic ability were partly reversed when an Akt activator, SC79, was administered. Furthermore, the anti-angiogenic ability of Apatinib can be enhanced in the presence of Akt inhibitor, and the inhibition of GSK3β attenuated the anti-angiogenic ability of Apatinib. Conclusion: Our results demonstrated that Apatinib treatment inhibited tumor growth, and Apatinib-induced suppression of Akt/GSK3β/ANG signaling pathway may play an important role in the inhibition of angiogenesis in ATC, supporting a potential therapeutic approach for using Apatinib in the treatment of ATC.

Molecular Therapeutic Targets for Glioma Angiogenesis

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Shingo Takano

2010-01-01

Full Text Available Due to the prominent angiogenesis that occurs in malignant glioma, antiangiogenic therapy has been attempted. There have been several molecular targets that are specific to malignant gliomas, as well as more broadly in systemic cancers. In this review, I will focus on some topics related to molecular therapeutic targets for glioma angiogenesis. First, important angiogenic factors that could be considered molecular targets are VEGF, VEGF-induced proteins on endothelial cells, tissue factor, osteopontin, v3 integrin, and thymidine phosphorylase as well as endogenous inhibitors, soluble Flt1, and thrombospondin 1. Second, hypoxic areas are also decreased by metronomic CPT11 treatment as well as temozolomide. Third, glioma-derived endothelial cells that are genetically and functionally distinct from normal endothelial cells should be targeted, for example, with SDF-1 and CXCR7 chemokine. Fourth, endothelial progenitor cells (EPCs likely contribute towards glioma angiogenesis in the brain and could be useful as a drug delivery tool. Finally, blockade of delta-like 4 (Dll4 results in a nonfunctioning vasculature and could be another important target distinct from VEGF.

Imaging techniques used for the real-time assessment of angiogenesis in digestive cancers

DEFF Research Database (Denmark)

Saftoiu, Adrian; Vilmann, Peter; Săftoiu, Adrian

2011-01-01

Angiogenesis has a critical role in primary tumor growth and the development of metastases. Several angiogenesis inhibitors were recently developed, being a very attractive target for digestive tumor therapy. However, individualized therapy should not only be based on the pre-treatment imaging...... of reviews was to analyze and enhance current knowledge and future perspectives about the real-time assessment of angiogenesis in digestive cancers, used for the longitudinal monitoring of the effects of chemo-radiotherapy (including anti-angiogenic therapies), as well as for the precise targeting of drugs...

Overexpression of inhibitor of DNA-binding (ID)-1 protein related to angiogenesis in tumor advancement of ovarian cancers

International Nuclear Information System (INIS)

Maw, Min Khine; Fujimoto, Jiro; Tamaya, Teruhiko

2009-01-01

The inhibitor of DNA-binding (ID) has been involved in cell cycle regulation, apoptosis and angiogenesis. This prompted us to study ID functions in tumor advancement of ovarian cancers. Sixty patients underwent surgery for ovarian cancers. In ovarian cancers, the levels of ID-1, ID-2 and ID-3 mRNAs were determined by real-time reverse transcription-polymerase chain reaction. The histoscore with the localization of ID-1 was determined by immunohistochemistry. Patient prognosis was analyzed with a 36-month survival rate. Microvessel counts were determined by immunohistochemistry for CD34 and factor VIII-related antigen. ID-1 histoscores and mRNA levels both significantly (p < 0.001) increased in ovarian cancers according to clinical stage, regardless of histopathological type. Furthermore, 30 patients with high ID-1 expression had a lower survival rate (53%) compared to patients with low ID-1 expression (80%). ID-1 histoscores and mRNA levels significantly (p < 0.0001) correlated with microvessel counts in ovarian cancers. ID-1 increased in ovarian cancer cells during tumor progression. Moreover, ID-1 expression levels correlated with microvessel counts. Therefore, ID-1 might work on tumor advancement via angiogenesis and is considered to be a candidate for a prognostic indicator in ovarian cancers

Friends Turned Foes: Angiogenic Growth Factors beyond Angiogenesis.

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Matkar, Pratiek N; Ariyagunarajah, Ramya; Leong-Poi, Howard; Singh, Krishna K

2017-10-02

Angiogenesis, the formation of new blood vessels from pre-existing ones is a biological process that ensures an adequate blood flow is maintained to provide the cells with a sufficient supply of nutrients and oxygen within the body. Numerous soluble growth factors and inhibitors, cytokines, proteases as well as extracellular matrix proteins and adhesion molecules stringently regulate the multi-factorial process of angiogenesis. The properties and interactions of key angiogenic molecules such as vascular endothelial growth factors (VEGFs), fibroblast growth factors (FGFs) and angiopoietins have been investigated in great detail with respect to their molecular impact on angiogenesis. Since the discovery of angiogenic growth factors, much research has been focused on their biological actions and their potential use as therapeutic targets for angiogenic or anti-angiogenic strategies in a context-dependent manner depending on the pathologies. It is generally accepted that these factors play an indispensable role in angiogenesis. However, it is becoming increasingly evident that this is not their only role and it is likely that the angiogenic factors have important functions in a wider range of biological and pathological processes. The additional roles played by these molecules in numerous pathologies and biological processes beyond angiogenesis are discussed in this review.

Angiogenesis and Tissue Engineering Research

Science.gov (United States)

2010-08-01

Model with the Angiogenesis Inhibitor Sunitinib. American Pediatric Surgical Association – 40th Annual Meeting, Fajardo, Puerto Rico, May 2009...Res 149(1):115-9. 14 5. Ray NF, Denton WG, Thamer M, Henderson SC, Perry S (1998) Abdominal adhesiolysis: inpatient care and expenditures in the...nude mice (n¼ 9). Mice were injected with near- infrared agents and imaged using intravital fluorescence microscope at 0, 7, and 35 days to validate in

Lysyl Oxidase Plays a Critical Role in Endothelial Cell Stimulation to Drive Tumor Angiogenesis

DEFF Research Database (Denmark)

Baker, Ann-Marie; Bird, Demelza; Welti, Jonathan C

2013-01-01

Identification of key molecules that drive angiogenesis is critical for the development of new modalities for the prevention of solid tumor progression. Using multiple models of colorectal cancer, we show that activity of the extracellular matrix-modifying enzyme lysyl oxidase (LOX) is essential...... for stimulating endothelial cells in vitro and angiogenesis in vivo. We show that LOX activates Akt through platelet-derived growth factor receptor ß (PDGFRß) stimulation, resulting in increased VEGF expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly or using inhibitors of PDGFRß...

Micronutrients attenuate progression of prostate cancer by elevating the endogenous inhibitor of angiogenesis, Platelet Factor-4

International Nuclear Information System (INIS)

Cervi, David; Pak, Brian; Venier, Natalie A; Sugar, Linda M; Nam, Robert K; Fleshner, Neil E; Klotz, Laurence H; Venkateswaran, Vasundara

2010-01-01

Longstanding evidence implicates an inadequate diet as a key factor in the onset and progression of prostate cancer. The purpose herein was to discover, validate and characterize functional biomarkers of dietary supplementation capable of suppressing the course of prostate cancer in vivo. The Lady transgenic mouse model that spontaneously develops prostate cancer received a diet supplemented with a micronutrient cocktail of vitamin E, selenium and lycopene ad libitum. A proteomic analysis was conducted to screen for serum biomarkers of this dietary supplementation. Candidate peptides were validated and identified by sequencing and analyzed for their presence within the prostates of all mice by immunohistochemistry. Dietary supplementation with the combined micronutrients significantly induced the expression of the megakaryocyte-specific inhibitor of angiogenesis, platelet factor-4 (P = 0.0025). This observation was made predominantly in mice lacking tumors and any manifestations associated with progressive disease beyond 37 weeks of life, at which time no survivors remained in the control group (P < 0.0001). While prostates of mice receiving standard chow were enlarged and burdened with poorly differentiated carcinoma, those of mice on the supplemented diet appeared normal. Immunohistochemical analysis revealed marked amplifications of both platelet binding and platelet factor-4 within the blood vessels of prostates from mice receiving micronutrients only. We present unprecedented data whereby these combined micronutrients effectively promotes tumor dormancy in early prostate cancer, following initiation mutations that may drive the angiogenesis-dependent response of the tumor, by inducing platelet factor-4 expression and concentrating it at the tumor endothelium through enhanced platelet binding

IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

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Toshifumi Tezuka

Full Text Available Plasminogen activator inhibitor (PAI-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp. IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

IMD-4690, a novel specific inhibitor for plasminogen activator inhibitor-1, reduces allergic airway remodeling in a mouse model of chronic asthma via regulating angiogenesis and remodeling-related mediators.

Science.gov (United States)

Tezuka, Toshifumi; Ogawa, Hirohisa; Azuma, Masahiko; Goto, Hisatsugu; Uehara, Hisanori; Aono, Yoshinori; Hanibuchi, Masaki; Yamaguchi, Yoichi; Fujikawa, Tomoyuki; Itai, Akiko; Nishioka, Yasuhiko

2015-01-01

Plasminogen activator inhibitor (PAI)-1 is the principal inhibitor of plasminogen activators, and is responsible for the degradation of fibrin and extracellular matrix. IMD-4690 is a newly synthesized inhibitor for PAI-1, whereas the effect on allergic airway inflammation and remodeling is still unclear. We examined the in vivo effects by using a chronic allergen exposure model of bronchial asthma in mice. The model was generated by an immune challenge for 8 weeks with house dust mite antigen, Dermatophagoides pteronyssinus (Dp). IMD-4690 was intraperitoneally administered during the challenge. Lung histopathology, hyperresponsiveness and the concentrations of mediators in lung homogenates were analyzed. The amount of active PAI-1 in the lungs was increased in mice treated with Dp. Administration with IMD-4690 reduced an active/total PAI-1 ratio. IMD-4690 also reduced the number of bronchial eosinophils in accordance with the decreased expressions of Th2 cytokines in the lung homogenates. Airway remodeling was inhibited by reducing subepithelial collagen deposition, smooth muscle hypertrophy, and angiogenesis. The effects of IMD-4690 were partly mediated by the regulation of TGF-β, HGF and matrix metalloproteinase. These results suggest that PAI-1 plays crucial roles in airway inflammation and remodeling, and IMD-4690, a specific PAI-1 inhibitor, may have therapeutic potential for patients with refractory asthma due to airway remodeling.

Endogenous developmental endothelial locus-1 limits ischemia-related angiogenesis by blocking inflammation

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Klotzsche - von Ameln, Anne; Cremer, Sebastian; Hoffmann, Jedrzej; Schuster, Peggy; Khedr, Sherif; Korovina, Irina; Troulinaki, Maria; Neuwirth, Ales; Sprott, David; Chatzigeorgiou, Antonios; Economopoulou, Matina; Orlandi, Alessia; Hain, Andreas; Zeiher, Andreas M.; Deussen, Andreas; Hajishengallis, George; Dimmeler, Stefanie; Chavakis, Triantafyllos; Chavakis, Emmanouil

2017-01-01

We have recently identified endothelial cell-secreted developmental endothelial locus-1 (Del-1) as an endogenous inhibitor of β2-integrin–dependent leukocyte infiltration. Del-1 was previously also implicated in angiogenesis. Here, we addressed the role of endogenously produced Del-1 in ischemia-related angiogenesis. Intriguingly, Del-1–deficient mice displayed increased neovascularization in two independent ischemic models (retinopathy of prematurity and hind-limb ischemia), as compared to Del-1–proficient mice. On the contrary, angiogenic sprouting in vitro or ex vivo (aortic ring assay) and physiological developmental retina angiogenesis were not affected by Del-1 deficiency. Mechanistically, the enhanced ischemic neovascularization in Del-1-deficiency was linked to higher infiltration of the ischemic tissue by CD45+ hematopoietic and immune cells. Moreover, Del-1-deficiency promoted β2-integrin–dependent adhesion of hematopoietic cells to endothelial cells in vitro, and the homing of hematopoietic progenitor cells and of immune cell populations to ischemic muscles in vivo. Consistently, the increased hind limb ischemia-related angiogenesis in Del-1 deficiency was completely reversed in mice lacking both Del-1 and the β2-integrin LFA-1. Additionally, enhanced retinopathy-associated neovascularization in Del-deficient mice was reversed by LFA-1 blockade. Our data reveal a hitherto unrecognized function of endogenous Del-1 as a local inhibitor of ischemia-induced angiogenesis by restraining LFA-1–dependent homing of pro-angiogenic hematopoietic cells to ischemic tissues. Our findings are relevant for the optimization of therapeutic approaches in the context of ischemic diseases. PMID:28447099

Imaging techniques used for the real-time assessment of angiogenesis in digestive cancers

DEFF Research Database (Denmark)

Săftoiu, Adrian; Vilmann, Peter

2011-01-01

Angiogenesis has a critical role in primary tumor growth and the development of metastases. Several angiogenesis inhibitors were recently developed, being a very attractive target for digestive tumor therapy. However, individualized therapy should not only be based on the pre-treatment imaging...... evaluation, but also on sensitive monitoring of microvascular changes during treatment. State-of-the-art imaging techniques have the potential to visualize and characterize angiogenesis, although the technology and methodologies employed are recent and need further validation. The aim of this series...... of reviews was to analyze and enhance current knowledge and future perspectives about the real-time assessment of angiogenesis in digestive cancers, used for the longitudinal monitoring of the effects of chemo-radiotherapy (including anti-angiogenic therapies), as well as for the precise targeting of drugs...

Nanobodies As Novel Agents for Targeting Angiogenesis in Solid Cancers

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Roghaye Arezumand

2017-12-01

Full Text Available Solid cancers are dependent on angiogenesis for sustenance. The FDA approval of Bevacizumab in 2004 inspired many scientists to develop more inhibitors of angiogenesis. Although several monoclonal antibodies (mAbs are being administered to successfully combat various pathologies, the complexity and large size of mAbs seem to narrow the therapeutic applications. To improve the performance of cancer therapeutics, including those blocking tumor angiogenesis, attractive strategies such as miniaturization of the antibodies have been introduced. Nanobodies (Nbs, small single-domain antigen-binding antibody fragments, are becoming promising therapeutic and diagnostic proteins in oncology due to their favorable unique structural and functional properties. This review focuses on the potential and state of the art of Nbs to inhibit the angiogenic process for therapy and the use of labeled Nbs for non-invasive in vivo imaging of the tumors.

Targeting vascular NADPH oxidase 1 blocks tumor angiogenesis through a PPARα mediated mechanism.

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Sarah Garrido-Urbani

Full Text Available Reactive oxygen species, ROS, are regulators of endothelial cell migration, proliferation and survival, events critically involved in angiogenesis. Different isoforms of ROS-generating NOX enzymes are expressed in the vasculature and provide distinct signaling cues through differential localization and activation. We show that mice deficient in NOX1, but not NOX2 or NOX4, have impaired angiogenesis. NOX1 expression and activity is increased in primary mouse and human endothelial cells upon angiogenic stimulation. NOX1 silencing decreases endothelial cell migration and tube-like structure formation, through the inhibition of PPARα, a regulator of NF-κB. Administration of a novel NOX-specific inhibitor reduced angiogenesis and tumor growth in vivo in a PPARα dependent manner. In conclusion, vascular NOX1 is a critical mediator of angiogenesis and an attractive target for anti-angiogenic therapies.

Does plasminogen activator inhibitor-1 drive lymphangiogenesis?

DEFF Research Database (Denmark)

Bruyère, Françoise; Melen-Lamalle, Laurence; Blacher, Silvia

2010-01-01

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and...

Ghrelin stimulates angiogenesis in human microvascular endothelial cells: Implications beyond GH release

International Nuclear Information System (INIS)

Li Aihua; Cheng Guangli; Zhu Genghui; Tarnawski, Andrzej S.

2007-01-01

Ghrelin, a peptide hormone isolated from the stomach, releases growth hormone and stimulates appetite. Ghrelin is also expressed in pancreas, kidneys, cardiovascular system and in endothelial cells. The precise role of ghrelin in endothelial cell functions remains unknown. We examined the expression of ghrelin and its receptor (GHSR1) mRNAs and proteins in human microvascular endothelial cells (HMVEC) and determined whether ghrelin affects in these cells proliferation, migration and in vitro angiogenesis; and whether MAPK/ERK2 signaling is important for the latter action. We found that ghrelin and GHSR1 are constitutively expressed in HMVEC. Treatment of HMVEC with exogenous ghrelin significantly increased in these cells proliferation, migration, in vitro angiogenesis and ERK2 phosphorylation. MEK/ERK2 inhibitor, PD 98059 abolished ghrelin-induced in vitro angiogenesis. This is First demonstration that ghrelin and its receptor are expressed in human microvascular endothelial cells and that ghrelin stimulates HMVEC proliferation, migration, and angiogenesis through activation of ERK2 signaling

A novel peptide derived from human apolipoprotein E is an inhibitor of tumor growth and ocular angiogenesis.

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Partha S Bhattacharjee

2011-01-01

Full Text Available Angiogenesis is a hallmark of tumor development and metastasis and now a validated target for cancer treatment. We previously reported that a novel dimer peptide (apoEdp derived from the receptor binding region of human apolipoprotein E (apoE inhibits virus-induced angiogenesis. However, its role in tumor anti-angiogenesis is unknown. This study demonstrates that apoEdp has anti-angiogenic property in vivo through reduction of tumor growth in a mouse model and ocular angiogenesis in a rabbit eye model. Our in vitro studies show that apoEdp inhibits human umbilical vein endothelial cell proliferation, migration, invasion and capillary tube formation. We document that apoEdp inhibits vascular endothelial growth factor-induced Flk-1 activation as well as downstream signaling pathways that involve c-Src, Akt, eNOS, FAK, and ERK1/2. These in vitro data suggest potential sites of the apoE dipeptide inhibition that could occur in vivo.This is the first evidence that a synthetic dimer peptide mimicking human apoE has anti-angiogenesis functions and could be an anti-tumor drug candidate.

Preventing High Altitude Cerebral Edema in Rats with Repurposed Anti-Angiogenesis Pharmacotherapy.

Science.gov (United States)

Tarshis, Samantha; Maltzahn, Joanne; Loomis, Zoe; Irwin, David C

2016-12-01

High altitude cerebral edema (HACE) is a fulminant, deadly, and yet still unpredictable brain disease. A new prophylactic treatment for HACE and its predecessor, acute mountain sickness (AMS), needs to be developed without the contraindications or adverse effect profiles of acetazolamide and dexamethasone. Since neovascularization signals are likely key contributors to HACE/AMS, our approach was to examine already existing anti-angiogenic drugs to inhibit potential initiating HACE pathway(s). This approach can also reveal crucial early steps in the frequently debated mechanism of HACE/AMS pathogenesis. We exposed four rat cohorts to hypobaric hypoxia and one to sea level (hyperbaric) conditions. The cohorts were treated with saline controls, an anti-angiogenesis drug (motesanib), a pro-angiogenesis drug (deferoxamine), or an intraperitoneal version of the established AMS prophylaxis drug, acetazolamide (benzolamide). Brain tissue was analyzed for cerebrovascular leak using the Evans Blue Dye (EVBD) protocol. We observed significantly increased EVBD in the altitude control and pro-angiogenesis (deferoxamine) cohorts, and significantly decreased EVBD in the anti-angiogenesis (motesanib), established treatment (benzolamide), and sea-level cohorts. Anti-angiogenesis-treated cohorts demonstrated less cerebrovascular extravasation than the altitude control and pro-angiogenesis treated rats, suggesting promise as an alternative prophylactic HACE/AMS treatment. The leak exacerbation with pro-angiogenesis treatment and improvement with anti-angiogenesis treatment support the hypothesis of early neovascularization signals provoking HACE. We demonstrate statistically significant evidence to guide further investigation for VEGF- and HIF-inhibitors as HACE/AMS prophylaxis, and as elucidators of still unknown HACE pathogenesis.Tarshis S, Maltzahn J, Loomis Z, Irwin DC. Preventing high altitude cerebral edema in rats with repurposed anti-angiogenesis pharmacotherapy. Aerosp Med

Angiogenesis Research to Improve Therapies for Vascular Leak Syndromes, Intra-Abdominal Adhesions, and Arterial Injuries

National Research Council Canada - National Science Library

Folkman, Judah; Puder, Mark; Bischoff, Joyce

2006-01-01

...) to develop angiogenesis inhibitors which would inhibit post-operative abdominal adhesions; and (iii) to isolate endothelial progenitor cells from blood capable of being expanded in vitro and applied to vascular grafts...

Angiogenesis Research to Improve Therapies for Vascular Leak Syndromes, Intra-Abdominal Adhesions, and Arterial Injuries

National Research Council Canada - National Science Library

Folkman, Judah; Puder, Mark; Bischoff, Joyce

2007-01-01

...) to develop angiogenesis inhibitors which would inhibit post-operative abdominal adhesions; and, (iii) to isolate endothelial progenitor cells from blood, capable of being expanded in vitro and applied to vascular grafts...

Angiogenesis Research to Improve Therapies for Vascular Leak Syndromes, Intra-abdominal Adhesions, and Arterial Injuries

National Research Council Canada - National Science Library

Folkman, Judah

2008-01-01

...) to develop angiogenesis inhibitors which would inhibit post-operative abdominal adhesions; and, (iii) to isolate endothelial progenitor cells from blood, capable of being expanded in vitro and applied to vascular grafts...

Statins and angiogenesis: Is it about connections?

International Nuclear Information System (INIS)

Khaidakov, Magomed; Wang, Wenze; Khan, Junaid A.; Kang, Bum-Yong; Hermonat, Paul L.; Mehta, Jawahar L.

2009-01-01

Statins, inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, have been shown to induce both angiogenic and angiostatic responses. We attempted to resolve this controversy by studying the effects of two different statins, rosuvastatin and simvastatin, in two different assay systems. In the matrigel angiogenesis assay, both statins enhanced tube formation by human umbilical vein endothelial cells (HUVECs, p < 0.01 vs. control). In the ex vivo mouse aortic ring sprouting assay, both statins virtually abolished new vessel formation (p < 0.01). As a basic difference between the two models of angiogenesis is dispersed state of endothelial cells vs. compact monolayer, we analyzed influence of statins on endothelial junction proteins. RT-PCR analysis and cytoimmunostaining of HUVECs treated with simvastatin revealed increased expression of VE-cadherin (p < 0.05). The blockade of VE-cadherin with a specific antibody reversed simvastatin-induced tube formation (p < 0.002). These data suggest that statins through VE-cadherin stimulation modulate cell-cell adhesion and diminish the ability of cells to proliferate and migrate. The observations of reduced angiogenesis in the intact vessel may relate to anti-atherosclerotic and anti-cancer effects of statins, and provide a feasible explanation for conflicting data under different experimental conditions.

Pharmacological blockade of cholesterol trafficking by cepharanthine in endothelial cells suppresses angiogenesis and tumor growth.

Science.gov (United States)

Lyu, Junfang; Yang, Eun Ju; Head, Sarah A; Ai, Nana; Zhang, Baoyuan; Wu, Changjie; Li, Ruo-Jing; Liu, Yifan; Yang, Chen; Dang, Yongjun; Kwon, Ho Jeong; Ge, Wei; Liu, Jun O; Shim, Joong Sup

2017-11-28

Cholesterol is an important modulator of membrane protein function and signaling in endothelial cells, thus making it an emerging target for anti-angiogenic agents. In this study, we employed a phenotypic screen that detects intracellular cholesterol distribution in endothelial cells (HUVEC) and identified 13 existing drugs as cholesterol trafficking inhibitors. Cepharanthine, an approved drug for anti-inflammatory and cancer management use, was amongst the candidates, which was selected for in-depth mechanistic studies to link cholesterol trafficking and angiogenesis. Cepharanthine inhibited the endolysosomal trafficking of free-cholesterol and low-density lipoprotein in HUVEC by binding to Niemann-Pick disease, type C1 (NPC1) protein and increasing the lysosomal pH. The blockade of cholesterol trafficking led to a cholesterol-dependent dissociation of mTOR from the lysosomes and inhibition of its downstream signaling. Cepharanthine inhibited angiogenesis in HUVEC and in zebrafish in a cholesterol-dependent manner. Furthermore, cepharanthine suppressed tumor growth in vivo by inhibiting angiogenesis and it enhanced the antitumor activity of the standard chemotherapy cisplatin in lung and breast cancer xenografts in mice. Altogether, these results strongly support the idea that cholesterol trafficking is a viable drug target for anti-angiogenesis and that the inhibitors identified among existing drugs, such as cepharanthine, could be potential anti-angiogenic and antitumor agents. Copyright © 2017 Elsevier B.V. All rights reserved.

Canonical hedgehog signaling augments tumor angiogenesis by induction of VEGF-A in stromal perivascular cells

Science.gov (United States)

Chen, Weiwei; Tang, Tracy; Eastham-Anderson, Jeff; Dunlap, Debra; Alicke, Bruno; Nannini, Michelle; Gould, Stephen; Yauch, Robert; Modrusan, Zora; DuPree, Kelly J.; Darbonne, Walter C.; Plowman, Greg; de Sauvage, Frederic J.; Callahan, Christopher A.

2011-01-01

Hedgehog (Hh) signaling is critical to the patterning and development of a variety of organ systems, and both ligand-dependent and ligand-independent Hh pathway activation are known to promote tumorigenesis. Recent studies have shown that in tumors promoted by Hh ligands, activation occurs within the stromal microenvironment. Testing whether ligand-driven Hh signaling promotes tumor angiogenesis, we found that Hh antagonism reduced the vascular density of Hh-producing LS180 and SW480 xenografts. In addition, ectopic expression of sonic hedgehog in low-Hh–expressing DLD-1 xenografts increased tumor vascular density, augmented angiogenesis, and was associated with canonical Hh signaling within perivascular tumor stromal cells. To better understand the molecular mechanisms underlying Hh-mediated tumor angiogenesis, we established an Hh-sensitive angiogenesis coculture assay and found that fibroblast cell lines derived from a variety of human tissues were Hh responsive and promoted angiogenesis in vitro through a secreted paracrine signal(s). Affymetrix array analyses of cultured fibroblasts identified VEGF-A, hepatocyte growth factor, and PDGF-C as candidate secreted proangiogenic factors induced by Hh stimulation. Expression studies of xenografts and angiogenesis assays using combinations of Hh and VEGF-A inhibitors showed that it is primarily Hh-induced VEGF-A that promotes angiogenesis in vitro and augments tumor-derived VEGF to promote angiogenesis in vivo. PMID:21597001

Matairesinol inhibits angiogenesis via suppression of mitochondrial reactive oxygen species

Energy Technology Data Exchange (ETDEWEB)

Lee, Boram; Kim, Ki Hyun; Jung, Hye Jin [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

2012-04-27

Highlights: Black-Right-Pointing-Pointer Matairesinol suppresses mitochondrial ROS generation during hypoxia. Black-Right-Pointing-Pointer Matairesinol exhibits potent anti-angiogenic activity both in vitro and in vivo. Black-Right-Pointing-Pointer Matairesinol could be a basis for the development of novel anti-angiogenic agents. -- Abstract: Mitochondrial reactive oxygen species (mROS) are involved in cancer initiation and progression and function as signaling molecules in many aspects of hypoxia and growth factor-mediated signaling. Here we report that matairesinol, a natural small molecule identified from the cell-based screening of 200 natural plants, suppresses mROS generation resulting in anti-angiogenic activity. A non-toxic concentration of matairesinol inhibited the proliferation of human umbilical vein endothelial cells. The compound also suppressed in vitro angiogenesis of tube formation and chemoinvasion, as well as in vivo angiogenesis of the chorioallantoic membrane at non-toxic doses. Furthermore, matairesinol decreased hypoxia-inducible factor-1{alpha} in hypoxic HeLa cells. These results demonstrate that matairesinol could function as a novel angiogenesis inhibitor by suppressing mROS signaling.

Dietary Proteins and Angiogenesis

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Miguel Ángel Medina

2014-01-01

Full Text Available Both defective and persistent angiogenesis are linked to pathological situations in the adult. Compounds able to modulate angiogenesis have a potential value for the treatment of such pathologies. Several small molecules present in the diet have been shown to have modulatory effects on angiogenesis. This review presents the current state of knowledge on the potential modulatory roles of dietary proteins on angiogenesis. There is currently limited available information on the topic. Milk contains at least three proteins for which modulatory effects on angiogenesis have been previously demonstrated. On the other hand, there is some scarce information on the potential of dietary lectins, edible plant proteins and high protein diets to modulate angiogenesis.

Mechanotransduction-modulated fibrotic microniches reveal the contribution of angiogenesis in liver fibrosis

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Liu, Longwei; You, Zhifeng; Yu, Hongsheng; Zhou, Lyu; Zhao, Hui; Yan, Xiaojun; Li, Dulei; Wang, Bingjie; Zhu, Lu; Xu, Yuzhou; Xia, Tie; Shi, Yan; Huang, Chenyu; Hou, Wei; Du, Yanan

2017-12-01

The role of pathological angiogenesis on liver fibrogenesis is still unknown. Here, we developed fibrotic microniches (FμNs) that recapitulate the interaction of liver sinusoid endothelial cells (LSECs) and hepatic stellate cells (HSCs). We investigated how the mechanical properties of their substrates affect the formation of capillary-like structures and how they relate to the progression of angiogenesis during liver fibrosis. Differences in cell response in the FμNs were synonymous of the early and late stages of liver fibrosis. The stiffness of the early-stage FμNs was significantly elevated due to condensation of collagen fibrils induced by angiogenesis, and led to activation of HSCs by LSECs. We utilized these FμNs to understand the response to anti-angiogenic drugs, and it was evident that these drugs were effective only for early-stage liver fibrosis in vitro and in an in vivo mouse model of liver fibrosis. Late-stage liver fibrosis was not reversed following treatment with anti-angiogenic drugs but rather with inhibitors of collagen condensation. Our work reveals stage-specific angiogenesis-induced liver fibrogenesis via a previously unrevealed mechanotransduction mechanism which may offer precise intervention strategies targeting stage-specific disease progression.

Repetitive Transient Ischemia-Induced Cardiac Angiogenesis is Mediated by Camkii Activation

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Zhuobin Chen

2018-05-01

Full Text Available Background/Aims: Coronary angiogenesis is an important protective mechanism in response to myocardial ischemia in coronary artery disease. However, the underlying mechanisms remain largely unclear. Here, we investigated the role of CaMKII activation in ischemia-induced cardiac angiogenesis. Methods: Repetitive transient ischemia model was established in C57/BL6 mice by daily multiple episodes (3 times/day of short time (5 min occlusion of the left anterior descending coronary artery for 7 days. Coronary angiogenesis was detected by immunofluorescent staining. RT-qPCR and Western blot analyses were used to detect the mRNA and protein levels of CaMKII, p-CaMKII and VEGF. Primary cardiac microvascular endothelial cells (CMECs were isolated to investigate the effects of KN93 on cell proliferation and migration in hypoxic condition. Results: We found that angiogenesis was induced in the ischemic myocardium and suppressed by chronic intraperitoneal injection of CaMKII inhibitor KN93. RT-qPCR and Western blot analyses showed that myocardial ischemia induced an increased expression and autophosphorylation of CaMKII. VEGF expression was increased in the ischemia model but blunted by KN93. Moreover, KN93 suppressed the proliferation and migration of cardiac endothelial cells in hypoxic condition in which the protein expression of CaMKII, p-CaMKII and VEGF was increased. Conclusion: CaMKII is an important mediator for the ischemia-induced coronary angiogenesis, in which CaMKII-triggered VEGF expression plays a key role.

Disruption of Angiogenesis by Anthocyanin-Rich Extracts of Hibiscus sabdariffa

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Joshua, Madu; Okere, Christiana; Sylvester, O’Donnell; Yahaya, Muhammad; Precious, Omale; Dluya, Thagriki; Um, Ji-Yeon; Neksumi, Musa; Boyd, Jessica; Vincent-Tyndall, Jennifer; Choo, Dong-Won; Gutsaeva, Diana R.; Jahng, Wan Jin

2017-01-01

Abnormal vessel formations contribute to the progression of specific angiogenic diseases including age-related macular degeneration. Adequate vessel growth and maintenance represent the coordinated process of endothelial cell proliferation, matrix remodeling, and differentiation. However, the molecular mechanism of the proper balance between angiogenic activators and inhibitors remains elusive. In addition, quantitative analysis of vessel formation has been challenging due to complex angiogenic morphology. We hypothesized that conjugated double bond containing-natural products, including anthocyanin extracts from Hibiscus sabdariffa, may control the proper angiogenesis. The current study was designed to determine whether natural molecules from African plant library modulate angiogenesis. Further, we questioned how the proper balance of anti- or pro-angiogenic signaling can be obtained in the vascular microenvironment by treating anthocyanin or fatty acids using chick chorioallantoic membrane angiogenesis model in ovo. The angiogenic morphology was analyzed systematically by measuring twenty one angiogenic indexes using Angiogenic Analyzer software. Chick chorioallantoic model demonstrated that anthocyanin-rich extracts inhibited angiogenesis in time- and concentration-dependent manner. Molecular modeling analysis proposed that hibiscetin as a component in Hibiscus may bind to the active site of vascular endothelial growth factor receptor 2 (VEGFR2) with ΔG= −8.42 kcal/mol of binding energy. Our results provided the evidence that anthocyanin is an angiogenic modulator that can be used to treat uncontrolled neovascular-related diseases, including age-related macular degeneration. PMID:28459020

New Therapeutic Window of Regenerative Opportunity in Diabetic Retinopathy by VESGEN Analysis

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Parsons-Wingert, Patricia A.

2012-01-01

Vascular pattern may serve as a useful new biomarker principle of complex, multi-scale signaling in pathological, physiological angiogenesis and microvascular remodeling. Each angiogenesis stimulator or inhibitor we have analyzed, including VEGF, bFGF, TGF-beta1, angiostatin and triamcinolone acetonide, has induced a novel "fingerprint" or "signature" biomarker vascular pattern that is spatio-temporally unique. Remodeling vasculature thereby provides an informative read-out of dominant molecular signaling, when analyzed by innovative, fractal-based VESsel GENeration (VESGEN) Analysis software. Using VESGEN to analyze ophthalmic clinical vascular images, we recently introduced a potential paradigm shift to the understanding of early-stage progression that suggests new regenerative opportunities for human diabetic retinopathy (DR), the major blinding disease for working-aged adults. In a pilot study, we discovered that angiogenesis oscillates as a surprising, homeostatic-like regeneration of retinal vessels during early progression of DR (IOVS 51(1):498). Results suggest that the term non-proliferative DR may be a misnomer. In new studies, normalization of the vasculature will be determined from the response of vascular pattern to therapeutic monitoring and treatment. We have mapped and quantified in vivo experimental models of angiogenesis, lymphangiogenesis and intravital blood flow from cellular/molecular to higher systems levels that include a murine model of infant retinopathy of prematurity (ROP); developing and pathological coronary and placental-like vessel models; progressive intestinal inflammation, growing murine tumors, and other pathological, physiological and therapeutically treated tissues of transgenic mice and avian embryos. Vascular Alterations, Visual Impairments (VIIP) & Increased Intracranial Pressure (ICP), Immunosuppression & Bone Loss: NASA-defined risk categories for human space exploration and ISS Utilization

Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

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Yu, Wei; Chai, Hongyan; Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue; Yang, Guifang; Cai, Xiaojun; Falck, John R.; Yang, Jing

2012-01-01

Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have

Increased expression of CYP4Z1 promotes tumor angiogenesis and growth in human breast cancer

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Yu, Wei [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Chai, Hongyan [Center for Gene Diagnosis, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Li, Ying; Zhao, Haixia; Xie, Xianfei; Zheng, Hao; Wang, Chenlong; Wang, Xue [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Yang, Guifang [Department of Pathology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Cai, Xiaojun [Department of Ophthalmology, Zhongnan Hospital, Wuhan University, Wuhan 430071 (China); Falck, John R. [Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390 (United States); Yang, Jing, E-mail: yangjingliu@yahoo.com.cn [Department of Pharmacology, School of Medicine, Wuhan University, Wuhan 430071 (China); Research Center of Food and Drug Evaluation, Wuhan University, Wuhan 430071 (China)

2012-10-01

Cytochrome P450 (CYP) 4Z1, a novel CYP4 family member, is over-expressed in human mammary carcinoma and associated with high-grade tumors and poor prognosis. However, the precise role of CYP4Z1 in tumor progression is unknown. Here, we demonstrate that CYP4Z1 overexpression promotes tumor angiogenesis and growth in breast cancer. Stable expression of CYP4Z1 in T47D and BT-474 human breast cancer cells significantly increased mRNA expression and production of vascular endothelial growth factor (VEGF)-A, and decreased mRNA levels and secretion of tissue inhibitor of metalloproteinase-2 (TIMP-2), without affecting cell proliferation and anchorage-independent cell growth in vitro. Notably, the conditioned medium from CYP4Z1-expressing cells enhanced proliferation, migration and tube formation of human umbilical vein endothelial cells, and promoted angiogenesis in the zebrafish embryo and chorioallantoic membrane of the chick embryo. In addition, there were lower levels of myristic acid and lauric acid, and higher contents of 20-hydroxyeicosatetraenoic acid (20-HETE) in CYP4Z1-expressing T47D cells compared with vector control. CYP4Z1 overexpression significantly increased tumor weight and microvessel density by 2.6-fold and 1.9-fold in human tumor xenograft models, respectively. Moreover, CYP4Z1 transfection increased the phosphorylation of ERK1/2 and PI3K/Akt, while PI3K or ERK inhibitors and siRNA silencing reversed CYP4Z1-mediated changes in VEGF-A and TIMP-2 expression. Conversely, HET0016, an inhibitor of the CYP4 family, potently inhibited the tumor-induced angiogenesis with associated changes in the intracellular levels of myristic acid, lauric acid and 20-HETE. Collectively, these data suggest that increased CYP4Z1 expression promotes tumor angiogenesis and growth in breast cancer partly via PI3K/Akt and ERK1/2 activation. -- Highlights: ► CYP4Z1 overexpression promotes human breast cancer growth and angiogenesis. ► The pro-angiogenic effects of CYP4Z1 have

Macrophage Metalloelastase (MMP-12) Deficiency Mitigates Retinal Inflammation and Pathological Angiogenesis in Ischemic Retinopathy

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Li, Jingming; Wang, Joshua J.; Peng, Qisheng; Chen, Chen; Humphrey, Mary Beth; Heinecke, Jay; Zhang, Sarah X.

2012-01-01

Pathological angiogenesis is a major cause of vision loss in ischemic and inflammatory retinal diseases. Recent evidence implicates macrophage metalloelastase (MMP-12), a macrophage-derived elastinolytic protease in inflammation, tissue remodeling and angiogenesis. However, little is known about the role of MMP-12 in retinal pathophysiology. The present study aims to explore the enzyme’s contributions to retinal angiogenesis in oxygen-induced retinopathy (OIR) using MMP-12 knockout (KO) mice. We find that MMP-12 expression was upregulated in OIR, accompanied by elevated macrophage infiltration and increased inflammatory markers. Compared to wildtype mice, MMP-12 KO mice had decreased levels of adhesion molecule and inflammatory cytokines and reduced vascular leakage in OIR. Concomitantly, these mice had markedly reduced macrophage content in the retina with impaired macrophage migratory capacity. Significantly, loss of MMP-12 attenuated retinal capillary dropout in early OIR and mitigated pathological retinal neovascularization (NV). Similar results were observed in the study using MMP408, a pharmacological inhibitor of MMP-12. Intriguingly, in contrast to reducing pathological angiogenesis, lack of MMP-12 accelerated revascularization of avascular retina in OIR. Taken together, we conclude that MMP-12 is a key regulator of macrophage infiltration and inflammation, contributing to retinal vascular dysfunction and pathological angiogenesis. PMID:23285156

Angiogenesis Research to Improve Therapies for Vascular Leak Syndromes, Intra-Abdominal Adhesions, and Arterial Injuries

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2009-04-01

which was isolated from the fungus Aspergillus fumigatus fresenius3 and is among the most potent inhibitors of angiogenesis. In animal models, TNP...Medical School) was conducted for each reaction step and mass spectrometry ( Proteomic core, Harvard Medical School) was performed on the conjugate. To

Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis

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Ray, Amlan K.; DasMahapatra, Pramathes; Swarnakar, Snehasikta

2016-01-01

Endometriosis is characterized by the ectopic development of the endometrium which relies on angiogenesis. Although studies have identified the involvement of different matrix metalloproteinases (MMPs) in endometriosis, no study has yet investigated the role of MMP-2 in endometriosis-associated angiogenesis. The present study aims to understand the regulation of MMP-2 activity in endothelial cells and on angiogenesis during progression of ovarian endometriosis. Histological and biochemical data showed increased expressions of vascular endothelial growth factor (VEGF), VEGF receptor-2, cycloxygenase (COX)-2, von Willebrand factor along with angiogenesis during endometriosis progression. Women with endometriosis showed decreased MMP-2 activity in eutopic endometrium as compared to women without endometriosis. However, ectopic ovarian endometrioma showed significantly elevated MMP-2 activity with disease severity. In addition, increased MT1MMP and decreased tissue inhibitors of metalloproteinases (TIMP)-2 expressions were found in the late stages of endometriosis indicating more MMP-2 activation with disease progression. In vitro study using human endothelial cells showed that prostaglandin E2 (PGE2) significantly increased MMP-2 activity as well as tube formation. Inhibition of COX-2 and/or phosphorylated AKT suppressed MMP-2 activity and endothelial tube formation suggesting involvement of PGE2 in regulation of MMP-2 activity during angiogenesis. Moreover, specific inhibition of MMP-2 by chemical inhibitor significantly reduced cellular migration, invasion and tube formation. In ovo assay showed decreased angiogenic branching upon MMP-2 inhibition. Furthermore, a significant reduction of lesion numbers was observed upon inhibition of MMP-2 and COX-2 in mouse model of endometriosis. In conclusion, our study establishes the involvement of MMP-2 activity via COX-2-PGE2-pAKT axis in promoting angiogenesis during endometriosis progression. PMID:27695098

Inhibitory Effect of Endostar on Specific Angiogenesis Induced by Human Hepatocellular Carcinoma

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Qing Ye

2015-01-01

Full Text Available To investigate the effect of endostar on specific angiogenesis induced by human hepatocellular carcinoma, this research systematically elucidated the inhibitory effect on HepG2-induced angiogenesis by endostar from 50 ng/mL to 50000 ng/mL. We employed fluorescence quantitative Boyden chamber analysis, wound-healing assay, flow cytometry examination using a coculture system, quantitative analysis of tube formation, and in vivo Matrigel plug assay induced by HCC conditioned media (HCM and HepG2 compared with normal hepatocyte conditioned media (NCM and L02. Then, we found that endostar as a tumor angiogenesis inhibitor could potently inhibit human umbilical vein endothelial cell (HUVEC migration in response to HCM after four- to six-hour action, inhibit HCM-induced HUVEC migration to the lesion part in a dose-dependent manner between 50 ng/mL and 5000 ng/mL at 24 hours, and reduce HUVEC proliferation in a dose-dependent fashion. Endostar inhibited HepG2-induced tube formation of HUVECs which peaked at 50 ng/mL. In vivo Matrigel plug formation was also significantly reduced by endostar in HepG2 inducing system rather than in L02 inducing system. It could be concluded that, at cell level, endostar inhibited the angiogenesis-related biological behaviors of HUVEC in response to HCC, including migration, adhesion proliferation, and tube formation. At animal level, endostar inhibited the angiogenesis in response to HCC in Matrigel matrix.

Contribution to Tumor Angiogenesis From Innate Immune Cells Within the Tumor Microenvironment: Implications for Immunotherapy

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Adriana Albini

2018-04-01

Full Text Available The critical role of angiogenesis in promoting tumor growth and metastasis is strongly established. However, tumors show considerable variation in angiogenic characteristics and in their sensitivity to antiangiogenic therapy. Tumor angiogenesis involves not only cancer cells but also various tumor-associated leukocytes (TALs and stromal cells. TALs produce chemokines, cytokines, proteases, structural proteins, and microvescicles. Vascular endothelial growth factor (VEGF and inflammatory chemokines are not only major proangiogenic factors but are also immune modulators, which increase angiogenesis and lead to immune suppression. In our review, we discuss the regulation of angiogenesis by innate immune cells in the tumor microenvironment, specific features, and roles of major players: macrophages, neutrophils, myeloid-derived suppressor and dendritic cells, mast cells, γδT cells, innate lymphoid cells, and natural killer cells. Anti-VEGF or anti-inflammatory drugs could balance an immunosuppressive microenvironment to an immune permissive one. Anti-VEGF as well as anti-inflammatory drugs could therefore represent partners for combinations with immune checkpoint inhibitors, enhancing the effects of immune therapy.

Pharmacokinetics of gene recombined angiogenesis inhibitor Kringle 5 in vivo using 131I specific markers and SPECT/CT

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Ge Yan

2016-10-01

Full Text Available The previous pharmacokinetic methods can be only limited to drug analysis in vitro, which provide less information on the distribution and metabolismof drugs, and limit the interpretation and assessment of pharmacokinetics, the determination of metabolic principles, and evaluation of treatment effect. The objective of the study was to investigate the pharmacokinetic characteristics of gene recombination angiogenesis inhibitor Kringle 5 in vivo. The SPECT/CT and specific 131I-Kringle 5 marked by Iodogen method were both applied to explore the pharmacokinetic characteristics of 131I-Kringle 5 in vivo, and to investigate the dynamic distributions of 131I-Kringle 5 in target organs. Labeling recombinant angiogenesis inhibitor Kringle 5 using 131I with longer half-life and imaging in vivo using SPECT instead of PET, could overcome the limitations of previous methods. When the doses of 131I-Kringle 5 were 10.0, 7.5 and 5.0 g/kg, respectively, the two-compartment open models can be determined within all the metabolic process in vivo. There were no significant differences in t1/2α, t1/2β, apparent volume of distribution and CL between those three levels. The ratio of AUC(0~∞ among three different groups of 10.0, 7.5 and 5.0 g/kg was 2.56:1.44:1.0, which was close to the ratio (2:1.5:1.0. It could be clear that in the range of 5.0–10.0 g/kg, Kringle 5 was characterized by the first-order pharmacokinetics. Approximately 30 min after 131I-Kringle 5 was injected, 131I-Kringle 5 could be observed to concentrate in the heart, kidneys, liver and other organs by means of planar imaging and tomography. After 1 h of being injected, more radionuclide retained in the bladder, but not in intestinal. It could be concluded that 131I-Kringle 5 is mainly excreted through the kidneys. About 2 h after the injection of 131I-Kringle 5, the radionuclide in the heart, kidneys, liver and other organs was gradually reduced, while more radionuclide was concentrated

HIF-2alpha-dependent PAI-1 induction contributes to angiogenesis in hepatocellular carcinoma

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Geis, Theresa, E-mail: geis@biochem.uni-frankfurt.de [Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Döring, Claudia, E-mail: C.Doering@em.uni-frankfurt.de [Dr. Senckenberg Institute of Pathology, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Popp, Rüdiger, E-mail: popp@vrc.uni-frankfurt.de [Institute for Vascular Signalling, Centre for Molecular Medicine, Faculty of Medicine Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt am Main (Germany); Grossmann, Nina, E-mail: grossmann@biochem.uni-frankfurt.de [Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Fleming, Ingrid, E-mail: fleming@vrc.uni-frankfurt.de [Institute for Vascular Signalling, Centre for Molecular Medicine, Faculty of Medicine Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60596 Frankfurt am Main (Germany); Hansmann, Martin-Leo, E-mail: m.l.hansmann@em.uni-frankfurt.de [Dr. Senckenberg Institute of Pathology, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Dehne, Nathalie, E-mail: dehne@biochem.uni-frankfurt.de [Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany); Brüne, Bernhard, E-mail: b.bruene@biochem.uni-frankfurt.de [Institute of Biochemistry I—Pathobiochemistry, Faculty of Medicine, Goethe-University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main (Germany)

2015-02-01

Hypoxia promotes progression of hepatocellular carcinoma (HCC), not only affecting tumor cell proliferation and invasion, but also angiogenesis and thus, increasing the risk of metastasis. Hypoxia inducible factors (HIF)-1α and -2α cause adaptation of tumors to hypoxia, still with uncertainties towards the angiogenic switch. We created a stable knockdown of HIF-1α and HIF-2α in HepG2 cells and generated cocultures of HepG2 spheroids with embryonic bodies as an in vitro tumor model mimicking the cancer microenvironment. The naturally occuring oxygen and nutrient gradients within the cocultures allow us to question the role of distinct HIF isoforms in regulating HCC angiogenesis. In cocultures with a HIF-2α knockdown, angiogenesis was attenuated, while the knockdown of HIF-1α was without effect. Microarray analysis identified plasminogen activator inhibitor 1 (PAI-1) as a HIF-2α target gene in HepG2 cells. The knockdown of PAI-1 in HepG2 cells also lowered angiogenesis. Blocking plasmin, the downstream target of PAI-1, with aprotinin in HIF-2α knockdown (k/d) cells proved a cause–effect relation and restored angiogenesis, with no effect on control cocultures. Suggestively, HIF-2α increases PAI-1 to lower concentrations of active plasmin, thereby supporting angiogenesis. We conclude that the HIF-2α target gene PAI-1 favors the angiogenic switch in HCC. - Highlights: • HepG2 were cocultured with stem cells to mimic a cancer microenvironment in vitro. • A knockdown of HIF-2α reduces angiogenesis. • PAI-1 was identified as a HIF-2α target gene in HCC by microarray analysis. • HIF-2α induces the angiogenic switch via inhibition of plasmin.

HIF-2alpha-dependent PAI-1 induction contributes to angiogenesis in hepatocellular carcinoma

International Nuclear Information System (INIS)

Geis, Theresa; Döring, Claudia; Popp, Rüdiger; Grossmann, Nina; Fleming, Ingrid; Hansmann, Martin-Leo; Dehne, Nathalie; Brüne, Bernhard

2015-01-01

Hypoxia promotes progression of hepatocellular carcinoma (HCC), not only affecting tumor cell proliferation and invasion, but also angiogenesis and thus, increasing the risk of metastasis. Hypoxia inducible factors (HIF)-1α and -2α cause adaptation of tumors to hypoxia, still with uncertainties towards the angiogenic switch. We created a stable knockdown of HIF-1α and HIF-2α in HepG2 cells and generated cocultures of HepG2 spheroids with embryonic bodies as an in vitro tumor model mimicking the cancer microenvironment. The naturally occuring oxygen and nutrient gradients within the cocultures allow us to question the role of distinct HIF isoforms in regulating HCC angiogenesis. In cocultures with a HIF-2α knockdown, angiogenesis was attenuated, while the knockdown of HIF-1α was without effect. Microarray analysis identified plasminogen activator inhibitor 1 (PAI-1) as a HIF-2α target gene in HepG2 cells. The knockdown of PAI-1 in HepG2 cells also lowered angiogenesis. Blocking plasmin, the downstream target of PAI-1, with aprotinin in HIF-2α knockdown (k/d) cells proved a cause–effect relation and restored angiogenesis, with no effect on control cocultures. Suggestively, HIF-2α increases PAI-1 to lower concentrations of active plasmin, thereby supporting angiogenesis. We conclude that the HIF-2α target gene PAI-1 favors the angiogenic switch in HCC. - Highlights: • HepG2 were cocultured with stem cells to mimic a cancer microenvironment in vitro. • A knockdown of HIF-2α reduces angiogenesis. • PAI-1 was identified as a HIF-2α target gene in HCC by microarray analysis. • HIF-2α induces the angiogenic switch via inhibition of plasmin

Defibrotide Stimulates Angiogenesis and Protects Endothelial Cells from Calcineurin Inhibitor-Induced Apoptosis via Upregulation of AKT/Bcl-xL.

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Wang, Xiangmin; Pan, Bin; Hashimoto, Yuko; Ohkawara, Hiroshi; Xu, Kailin; Zeng, Lingyu; Ikezoe, Takayuki

2018-01-01

Sinusoidal obstruction syndrome is a life-threatening complication that can occur after haematopoietic stem cell transplantation. Defibrotide (DF) has been approved for the treatment of individuals with severe sinusoidal obstruction syndrome following haematopoietic stem cell transplantation in the European Union and the United States. However, the precise mechanisms by which DF protects endothelial cells remain to be elucidated. In this study, we found that DF stimulated angiogenesis in vitro and in vivo as assessed by vascular tube formation, scratch-wound repair and Matrigel plug assays. These effects were associated with an activation of pro-survival signalling pathways, including AKT (protein kinase B), ERK (extracellular signal-regulated kinases) and p38. More importantly, DF alleviated calcineurin inhibitor-induced growth inhibition and apoptosis of human umbilical vein endothelial cells and human hepatic sinusoidal endothelial cells in parallel with upregulation of anti-apoptotic protein B-cell lymphoma-extra-large (Bcl-xL), which was mediated by AKT (protein kinase B). Notably, these effects were abrogated when Bcl-xL was depleted by small interfering RNA (ribonucleic acid). In addition, DF counteracted calcineurin inhibitor-induced activation of nuclear factor-κB and Janus kinase 2 (JAK2)/Signal Transducer and Activator of Transcription 3 (STAT3) signalling and production of cytokines in vascular endothelial cell-derived EA.hy926 cells. Taken together, DF has pro-angiogenic, anti-apoptotic and anti-inflammatory effects on endothelial cells. DF is a potentially useful agent to prevent the development of, and treat individuals with, endothelial cell injury-related complications after haematopoietic stem cell transplantation. Schattauer GmbH Stuttgart.

Angiogenesis, Cancer, and Vascular Aging

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Junji Moriya

2017-10-01

Full Text Available Several lines of evidence have revealed that the angiogenic response to ischemic injury declines with age, which might account for the increased morbidity and mortality of cardiovascular disease (CVD among the elderly. While impairment of angiogenesis with aging leads to delayed wound healing or exacerbation of atherosclerotic ischemic diseases, it also inhibits the progression of cancer. Age-related changes of angiogenesis have been considered to at least partly result from vascular aging or endothelial cell senescence. There is considerable evidence supporting the hypothesis that vascular cell senescence contributes to the pathogenesis of age-related CVD, suggesting that vascular aging could be an important therapeutic target. Since therapeutic angiogenesis is now regarded as a promising concept for patients with ischemic CVD, it has become even more important to understand the detailed molecular mechanisms underlying impairment of angiogenesis in older patients. To improve the usefulness of therapeutic angiogenesis, approaches are needed that can compensate for impaired angiogenic capacity in the elderly while not promoting the development or progression of malignancy. In this review, we briefly outline the mechanisms of angiogenesis and vascular aging, followed by a description of how vascular aging leads to impairment of angiogenesis. We also examine potential therapeutic approaches that could enhance angiogenesis and/or vascular function in the elderly, as well as discussing the possibility of anti-senescence therapy or reversal of endothelial cell senescence.

Angiogenesis in symptomatic intracranial atherosclerosis: predominance of the inhibitor endostatin is related to a greater extent and risk of recurrence.

Science.gov (United States)

Arenillas, Juan F; Alvarez-Sabín, José; Montaner, Joan; Rosell, Anna; Molina, Carlos A; Rovira, Alex; Ribó, Marc; Sánchez, Esther; Quintana, Manuel

2005-01-01

Angiogenesis may be beneficial in chronic myocardial and limb ischemia, but its role in intracranial atherosclerosis remains unknown. We aimed to investigate the relationship between the pro-angiogenic vascular endothelial growth factor (VEGF) and the anti-angiogenic endostatin, and the extent and risk of recurrence of symptomatic intracranial atherosclerosis. Of a total of 94 consecutive patients with symptomatic intracranial stenoses, 40 fulfilled all inclusion criteria. Intracranial stenoses were confirmed by magnetic resonance angiography. Magnetic resonance imaging (MRI) including diffusion-weighted sequences was conducted. Plasmatic VEGF and endostatin were determined from blood samples obtained 3 months after stroke onset, and patients were followed-up thereafter. A total of 144 intracranial stenoses were confirmed (median number per patient=3). Endostatin/VEGF ratio gradually augmented with the increasing number of intracranial stenoses (r=0.35, P=0.02). Diabetes mellitus (OR, 6.04; CI, 1.1 to 32.2; P=0.03) and a higher endostatin/VEGF ratio (OR, 15.7; CI, 2.2 to 112.3; P=0.006) were independently associated with a greater extent of intracranial atherosclerosis. During a median follow-up of 13 months, 8 patients (20%) experienced a new cerebral ischemic event. A higher baseline endostatin concentration was an independent predictor of new events (hazard ratio, 7.24; CI, 1.6 to 33.8; P=0.011) in a Cox regression model after adjustment for age, sex, number of stenotic vessels, and risk factors. Patients with a higher endostatin level had a lower survival free of new events (P=0.01, log-rank test). A predominance of the inhibitor endostatin within the endogenous angiogenic response is associated with a greater extent and risk of recurrence of symptomatic intracranial atherosclerosis, suggesting that angiogenesis may be beneficial in this condition.

Wogonin inhibits tumor angiogenesis via degradation of HIF-1α protein

International Nuclear Information System (INIS)

Song, Xiuming; Yao, Jing; Wang, Fei; Zhou, Mi; Zhou, Yuxin; Wang, Hu; Wei, Libin; Zhao, Li; Li, Zhiyu; Lu, Na; Guo, Qinglong

2013-01-01

Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found that wogonin decreased the expression of HIF-1α by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1α by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel–Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1α. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1α and promoted its degradation in proteasome. We also found that wogonin could inhibit nuclear translocation of HIF-1α. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1α in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1α directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1α and provided a new insight into the mechanisms of wogonin against cancers. - Highlights: • Wogonin is an all around inhibitor of VEGF signaling. • We firstly demonstrate that wogonin inhibits secretion of VEGF by decreasing HIF-1α. • Wogonin enhances PDH and VHL expression and inhibits Hsp90 function. �

Wogonin inhibits tumor angiogenesis via degradation of HIF-1α protein

Energy Technology Data Exchange (ETDEWEB)

Song, Xiuming; Yao, Jing; Wang, Fei; Zhou, Mi; Zhou, Yuxin; Wang, Hu; Wei, Libin; Zhao, Li; Li, Zhiyu; Lu, Na, E-mail: luna555@163.com; Guo, Qinglong, E-mail: anticancer_drug@yahoo.com.cn

2013-09-01

Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found that wogonin decreased the expression of HIF-1α by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1α by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel–Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1α. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1α and promoted its degradation in proteasome. We also found that wogonin could inhibit nuclear translocation of HIF-1α. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1α in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1α directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1α and provided a new insight into the mechanisms of wogonin against cancers. - Highlights: • Wogonin is an all around inhibitor of VEGF signaling. • We firstly demonstrate that wogonin inhibits secretion of VEGF by decreasing HIF-1α. • Wogonin enhances PDH and VHL expression and inhibits Hsp90 function. �

MRI monitoring of tumor response following angiogenesis inhibition in an experimental human breast cancer model

International Nuclear Information System (INIS)

Turetschek, Karl; Preda, Anda; Shames, David M.; Novikov, Viktor; Roberts, Timothy P.L.; Fu, Yanjun; Brasch, Robert C.; Floyd, Eugenia; Carter, Wayne O.; Wood, Jeanette M.

2003-01-01

The aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA) 30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (K PS ) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (P PS ) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (P PS values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (P PS ), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy. (orig.)

Tryptase-positive mast cells correlate with angiogenesis in early breast cancer patients.

Science.gov (United States)

Ranieri, Girolamo; Ammendola, Michele; Patruno, Rosa; Celano, Giuseppe; Zito, Francesco Alfredo; Montemurro, Severino; Rella, Addolorata; Di Lecce, Valentina; Gadaleta, Cosmo Damiano; Battista De Sarro, Giovanni; Ribatti, Domenico

2009-07-01

Literature data indicate that mast cells (MCs) are involved in tumor angiogenesis due to the release of several pro-angiogenetic factors among which tryptase, a serine protease stored in MCs granules, is one of the most active. However, no data are available concerning the role of MCs in angiogenesis in primary human breast cancer. In this study, we have evaluated the correlations between the number of MCs positive to tryptase (MCDPT), the area occupied by MCs positive to tryptase (MCAPT) and microvascular density (MVD) and endothelial area (EA) in a series of 88 primary T1-3, N0-2 M0 female breast cancer, by means of immunohistochemistry and image analysis methods. Data demonstrated a significant (r = from 0.78 to 0.89; p-value from 0.001 to 0.002 by Pearson's analysis respectively) correlation between MCDPT, MCAPT, MVD, EA to each other. No correlation concerning MCDPT, MCAPT, MVD, EA and the main clinicopathological features was found. Our results suggest that tryptase-positive MCs play a role in breast cancer angiogenesis. In this context several tryptase inhibitors such as gabexate mesilate and nafamostat mesilate might be evaluated in clinical trials as a new anti-angiogenetic approach.

Rapamycin enhances the anti-angiogenesis and anti-proliferation ability of YM155 in oral squamous cell carcinoma.

Science.gov (United States)

Li, Kong-Liang; Wang, Yu-Fan; Qin, Jia-Ruo; Wang, Feng; Yang, Yong-Tao; Zheng, Li-Wu; Li, Ming-Hua; Kong, Jie; Zhang, Wei; Yang, Hong-Yu

2017-06-01

YM155, a small molecule inhibitor of survivin, has been studied in many tumors. It has been shown that YM155 inhibited oral squamous cell carcinoma through promoting apoptosis and autophagy and inhibiting proliferation. It was found that YM155 also inhibited the oral squamous cell carcinoma-mediated angiogenesis through the inactivation of the mammalian target of rapamycin pathway. Rapamycin, a mammalian target of rapamycin inhibitor, played an important role in the proliferation and angiogenesis of oral squamous cell carcinoma cell lines. In our study, cell proliferation assay, transwell assay, tube formation assay, and western blot assay were used to investigate the synergistic effect of rapamycin on YM155 in oral squamous cell carcinoma. Either in vitro or in vivo, rapamycin and YM155 exerted a synergistic effect on the inhibition of survivin and vascular endothelial growth factor through mammalian target of rapamycin pathway. Overall, our results revealed that low-dose rapamycin strongly promoted the sensitivity of oral squamous cell carcinoma cell lines to YM155.

Mechanisms of angiogenesis in a Curculigoside A-treated rat model of cerebral ischemia and reperfusion injury

International Nuclear Information System (INIS)

Zhu, Haibo; He, Jie; Ye, Liang; Lin, Fei; Hou, Jian; Zhong, Yan; Jiang, Wanglin

2015-01-01

Curculigoside A has shown protective effects against rat cortical neuron damage in vivo. However, the molecular mechanisms through which Curculigoside A affords this protection are unclear. In the present study, we sought to elucidate the mechanisms of angiogenesis in rat aortic endothelial cells (RAEC), rat aortic smooth muscle cells (RASMC) as well as a rat model of cerebral ischemia and reperfusion injury following treatment with Curculigoside A. We examined the role of Curculigoside A on RAEC and RASMC proliferation, migration, and tube formation in vitro and in a cerebral ischemia and reperfusion injury rat model. We used the recombinant Dickkopf (DKK)-1 protein, a Wnt/β-catenin inhibitor, and the recombinant WIF-1 protein, a Wnt5a antagonist to determine mechanisms. In addition, we measured leakage of the blood–brain barrier (BBB) and tested for angiogenesis associated proteins. Our data suggest that Curculigoside A induces angiogenesis in vitro by increasing proliferation, migration and tube formation in RAEC and RASMC. The increase in Curculigoside A-induced proliferation and tube formation was counteracted by DKK-1 and WIF-1. Curculigoside A increased expression of VEGF, p-VEGFR, p-CREB, Egr-3, VCAM-1, Ang1 and Tie2 while prohibiting BBB leakage in cerebral ischemia and reperfusion injured rats. However, Cyclosporine A, a CREB inhibitor, reduced the expression of p-CREB, Egr-3, VCAM-1, Ang1 and Tie2. These data suggest that Curculigoside A induces cell proliferation and angiogenesis through the Wnt5a/β-catenin and VEGF/CREB/Egr-3/VCAM-1 signaling axis and promotes maturation and stability of new blood vessels via increasing Ang1 and Tie-2 expression. - Highlights: • Curculigoside A induces cell proliferation through Wnt5a/β-catenin pathway. • Curculigoside A induces angiogenesis via VEGF/CREB/Egr-3/VCAM-1 signaling axis. • Curculigoside A promotes blood vessel maturation via Ang1/Tie2 pathway.

Mechanisms of angiogenesis in a Curculigoside A-treated rat model of cerebral ischemia and reperfusion injury

Energy Technology Data Exchange (ETDEWEB)

Zhu, Haibo [School of Public Health and Management, Binzhou Medical University, Yantai (China); Institute of Toxicology, Binzhou Medical University, Yantai (China); He, Jie [State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai 264003 (China); Ye, Liang [School of Public Health and Management, Binzhou Medical University, Yantai (China); Institute of Toxicology, Binzhou Medical University, Yantai (China); Lin, Fei; Hou, Jian; Zhong, Yan [State Key Laboratory of Long-acting Targeting Drug Delivery Technologies (Luye Pharma Group Ltd.), Yantai 264003 (China); Jiang, Wanglin, E-mail: jwl518@163.com [School of Pharmaceutical Sciences, Institute of Materia Medica, Binzhou Medical University, Yantai (China)

2015-11-01

Curculigoside A has shown protective effects against rat cortical neuron damage in vivo. However, the molecular mechanisms through which Curculigoside A affords this protection are unclear. In the present study, we sought to elucidate the mechanisms of angiogenesis in rat aortic endothelial cells (RAEC), rat aortic smooth muscle cells (RASMC) as well as a rat model of cerebral ischemia and reperfusion injury following treatment with Curculigoside A. We examined the role of Curculigoside A on RAEC and RASMC proliferation, migration, and tube formation in vitro and in a cerebral ischemia and reperfusion injury rat model. We used the recombinant Dickkopf (DKK)-1 protein, a Wnt/β-catenin inhibitor, and the recombinant WIF-1 protein, a Wnt5a antagonist to determine mechanisms. In addition, we measured leakage of the blood–brain barrier (BBB) and tested for angiogenesis associated proteins. Our data suggest that Curculigoside A induces angiogenesis in vitro by increasing proliferation, migration and tube formation in RAEC and RASMC. The increase in Curculigoside A-induced proliferation and tube formation was counteracted by DKK-1 and WIF-1. Curculigoside A increased expression of VEGF, p-VEGFR, p-CREB, Egr-3, VCAM-1, Ang1 and Tie2 while prohibiting BBB leakage in cerebral ischemia and reperfusion injured rats. However, Cyclosporine A, a CREB inhibitor, reduced the expression of p-CREB, Egr-3, VCAM-1, Ang1 and Tie2. These data suggest that Curculigoside A induces cell proliferation and angiogenesis through the Wnt5a/β-catenin and VEGF/CREB/Egr-3/VCAM-1 signaling axis and promotes maturation and stability of new blood vessels via increasing Ang1 and Tie-2 expression. - Highlights: • Curculigoside A induces cell proliferation through Wnt5a/β-catenin pathway. • Curculigoside A induces angiogenesis via VEGF/CREB/Egr-3/VCAM-1 signaling axis. • Curculigoside A promotes blood vessel maturation via Ang1/Tie2 pathway.

Suppression of tumor growth, invasion and angiogenesis of human gastric cancer by adenovirus-mediated expression of NK4

NARCIS (Netherlands)

Heideman, Daniëlle A. M.; van Beusechem, Victor W.; Bloemena, Elisabeth; Snijders, Peter J. F.; Craanen, Mikael E.; Offerhaus, G. Johan A.; Derksen, Patrick W. B.; de Bruin, Michiel; Witlox, M. Adhiambo; Molenaar, Bonnie; Meijer, Chris J. L. M.; Gerritsen, Winald R.

2004-01-01

Background To improve the prognosis of patients with gastric cancer it is important to develop novel treatment modalities targeting the malignant behavior of tumor cells. Concerning this, NK4, which acts as HGF-antagonist and angiogenesis inhibitor, might be a potential therapeutic agent for gastric

Thiodigalactoside inhibits murine cancers by concurrently blocking effects of galectin-1 on immune dysregulation, angiogenesis and protection against oxidative stress

Czech Academy of Sciences Publication Activity Database

Ito, K.; Scott, S.A.; Cutler, S.; Dong, L.-F.; Neužil, Jiří; Blanchard, H.; Ralph, S.J.

2011-01-01

Roč. 14, č. 3 (2011), s. 293-307 ISSN 0969-6970 Institutional research plan: CEZ:AV0Z50520701 Keywords : Galectin-1 inhibitor * oxidative stress * angiogenesis Subject RIV: FD - Oncology ; Hematology Impact factor: 6.063, year: 2011

Fucoidan/FGF-2 induces angiogenesis through JNK- and p38-mediated activation of AKT/MMP-2 signalling

Energy Technology Data Exchange (ETDEWEB)

Kim, Beom Su [Wonkwang Bone Regeneration Research Institute, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Bonecell Biotech Inc., 77, Dunsan-dong, Seo-gu, Daejeon 302-830 (Korea, Republic of); Park, Ji-Yun [Bonecell Biotech Inc., 77, Dunsan-dong, Seo-gu, Daejeon 302-830 (Korea, Republic of); Kang, Hyo-Jin [Wonkwang Bone Regeneration Research Institute, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Kim, Hyung-Jin [Department of Microbiology, School of Medicine, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Lee, Jun, E-mail: omslee@wku.ac.kr [Wonkwang Bone Regeneration Research Institute, Wonkwang University, Iksan, Jeonbuk 570-749 (Korea, Republic of); Bonecell Biotech Inc., 77, Dunsan-dong, Seo-gu, Daejeon 302-830 (Korea, Republic of)

2014-08-08

), c-Jun N-terminal kinase (JNK), p38, and AKT. MMP-2 activation was also significantly increased. Specific inhibitors of p38 (SB203580) and JNK (SP600125) inhibited tube formation and wound healing, while an ERK inhibitor (PD98059) did not. MMP-2 activation and AKT phosphorylation were also attenuated and associated with the suppression of p38 and JNK phosphorylation, but not with that of ERK. These results indicate that fucoidan, in the presence of FGF-2, induces angiogenesis through AKT/MMP-2 signalling by activating p38 and JNK. These findings provide basic molecular information on the effect of fucoidan on angiogenesis in the presence of FGF-2.

Fucoidan/FGF-2 induces angiogenesis through JNK- and p38-mediated activation of AKT/MMP-2 signalling

International Nuclear Information System (INIS)

Kim, Beom Su; Park, Ji-Yun; Kang, Hyo-Jin; Kim, Hyung-Jin; Lee, Jun

2014-01-01

), c-Jun N-terminal kinase (JNK), p38, and AKT. MMP-2 activation was also significantly increased. Specific inhibitors of p38 (SB203580) and JNK (SP600125) inhibited tube formation and wound healing, while an ERK inhibitor (PD98059) did not. MMP-2 activation and AKT phosphorylation were also attenuated and associated with the suppression of p38 and JNK phosphorylation, but not with that of ERK. These results indicate that fucoidan, in the presence of FGF-2, induces angiogenesis through AKT/MMP-2 signalling by activating p38 and JNK. These findings provide basic molecular information on the effect of fucoidan on angiogenesis in the presence of FGF-2

Monitoring angiogenesis using magnetic resonance methods

DEFF Research Database (Denmark)

Holm, David Alberg

2008-01-01

When a tumor reaches a certain size it can no longer rely on passive perfusion for nutrition. The tumor therefore emits signaling molecules which stimulating surrounding vessels to divide and grow towards the tumor, a process known as angiogenesis. Very little angiogenesis is present in healthy...... adults where it is primaily found in wound healing, pregnancy and during the menstrual cycle. This thesis focus on the negative consequences of angiogenesis in cancer. It consists of a an initial overview followed by four manuscripts. The overview gives a short introduction to the process of angiogenesis...... and the involved signaling molecules. Subsequently, a short review of contrast agents and perfusion measurements is given. Finally, methods for monitoring angiogenesis using magnetic resonance imaging are reviewed. A method for monitoring early stages of angiogenesis as well as the effect of anti...

Angiogenesis in liver fibrosis

NARCIS (Netherlands)

Adlia, Amirah

2017-01-01

Angiogenesis emerges in parallel with liver fibrosis, but it is still unclear whether angiogenesis is a defense mechanism of the body in response to fibrosis, or whether it aggravates the fibrotic condition. In this thesis, Amirah Adlia applied different approaches to elucidate the role of

Evidence that tumor necrosis factor-related apoptosis inducing ligand (TRAIL) inhibits angiogenesis by inducing vascular endothelial cell apoptosis

International Nuclear Information System (INIS)

Chen, Pei-Lin; Easton, Alexander S.

2010-01-01

Tumor necrosis factor (TNF) and its related ligands TNF-related apoptosis inducing ligand (TRAIL) and Fas ligand (FasL) play roles in the regulation of vascular responses, but their effect on the formation of new blood vessels (angiogenesis) is unclear. Therefore, we have examined the effects of these ligands on angiogenesis modeled with primary cultures of human umbilical vein endothelial cells (HUVEC). To examine angiogenesis in the context of the central nervous system, we have also modeled cerebral angiogenesis with the human brain endothelial cell line hCMEC/D3. Parameters studied were bromodeoxyuridine (BrdU) incorporation and cell number (MTT) assay (to assess endothelial proliferation), scratch assay (migration) and networks on Matrigel (tube formation). In our hands, neither TRAIL nor FasL (1, 10, and 100 ng/ml) had an effect on parameters of angiogenesis in the HUVEC model. In hCMEC/D3 cells by contrast, TRAIL inhibited all parameters (10-100 ng/ml, 24 h). This was due to apoptosis, since its action was blocked by the pan-caspase inhibitor zVADfmk (5 x 10 -5 mol/l) and TRAIL increased caspase-3 activity 1 h after application. However FasL (100 ng/ml) increased BrdU uptake without other effects. We conclude that TRAIL has different effects on in vitro angiogenesis depending on which model is used, but that FasL is generally ineffective when applied in vitro. The data suggest that TRAIL primarily influences angiogenesis by the induction of vascular endothelial apoptosis, leading to vessel regression.

Angiogenesis and Its Therapeutic Opportunities

Directory of Open Access Journals (Sweden)

So Young Yoo

2013-01-01

Full Text Available Angiogenesis plays critical roles in human physiology that range from reproduction and fetal growth to wound healing and tissue repair. The sophisticated multistep process is tightly regulated in a spatial and temporal manner by “on-off switch signals” between angiogenic factors, extracellular matrix components, and endothelial cells. Uncontrolled angiogenesis may lead to several angiogenic disorders, including vascular insufficiency (myocardial or critical limb ischemia and vascular overgrowth (hemangiomas, vascularized tumors, and retinopathies. Thus, numerous therapeutic opportunities can be envisaged through the successful understanding and subsequent manipulation of angiogenesis. Here, we review the clinical implications of angiogenesis and discuss pro- and antiangiogenic agents that offer potential therapy for cancer and other angiogenic diseases.

Notch-1 mediates hypoxia-induced angiogenesis in rheumatoid arthritis.

Science.gov (United States)

Gao, Wei; Sweeney, Catherine; Connolly, Mary; Kennedy, Aisling; Ng, Chin Teck; McCormick, Jennifer; Veale, Douglas J; Fearon, Ursula

2012-07-01

To examine the effect of hypoxia on Notch-1 signaling pathway components and angiogenesis in inflammatory arthritis. The expression and regulation of Notch-1, its ligand delta-like protein 4 (DLL-4) and downstream signaling components (hairy-related transcription factor 1 [HRT-1], HRT-2), and hypoxia-inducible factor 1α (HIF-1α) under normoxic and hypoxic conditions (1-3%) were assessed in synovial tissue specimens from patients with inflammatory arthritis and controls and in human dermal microvascular endothelial cells (HDMECs) by immunohistology, dual immunofluorescence staining (Notch-1/factor VIII), Western blotting, and real-time polymerase chain reaction. In vivo synovial tissue oxygen levels (tissue PO2) were measured under direct visualization at arthroscopy. HDMEC activation under hypoxic conditions in the presence of Notch-1 small interfering RNA (siRNA), the γ-secretase inhibitor DAPT, or dimethyloxalylglycine (DMOG) was assessed by Matrigel tube formation assay, migration assay, invasion assay, and matrix metalloproteinase 2 (MMP-2)/MMP-9 zymography. Expression of Notch-1, its ligand DLL-4, and HRT-1 was demonstrated in synovial tissue, with the strongest expression localized to perivascular/vascular regions. Localization of Notch-1 to synovial endothelium was confirmed by dual immunofluorescence staining. Notch-1 intracellular domain (NICD) expression was significantly higher in synovial tissue from patients with tissue PO2 of PO2 of >20 mm Hg (>3% O2). Exposure of HDMECs to 3% hypoxia induced HIF-1α and NICD protein expression and DLL-4, HRT-1, and HRT-2 messenger RNA expression. DMOG directly induced NICD expression, while Notch-1 siRNA inhibited hypoxia-induced HIF-1α expression, suggesting that Notch-1/HIF-1α signaling is bidirectional. Finally, 3% hypoxia-induced angiogenesis, endothelial cell migration, endothelial cell invasion, and proMMP-2 and proMMP-9 activities were inhibited by Notch-1 siRNA and/or the γ-secretase inhibitor DAPT. Our

D-Amino acid oxidase-induced oxidative stress, 3-bromopyruvate and citrate inhibit angiogenesis, exhibiting potent anticancer effects.

Science.gov (United States)

El Sayed, S M; El-Magd, R M Abou; Shishido, Y; Yorita, K; Chung, S P; Tran, D H; Sakai, T; Watanabe, H; Kagami, S; Fukui, K

2012-10-01

Angiogenesis is critical for cancer growth and metastasis. Steps of angiogenesis are energy consuming, while vascular endothelial cells are highly glycolytic. Glioblastoma multiforme (GBM) is a highly vascular tumor and this enhances its aggressiveness. D-amino acid oxidase (DAO) is a promising therapeutic protein that induces oxidative stress upon acting on its substrates. Oxidative stress-energy depletion (OSED) therapy was recently reported (El Sayed et al., Cancer Gene Ther, 19, 1-18, 2012). OSED combines DAO-induced oxidative stress with energy depletion caused by glycolytic inhibitors such as 3-bromopyruvate (3BP), a hexokinase II inhibitor that depleted ATP in cancer cells and induced production of hydrogen peroxide. 3BP disturbs the Warburg effect and antagonizes effects of lactate and pyruvate (El Sayed et al., J Bioenerg Biomembr, 44, 61-79, 2012). Citrate is a natural organic acid capable of inhibiting glycolysis by targeting phosphofructokinase. Here, we report that DAO, 3BP and citrate significantly inhibited angiogenesis, decreased the number of vascular branching points and shortened the length of vascular tubules. OSED delayed the growth of C6/DAO glioma cells. 3BP combined with citrate delayed the growth of C6 glioma cells and decreased significantly the number and size of C6 glioma colonies in soft agar. Human GBM cells (U373MG) were resistant to chemotherapy e.g. cisplatin and cytosine arabinoside, while 3BP was effective in decreasing the viability and disturbing the morphology of U373MG cells.

A mutation in the mitochondrial protein UQCRB promotes angiogenesis through the generation of mitochondrial reactive oxygen species

Energy Technology Data Exchange (ETDEWEB)

Chang, Junghwa [Chemical Genomics National Research Lab., Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Jung, Hye Jin [Department of Pharmaceutical Engineering, Sun Moon University, Asansi, Chungnam 330-150 (Korea, Republic of); Jeong, Seung Hun; Kim, Hyoung Kyu; Han, Jin [National Research Laboratory for Mitochondrial Signaling, Department of Physiology, College of Medicine, Department of Health Sciences and Technology, Cardiovascular and Metabolic Disease Center, Inje University, Busan (Korea, Republic of); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics National Research Lab., Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Department of Internal Medicine, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of)

2014-12-12

Highlights: • We constructed mitochondrial protein UQCRB mutant stable cell lines on the basis of a human case report. • These mutant cell lines exhibit pro-angiogenic activity with enhanced VEGF expression. • Proliferation of mutant cell lines was regulated by UQCRB inhibitors. • UQCRB may have a functional role in angiogenesis. - Abstract: Ubiquinol-cytochrome c reductase binding protein (UQCRB) is one of the subunits of mitochondrial complex III and is a target protein of the natural anti-angiogenic small molecule terpestacin. Previously, the biological role of UQCRB was thought to be limited to the maintenance of complex III. However, the identification and validation of UQCRB as a target protein of terpestacin enabled the role of UQCRB in oxygen sensing and angiogenesis to be elucidated. To explore the biological role of this protein further, UQCRB mutant stable cell lines were generated on the basis of a human case report. We demonstrated that these cell lines exhibited glycolytic and pro-angiogenic activities via mitochondrial reactive oxygen species (mROS)-mediated HIF1 signal transduction. Furthermore, a morphological abnormality in mitochondria was detected in UQCRB mutant stable cell lines. In addition, the proliferative effect of the UQCRB mutants was significantly regulated by the UQCRB inhibitors terpestacin and A1938. Collectively, these results provide a molecular basis for UQCRB-related biological processes and reveal potential key roles of UQCRB in angiogenesis and mitochondria-mediated metabolic disorders.

A mutation in the mitochondrial protein UQCRB promotes angiogenesis through the generation of mitochondrial reactive oxygen species

International Nuclear Information System (INIS)

Chang, Junghwa; Jung, Hye Jin; Jeong, Seung Hun; Kim, Hyoung Kyu; Han, Jin; Kwon, Ho Jeong

2014-01-01

Highlights: • We constructed mitochondrial protein UQCRB mutant stable cell lines on the basis of a human case report. • These mutant cell lines exhibit pro-angiogenic activity with enhanced VEGF expression. • Proliferation of mutant cell lines was regulated by UQCRB inhibitors. • UQCRB may have a functional role in angiogenesis. - Abstract: Ubiquinol-cytochrome c reductase binding protein (UQCRB) is one of the subunits of mitochondrial complex III and is a target protein of the natural anti-angiogenic small molecule terpestacin. Previously, the biological role of UQCRB was thought to be limited to the maintenance of complex III. However, the identification and validation of UQCRB as a target protein of terpestacin enabled the role of UQCRB in oxygen sensing and angiogenesis to be elucidated. To explore the biological role of this protein further, UQCRB mutant stable cell lines were generated on the basis of a human case report. We demonstrated that these cell lines exhibited glycolytic and pro-angiogenic activities via mitochondrial reactive oxygen species (mROS)-mediated HIF1 signal transduction. Furthermore, a morphological abnormality in mitochondria was detected in UQCRB mutant stable cell lines. In addition, the proliferative effect of the UQCRB mutants was significantly regulated by the UQCRB inhibitors terpestacin and A1938. Collectively, these results provide a molecular basis for UQCRB-related biological processes and reveal potential key roles of UQCRB in angiogenesis and mitochondria-mediated metabolic disorders

Imaging angiogenesis.

Science.gov (United States)

Charnley, Natalie; Donaldson, Stephanie; Price, Pat

2009-01-01

There is a need for direct imaging of effects on tumor vasculature in assessment of response to antiangiogenic drugs and vascular disrupting agents. Imaging tumor vasculature depends on differences in permeability of vasculature of tumor and normal tissue, which cause changes in penetration of contrast agents. Angiogenesis imaging may be defined in terms of measurement of tumor perfusion and direct imaging of the molecules involved in angiogenesis. In addition, assessment of tumor hypoxia will give an indication of tumor vasculature. The range of imaging techniques available for these processes includes positron emission tomography (PET), dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), perfusion computed tomography (CT), and ultrasound (US).

Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

Energy Technology Data Exchange (ETDEWEB)

Cho, Yoon Sun; Jung, Hye Jin [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of); Seok, Seung Hyeok [Department of Microbiology and Immunology, Institute for Experimental Animals, Seoul National University College of Medicine, Seoul 110-799 (Korea, Republic of); Payumo, Alexander Y.; Chen, James K. [Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305 (United States); Kwon, Ho Jeong, E-mail: kwonhj@yonsei.ac.kr [Chemical Genomics National Research Laboratory, Department of Biotechnology, Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749 (Korea, Republic of)

2013-04-19

Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases.

Functional inhibition of UQCRB suppresses angiogenesis in zebrafish

International Nuclear Information System (INIS)

Cho, Yoon Sun; Jung, Hye Jin; Seok, Seung Hyeok; Payumo, Alexander Y.; Chen, James K.; Kwon, Ho Jeong

2013-01-01

Highlights: ► This is the first functional characterization of UQCRB in vivo model. ► Angiogenesis is inhibited with UQCRB loss of function in zebrafish. ► UQCRB is introduced as a prognostic marker for mitochondria- and angiogenesis-related diseases. -- Abstract: As a subunit of mitochondrial complex III, UQCRB plays an important role in complex III stability, electron transport, and cellular oxygen sensing. Herein, we report UQCRB function regarding angiogenesis in vivo with the zebrafish (Danio rerio). UQCRB knockdown inhibited angiogenesis in zebrafish leading to the suppression of VEGF expression. Moreover, the UQCRB-targeting small molecule terpestacin also inhibited angiogenesis and VEGF levels in zebrafish, supporting the role of UQCRB in angiogenesis. Collectively, UQCRB loss of function by either genetic and pharmacological means inhibited angiogenesis, indicating that UQCRB plays a key role in this process and can be a prognostic marker of angiogenesis- and mitochondria-related diseases

Curcumin inhibited HGF-induced EMT and angiogenesis through regulating c-Met dependent PI3K/Akt/mTOR signaling pathways in lung cancer

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Demin Jiao

2016-01-01

Full Text Available The epithelial-mesenchymal transition (EMT and angiogenesis have emerged as two pivotal events in cancer progression. Curcumin has been extensively studied in preclinical models and clinical trials of cancer prevention due to its favorable toxicity profile. However, the possible involvement of curcumin in the EMT and angiogenesis in lung cancer remains unclear. This study found that curcumin inhibited hepatocyte growth factor (HGF-induced migration and EMT-related morphological changes in A549 and PC-9 cells. Moreover, pretreatment with curcumin blocked HGF-induced c-Met phosphorylation and downstream activation of Akt, mTOR, and S6. These effects mimicked that of c-Met inhibitor SU11274 or PI3 kinase inhibitor LY294002 or mTOR inhibitor rapamycin treatment. c-Met gene overexpression analysis further demonstrated that curcumin suppressed lung cancer cell EMT by inhibiting c-Met/Akt/mTOR signaling pathways. In human umbilical vein endothelial cells (HUVECs, we found that curcumin also significantly inhibited PI3K/Akt/mTOR signaling and induced apoptosis and reduced migration and tube formation of HGF-treated HUVEC. Finally, in the experimental mouse model, we showed that curcumin inhibited HGF-stimulated tumor growth and induced an increase in E-cadherin expression and a decrease in vimentin, CD34, and vascular endothelial growth factor (VEGF expression. Collectively, these findings indicated that curcumin could inhibit HGF-promoted EMT and angiogenesis by targeting c-Met and blocking PI3K/Akt/mTOR pathways.

[Markers of angiogenesis in tumor growth].

Science.gov (United States)

Nefedova, N A; Kharlova, O A; Danilova, N V; Malkov, P G; Gaifullin, N M

2016-01-01

Angiogenesis is a process of new blood vessels formation. The role of angiogenesis in growth, invasion and metastasis of malignant tumours is nowdays universally recognized. Though, investigation of mechanisms of blood vessels formation and elaboration methods for assessment of tumour angiogenesis are still up-dated. Another important concern are different aspects of usage of immunohistochemical markers of blood vessels endothelium (CD31 and CD34) for assessment of tumour aggressiveness and prognosis. The problems of malignant lymphangiogenesis are also up-to-date. The focus is on methods of immunohistochemical visualization of forming lymphatic vessels, role of podoplanin, the most reliable marker of lymphatic vessels, in their identification, and formulization of the main criteria for lymphangiogenesis estimation, its correlation with metastatic activity and prognostic potential. Studying of angiogenesis and lymph angiogenesis in malignant tumors is important and challenging direction for researching tumour progression and invention of antiangiogenic therapy.

Pachymic acid modified carbon nanoparticles reduced angiogenesis via inhibition of MMP-3.

Science.gov (United States)

Ma, Jun; Liu, Jun; Lu, Chun-Wei; Cai, Ding-Fang

2015-01-01

Angiogenesis is a process of new blood vessel generation, which is consistently and robustly correlated with tumor formation, growth, and metastasis. The disruption of angiogenesis, and the imbalanced endothelial remodeling and regression, are the main pathogenesis of malignant tumor. Recently, multi-walled nanotubes (MWNTs) have been proposed as a new tool for drug delivery in cancer treatment, which also displayed anti-angiogenic property. In the present study, we modified MWNTs with pachymic acid (PA) extracted from Heterosmilax chinensis, a traditional Chinese medicine used for cancer treatment, and compared their effects on blood vessel development. MWNTs and PA/MWNTs were evaluated for their influences on chorioallantoic membrane (CAM) vessel morphology and extracellular matrix metalloproteinase-3 (MMP-3) expression, a crucial proteinase associated with tumor metastasis. MWNTs functioned as an inhibitor of forming branch while PA was not able to promote this inhibition. Subsequently, MWNTs suppressed the endothelial cell maturation, accounting for the ceased elongation of CAM blood vessel, while PA/MWNTs increased the suppressive effect, indicating the potential roles of PA in preventing angiogenesis. PA/MWNTs also showed greater anti-angiogenic property as MMP-3 expression in CAM tissue was significantly decreased by PA/MWNTs compared to MWNTs. These results emphasize the anti-angiogenic activities of PA, supporting a new promising therapy for cancer from the perspective of traditional Chinese medicine.

Carbazole is a naturally occurring inhibitor of angiogenesis and inflammation isolated from antipsoriatic coal tar

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Jack L. Arbiser; Baskaran Govindarajan; Traci E. Battle; Rebecca Lynch; David A. Frank; Masuko Ushio-Fukai; Betsy N. Perry; David F. Stern; G. Tim Bowden; Anquan Liu; Eva Klein; Pawel J. Kolodziejski; N. Tony Eissa; Chowdhury F. Hossain; Dale G. Nagle [Emory University School of Medicine, Atlanta, GA (United States). Department of Dermatology

2006-06-15

Coal tar is one of the oldest and an effective treatment for psoriasis. Coal tar has been directly applied to the skin, or used in combination with UV light as part of the Goeckerman treatment. The use of coal tar has caused long-term remissions in psoriasis, but has fallen out of favor because the treatment requires hospitalization and coal tar is poorly acceptable aesthetically to patients. Thus, determining the active antipsoriatic component of coal tar is of considerable therapeutic interest. We fractionated coal tar into its components, and tested them using the SVR angiogenesis inhibitor assay. Treatment of SVR endothelial cells with coal tar fractions resulted in the isolation of a single fraction with antiangiogenic activity. The active antiangiogenic compound in coal tar is carbazole. In addition to antiangiogenic activity, carbazole inhibited the production of inflammatory IL-15 by human mononuclear cells. IL-15 is elevated in psoriasis and is thought to contribute to psoriatic inflammation. Carbazole treatment also reduced activity of inducible nitric oxide synthase (iNOS), which is proinflammatory and elevated in psoriasis. The effect of carbazole on upstream pathways in human psoriasis was determined, and carbazole was shown to inhibit signal transducer and activator of transcription (stat)3-mediated transcription, which has been shown to be relevant in human psoriasis. IL-15, iNOS, and stat3 activation require the activation of the small GTPase rac for optimal activity. Carbazole was found to inhibit rac activation as a mechanism for its inhibition of downstream inflammatory and angiogenic pathways. Given its antiangiogenic and anti-inflammatory activities, carbazole is likely a major component of the antipsoriatic activity of coal tar. Carbazole and derivatives may be useful in the therapy of human psoriasis.

Cannabidiol inhibits angiogenesis by multiple mechanisms.

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Solinas, M; Massi, P; Cantelmo, A R; Cattaneo, M G; Cammarota, R; Bartolini, D; Cinquina, V; Valenti, M; Vicentini, L M; Noonan, D M; Albini, A; Parolaro, D

2012-11-01

Several studies have demonstrated anti-proliferative and pro-apoptotic actions of cannabinoids on various tumours, together with their anti-angiogenic properties. The non-psychoactive cannabinoid cannabidiol (CBD) effectively inhibits the growth of different types of tumours in vitro and in vivo and down-regulates some pro-angiogenic signals produced by glioma cells. As its anti-angiogenic properties have not been thoroughly investigated to date, and given its very favourable pharmacological and toxicological profile, here, we evaluated the ability of CBD to modulate tumour angiogenesis. Firstly, we evaluated the effect of CBD on human umbilical vein endothelial cell (HUVEC) proliferation and viability - through [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay and FACS analysis - and in vitro motility - both in a classical Boyden chamber test and in a wound-healing assay. We next investigated CBD effects on different angiogenesis-related proteins released by HUVECs, using an angiogenesis array kit and an ELISA directed at MMP2. Then we evaluated its effects on in vitro angiogenesis in treated HUVECs invading a Matrigel layer and in HUVEC spheroids embedded into collagen gels, and further characterized its effects in vivo using a Matrigel sponge model of angiogenesis in C57/BL6 mice. CBD induced HUVEC cytostasis without inducing apoptosis, inhibited HUVEC migration, invasion and sprouting in vitro, and angiogenesis in vivo in Matrigel sponges. These effects were associated with the down-modulation of several angiogenesis-related molecules. This study reveals that CBD inhibits angiogenesis by multiple mechanisms. Its dual effect on both tumour and endothelial cells supports the hypothesis that CBD has potential as an effective agent in cancer therapy. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Role and mechanism of arsenic in regulating angiogenesis.

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Ling-Zhi Liu

Full Text Available Arsenic is a wide spread carcinogen associated with several kinds of cancers including skin, lung, bladder, and liver cancers. Lung is one of the major targets of arsenic exposure. Angiogenesis is the pivotal process during carcinogenesis and chronic pulmonary diseases, but the role and mechanism of arsenic in regulating angiogenesis remain to be elucidated. In this study we show that short time exposure of arsenic induces angiogenesis in both human immortalized lung epithelial cells BEAS-2B and adenocarcinoma cells A549. To study the molecular mechanism of arsenic-inducing angiogenesis, we find that arsenic induces reactive oxygen species (ROS generation, which activates AKT and ERK1/2 signaling pathways and increases the expression of hypoxia-inducible factor 1 (HIF-1 and vascular endothelial growth factor (VEGF. Inhibition of ROS production suppresses angiogenesis by decreasing AKT and ERK activation and HIF-1 expression. Inhibition of ROS, AKT and ERK1/2 signaling pathways is sufficient to attenuate arsenic-inducing angiogenesis. HIF-1 and VEGF are downstream effectors of AKT and ERK1/2 that are required for arsenic-inducing angiogenesis. These results shed light on the mechanism of arsenic in regulating angiogenesis, and are helpful to develop mechanism-based intervention to prevent arsenic-induced carcinogenesis and angiogenesis in the future.

Halofuginone Inhibits Angiogenesis and Growth in Implanted Metastatic Rat Brain Tumor Model-an MRI Study

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Rinat Abramovitch

2004-09-01

Full Text Available Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF is a potent inhibitor of collagen type α1(I. In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI, we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous histiocytoma metastatic rat brain tumor model. Here we demonstrate that treatment with HF effectively and dose-dependently reduced tumor growth and angiogenesis. On day 13, HF-treated tumors were fivefold smaller than control (P < .001. Treatment with HF significantly prolonged survival of treated animals (142%; P = .001. In HF-treated rats, tumor vascularization was inhibited by 30% on day 13 and by 37% on day 19 (P < .05. Additionally, HF treatment inhibited vessel maturation (P = .03. Finally, in HF-treated rats, we noticed the appearance of a few clusters of satellite tumors, which were distinct from the primary tumor and usually contained vessel cores. This phenomenon was relatively moderate when compared to previous reports of other antiangiogenic agents used to treat brain tumors. We therefore conclude that HF is effective for treatment of metastatic brain tumors.

Nitric oxide mediates angiogenesis induced in vivo by platelet-activating factor and tumor necrosis factor-alpha.

Science.gov (United States)

Montrucchio, G.; Lupia, E.; de Martino, A.; Battaglia, E.; Arese, M.; Tizzani, A.; Bussolino, F.; Camussi, G.

1997-01-01

We evaluated the role of an endogenous production of nitric oxide (NO) in the in vitro migration of endothelial cells and in the in vivo angiogenic response elicited by platelet-activating factor (PAF), tumor necrosis factor-alpha (TNF), and basic fibroblast growth factor (bFGF). The NO synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), but not its enantiomer D-NAME, prevented chemotaxis of endothelial cells induced in vitro by PAF and by TNF. The motogenic activity of TNF was also inhibited by WEB 2170, a specific PAF-receptor antagonist. In contrast, chemotaxis induced by bFGF was not prevented by L-NAME or by WEB 2170. Angiogenesis was studied in vivo in a murine model in which Matrigel was used as a vehicle for the delivery of mediators. In this model, the angiogenesis induced by PAF and TNF was inhibited by WEB 2170 and L-NAME but not by D-NAME. In contrast, angiogenesis induced by bFGF was not affected by L-NAME or by WEB 2170. TNF, but not bFGF, induced PAF synthesis within Matrigel. These results suggest that NO mediates the angiogenesis induced by PAF as well as that induced by TNF, which is dependent on the production of PAF. In contrast, the angiogenic effect of bFGF appears to be both PAF and NO independent. Images Figure 3 Figure 4 PMID:9250168

Vascular grading of angiogenesis

DEFF Research Database (Denmark)

Hansen, S; Grabau, D A; Sørensen, Flemming Brandt

2000-01-01

The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11...... years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers...... for 24% of the patients, who had a shift in prognostic group, as compared to NPI, and implied a better prognostic dissemination. We concluded that the angiogenesis determined by vascular grading has independent prognostic value of clinical relevance for patients with breast cancer....

Vascular grading of angiogenesis

DEFF Research Database (Denmark)

Hansen, S; Grabau, D A; Sørensen, Flemming Brandt

2000-01-01

The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11...... years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers...... impact for 24% of the patients, who had a shift in prognostic group, as compared to NPI, and implied a better prognostic dissemination. We concluded that the angiogenesis determined by vascular grading has independent prognostic value of clinical relevance for patients with breast cancer....

Hypoxia independent drivers of melanoma angiogenesis

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Svenja eMeierjohann

2015-05-01

Full Text Available Tumor angiogenesis is a process which is traditionally regarded as the tumor`s response to low nutrient supply occurring under hypoxic conditions. However, hypoxia is not a prerequisite for angiogenesis. The fact that even single tumor cells or small tumor cell aggregates are capable of attracting blood vessels reveals the early metastatic capability of tumor cells. This review sheds light on the hypoxia independent mechanisms of tumor angiogenesis in melanoma.

CCL5 promotes VEGF-dependent angiogenesis by down-regulating miR-200b through PI3K/Akt signaling pathway in human chondrosarcoma cells

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Liu, Guan-Ting; Chen, Hsien-Te; Tsou, Hsi-Kai; Tan, Tzu-Wei; Fong, Yi-Chin; Chen, Po-Chen; Yang, Wei-Hung; Wang, Shih-Wei; Chen, Jui-Chieh; Tang, Chih-Hsin

2014-01-01

Chondrosarcoma is the second most common primary malignant bone cancer, with potential for local invasion and distant metastasis. Chemokine CCL5 (formerly RANTES) of the CC-chemokine family plays a crucial role in metastasis. Angiogenesis is essential for the cancer metastasis. However, correlation of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is still unknown. CCL5-mediated VEGF expression was assessed by qPCR, ELISA, and Western blotting. CCL5-induced angiogenesis was examined by migration and tube formation in endothelial progenitor cells in vitro. CCL5 increased VEGF expression and also promoted chondrosarcoma conditional medium-mediated angiogenesis in vitro and in vivo. Stimulation of chondrosarcoma with CCL5 augmented PI3K and Akt phosphorylation, while PI3K and Akt inhibitor or siRNA abolished CCL5-induced VEGF expression and angiogenesis. We also demonstrated CCL5 inhibiting miR-200b expression and miR-200b mimic reversing the CCL5-enhanced VEGF expression and angiogenesis. Moreover, in chondrosarcoma patients showed the positive correlation between CCL5 and VEGF; negative correlation between CCL5 and miR-200b. Taken together, results demonstrate CCL5 promoting VEGF-dependent angiogenesis in human chondrosarcoma cells by down-regulating miR-200b through PI3K/Akt signaling pathway. PMID:25301739

Butein Inhibits Angiogenesis of Human Endothelial Progenitor Cells via the Translation Dependent Signaling Pathway

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Ching-Hu Chung

2013-01-01

Full Text Available Compelling evidence indicates that bone marrow-derived endothelial progenitor cells (EPCs can contribute to postnatal neovascularization and tumor angiogenesis. EPCs have been shown to play a “catalytic” role in metastatic progression by mediating the angiogenic switch. Understanding the pharmacological functions and molecular targets of natural products is critical for drug development. Butein, a natural chalcone derivative, has been reported to exert potent anticancer activity. However, the antiangiogenic activity of butein has not been addressed. In this study, we found that butein inhibited serum- and vascular endothelial growth factor- (VEGF- induced cell proliferation, migration, and tube formation of human EPCs in a concentration dependent manner without cytotoxic effect. Furthermore, butein markedly abrogated VEGF-induced vessels sprouting from aortic rings and suppressed microvessel formation in the Matrigel implant assay in vivo. In addition, butein concentration-dependently repressed the phosphorylation of Akt, mTOR, and the major downstream effectors, p70S6K, 4E-BP1, and eIF4E in EPCs. Taken together, our results demonstrate for the first time that butein exhibits the antiangiogenic effect both in vitro and in vivo by targeting the translational machinery. Butein is a promising angiogenesis inhibitor with the potential for treatment of cancer and other angiogenesis-related diseases.

Molecular Imaging of Ovarian Carcinoma Angiogenesis

National Research Council Canada - National Science Library

Chen, Xiaoyuan

2007-01-01

.... Ovarian cancer is angiogenesis dependent. Integrin , a key player in tumor angiogenesis and metastasis, has been identified as a target for diagnostic and therapeutic interventions for several highly proliferative and metastatic tumor types...

Mechanical and Chemical Signaling in Angiogenesis

CERN Document Server

2013-01-01

This volume of Studies in Mechanobiology, Tissue Engineering and Biomaterials describes the most recent advances in angiogenesis research at all biological length scales: molecular, cellular and tissue, in both in vivo and in vitro settings.  Angiogenesis experts from diverse fields including engineering, cell and developmental biology, and chemistry have contributed chapters which focus on the mechanical and chemical signals which affect and promote blood vessel growth. Specific emphasis is given to novel methodologies and biomaterials that have been developed and applied to angiogenesis research. 

VASCULAR REMODELING IN HYPERTENSION: ANGIOGENESIS FEATURES

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L. A. Haisheva

2014-07-01

Full Text Available Aim — cross-sectional study of changes in various segments of the vascular bed in arterial hypertension (AH, defining the role of inducers and inhibitors of angiogenesis in these processes.Materials and methods. The study included 99 patients with arterial hypertension of I–II degree, average age of 63.2 ± 2.6 years, diseaseduration 9.2 ± 7.2 years.Results. It was found that patients with arterial hypertension have disorders in all segments of vascular bed: endothelial dysfunction (highvWF, microcirculatory disorders, and increased pulse wave velocity (PWV of elastic-type vessels. The level of angioginesis factors doesnot depend on such parameters as gender, age, body mass index. Smoking and duration of hypertension influence on vascular endothelialgrowth factor raise and endostatin levels are higher in patients with family history of cardiovascular diseases. Duration of disease is directlycorrelated with microcirculatory disorders and the PWV, correlation between microcirculatory disorders and pulse wave velocity indicatetheir common processes.

Galectins in angiogenesis: consequences for gestation.

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Blois, Sandra M; Conrad, Melanie L; Freitag, Nancy; Barrientos, Gabriela

2015-04-01

Members of the galectin family have been shown to exert several roles in the context of reproduction. They contribute to placentation, maternal immune regulation and facilitate angiogenesis encompassing decidualisation and placenta formation during pregnancy. In the context of neo-vascularisation, galectins have been shown to augment signalling pathways that lead to endothelial cell activation, cell proliferation, migration and tube formation in vitro in addition to angiogenesis in vivo. Angiogenesis during gestation ensures not only proper foetal growth and development, but also maternal health. Consequently, restriction of placental blood flow has major consequences for both foetus and mother, leading to pregnancy diseases. In this review we summarise both the established and the emerging roles of galectin in angiogenesis and discuss the possible implications during healthy and pathological gestation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Myocardial overexpression of TIMP3 after myocardial infarction exerts beneficial effects by promoting angiogenesis and suppressing early proteolysis.

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Takawale, Abhijit; Zhang, Pu; Azad, Abul; Wang, Wang; Wang, Xiuhua; Murray, Allan G; Kassiri, Zamaneh

2017-08-01

Myocardial infarction (MI) results in loss of cardiomyocytes, adverse extracellular matrix (ECM) and structural remodeling, and left ventricular (LV) dilation and dysfunction. Tissue inhibitors of metalloproteinase (TIMPs) inhibit matrix metalloproteinases (MMPs), the main regulators of ECM turnover. TIMPs also have MMP-independent functions. TIMP3 levels are reduced in the heart within 24 h of MI in mice. We investigated if overexpression of TIMP3 post-MI limits adverse remodeling and LV dilation and dysfunction. MI was induced by left anterior descending coronary artery ligation in 10- to 12-wk-old male C57BL/6J mice, and adenoviral constructs expressing human (h)TIMP3 (Ad-hTIMP3) or no TIMP (Ad-Null) were injected in the peri-infarct zone (5.4 × 10 7 plaque-forming units/heart, 5 injections/heart). Cardiac function assessed by echocardiography showed improved LV physiology and reduced LV dilation after TIMP3 overexpression compared with the Ad-Null-MI group. Post-MI adverse remodeling was attenuated in the Ad-hTIMP3-MI group, as assessed by greater cardiomyocyte density, less infarct expansion, and ECM disruption. TIMP3 overexpression blunted the early rise in proteolytic activities post-MI. A higher density of coronary arteries and a greater number of proliferating endothelial cells were detected in the infarct and peri-infarct regions in the Ad-hTIMP3-MI group compared with the Ad-Null-MI group. In vitro three-dimensional angiogenesis assay confirmed that recombinant TIMP3 promotes angiogenesis in human endothelial cells, although biphasically and in a dose-dependent manner. Intriguingly, overexpression of Ad-hTIMP3 at 10-fold higher concentration had no beneficial effects, consistent with antiangiogenic effects of TIMP3 at higher doses. In conclusion, optimal overexpression of TIMP3 can be a promising therapeutic approach to limit adverse post-MI remodeling by dually inhibiting early proteolysis and promoting angiogenesis. NEW & NOTEWORTHY Here, we report

PTP1B inhibitor promotes endothelial cell motility by activating the DOCK180/Rac1 pathway.

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Wang, Yuan; Yan, Feng; Ye, Qing; Wu, Xiao; Jiang, Fan

2016-04-07

Promoting endothelial cell (EC) migration is important not only for therapeutic angiogenesis, but also for accelerating re-endothelialization after vessel injury. Several recent studies have shown that inhibition of protein tyrosine phosphatase 1B (PTP1B) may promote EC migration and angiogenesis by enhancing the vascular endothelial growth factor receptor-2 (VEGFR2) signalling. In the present study, we demonstrated that PTP1B inhibitor could promote EC adhesion, spreading and migration, which were abolished by the inhibitor of Rac1 but not RhoA GTPase. PTP1B inhibitor significantly increased phosphorylation of p130Cas, and the interactions among p130Cas, Crk and DOCK180; whereas the phosphorylation levels of focal adhesion kinase, Src, paxillin, or Vav2 were unchanged. Gene silencing of DOCK180, but not Vav2, abrogated the effects of PTP1B inhibitor on EC motility. The effects of PTP1B inhibitor on EC motility and p130Cas/DOCK180 activation persisted in the presence of the VEGFR2 antagonist. In conclusion, we suggest that stimulation of the DOCK180 pathway represents an alternative mechanism of PTP1B inhibitor-stimulated EC motility, which does not require concomitant VEGFR2 activation as a prerequisite. Therefore, PTP1B inhibitor may be a useful therapeutic strategy for promoting EC migration in cardiovascular patients in which the VEGF/VEGFR functions are compromised.

Angiogenesis in prostate cancer : onset, progression and imaging

NARCIS (Netherlands)

Russo, G.; Mischi, M.; Scheepens, W.; Rosette, de la J.J.M.C.H.; Wijkstra, H.

2012-01-01

Today, angiogenesis is known to play a key role in cancer growth and development. Emerging cancer treatments are based on the suppression of angiogenesis, and modern imaging techniques investigate changes in the microvasculature that are caused by angiogenesis. As for other forms of cancers,

Ginsenoside-Rg{sub 1} induces angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a

Energy Technology Data Exchange (ETDEWEB)

Kwok, Hoi-Hin [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Chan, Lai-Sheung [Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Poon, Po-Ying [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Yue, Patrick Ying-Kit [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Wong, Ricky Ngok-Shun, E-mail: rnswong@hkbu.edu.hk [Dr. Gilbert Hung Ginseng Laboratory, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China); Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong SAR (China)

2015-09-15

Therapeutic angiogenesis has been implicated in ischemic diseases and wound healing. Ginsenoside-Rg{sub 1} (Rg{sub 1}), one of the most abundant active components of ginseng, has been demonstrated as an angiogenesis-stimulating compound in different models. There is increasing evidence implicating microRNAs (miRNAs), a group of non-coding RNAs, as important regulators of angiogenesis, but the role of microRNAs in Rg{sub 1}-induced angiogenesis has not been fully explored. In this report, we found that stimulating endothelial cells with Rg{sub 1} could reduce miR-23a expression. In silico experiments predicted hepatocyte growth factor receptor (MET), a well-established mediator of angiogenesis, as the target of miR-23a. Transfection of the miR-23a precursor or inhibitor oligonucleotides validated the inverse relationship of miR-23a and MET expression. Luciferase reporter assays further confirmed the interaction between miR-23a and the MET mRNA 3′-UTR. Intriguingly, ginsenoside-Rg{sub 1} was found to increase MET protein expression in a time-dependent manner. We further demonstrated that ginsenoside-Rg{sub 1}-induced angiogenic activities were indeed mediated through the down-regulation of miR-23a and subsequent up-regulation of MET protein expression, as confirmed by gain- and loss-of-function angiogenic experiments. In summary, our results demonstrated that ginsenoside-Rg{sub 1} could induce angiogenesis by the inverse regulation of MET tyrosine kinase receptor expression through miR-23a. This study has broadened our understanding of the non-genomic effects of ginsenoside-Rg{sub 1,} and provided molecular evidence that warrant further development of natural compound as novel angiogenesis-promoting therapy. - Highlights: • Therapeutic angiogenesis has been implicated in ischemic diseases and wound healing. • Ginsenoside-Rg{sub 1} (Rg{sub 1}) has been demonstrated as an angiogenesis-stimulating compound. • We found that Rg{sub 1} induces angiogenesis by

PNU-145156E, a novel angiogenesis inhibitor, in patients with solid tumors : A phase I and pharmacokinetic study

NARCIS (Netherlands)

Groen, HJM; de Vries, EGE; Wynendaele, W; van der Graaf, WTA; Lechuga, EFMJ; Poggesi, [No Value; Dirix, LY; van Oosterom, AT

2001-01-01

Our aim was to establish, in patients with solid tumors, the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacology of PNU-145156E, a new sulfonated distamycin A derivative that blocked circulating angiogenesis-promoting growth factors in animal studies and exhibited an antitumor

Histone Deacetylase Inhibitors as Anticancer Drugs.

Science.gov (United States)

Eckschlager, Tomas; Plch, Johana; Stiborova, Marie; Hrabeta, Jan

2017-07-01

Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC) and histone acetyltransferases (HAT). HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

Histone Deacetylase Inhibitors as Anticancer Drugs

Directory of Open Access Journals (Sweden)

Tomas Eckschlager

2017-07-01

Full Text Available Carcinogenesis cannot be explained only by genetic alterations, but also involves epigenetic processes. Modification of histones by acetylation plays a key role in epigenetic regulation of gene expression and is controlled by the balance between histone deacetylases (HDAC and histone acetyltransferases (HAT. HDAC inhibitors induce cancer cell cycle arrest, differentiation and cell death, reduce angiogenesis and modulate immune response. Mechanisms of anticancer effects of HDAC inhibitors are not uniform; they may be different and depend on the cancer type, HDAC inhibitors, doses, etc. HDAC inhibitors seem to be promising anti-cancer drugs particularly in the combination with other anti-cancer drugs and/or radiotherapy. HDAC inhibitors vorinostat, romidepsin and belinostat have been approved for some T-cell lymphoma and panobinostat for multiple myeloma. Other HDAC inhibitors are in clinical trials for the treatment of hematological and solid malignancies. The results of such studies are promising but further larger studies are needed. Because of the reversibility of epigenetic changes during cancer development, the potency of epigenetic therapies seems to be of great importance. Here, we summarize the data on different classes of HDAC inhibitors, mechanisms of their actions and discuss novel results of preclinical and clinical studies, including the combination with other therapeutic modalities.

Positron emission tomography tracers for imaging angiogenesis

International Nuclear Information System (INIS)

Haubner, Roland; Beer, Ambros J.; Wang, Hui; Chen, Xiaoyuan

2010-01-01

Position emission tomography imaging of angiogenesis may provide non-invasive insights into the corresponding molecular processes and may be applied for individualized treatment planning of antiangiogenic therapies. At the moment, most strategies are focusing on the development of radiolabelled proteins and antibody formats targeting VEGF and its receptor or the ED-B domain of a fibronectin isoform as well as radiolabelled matrix metalloproteinase inhibitors or α v β 3 integrin antagonists. Great efforts are being made to develop suitable tracers for different target structures. All of the major strategies focusing on the development of radiolabelled compounds for use with positron emission tomography are summarized in this review. However, because the most intensive work is concentrated on the development of radiolabelled RGD peptides for imaging α v β 3 expression, which has successfully made its way from bench to bedside, these developments are especially emphasized. (orig.)

Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo

International Nuclear Information System (INIS)

Klenke, Frank M; Abdollahi, Amir; Bertl, Elisabeth; Gebhard, Martha-Maria; Ewerbeck, Volker; Huber, Peter E; Sckell, Axel

2007-01-01

As chondrosarcomas are resistant to chemotherapy and ionizing radiation, therapeutic options are limited. Radical surgery often cannot be performed. Therefore, additional therapies such as antiangiogenesis represent a promising strategy for overcoming limitations in chondrosarcoma therapy. There is strong experimental evidence that SU6668, an inhibitor of the angiogenic tyrosine kinases Flk-1/KDR, PDGFRbeta and FGFR1 can induce growth inhibition of various primary tumors. However, the effectiveness of SU6668 on malignant primary bone tumors such as chondrosarcomas has been rarely investigated. Therefore, the aim of this study was to investigate the effects of SU6668 on chondrosarcoma growth, angiogenesis and microcirculation in vivo. In 10 male severe combined immunodeficient (SCID) mice, pieces of SW1353 chondrosarcomas were implanted into a cranial window preparation where the calvaria serves as the site for the orthotopic implantation of bone tumors. From day 7 after tumor implantation, five animals were treated with SU6668 (250 mg/kg body weight, s.c.) at intervals of 48 hours (SU6668), and five animals with the equivalent amount of the CMC-based vehicle (Control). Angiogenesis, microcirculation, and growth of SW 1353 tumors were analyzed by means of intravital microscopy. SU6668 induced a growth arrest of chondrosarcomas within 7 days after the initiation of the treatment. Compared to Controls, SU6668 decreased functional vessel density and tumor size, respectively, by 37% and 53% on day 28 after tumor implantation. The time course of the experiments demonstrated that the impact on angiogenesis preceded the anti-tumor effect. Histological and immunohistochemical results confirmed the intravital microscopy findings. SU6668 is a potent inhibitor of chondrosarcoma tumor growth in vivo. This effect appears to be induced by the antiangiogenic effects of SU6668, which are mediated by the inhibition of the key angiogenic receptor tyrosine kinases Flk-1/KDR, PDGFRbeta

WNT Signaling Is Required for Peritoneal Membrane Angiogenesis.

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Padwal, Manreet Kaur; Cheng, Genyang; Liu, Limin; Boivin, Felix J; Gangji, Azim; Brimble, Kenneth Scott; Bridgewater, Darren; Margetts, Peter J

2018-01-24

The WNT signaling pathway is involved in wound healing and fibrosis. We evaluated the WNT signaling pathway in peritoneal membrane injury. We assessed WNT1 protein expression in the peritoneal effluents of 54 stable peritoneal dialysis (PD) patients and WNT-related gene expression in ex vivo mesothelial cell cultures from 21 PD patients. In a transforming growth factor beta (TGFB) mediated animal model of peritoneal fibrosis, we evaluated regulation of the WNT pathway and the effect of WNT inhibition on peritoneal fibrosis and angiogenesis. WNT1 and WNT2 gene expression were positively correlated with peritoneal membrane solute transport in PD patients. In the mouse peritoneum, TGFΒ-induced peritoneal fibrosis was associated with increased expression of WNT2 and WNT4. Peritoneal b-catenin protein was significantly upregulated after infection with AdTGFB along with elements of the WNT signaling pathway. Treatment with a b-catenin inhibitor (ICG-001) in mice with AdTGFB-induced peritoneal fibrosis resulted in attenuation of peritoneal angiogenesis and reduced vascular endothelial growth factor. Similar results were also observed with the WNT antagonist Dickkopf related protein (DKK) 1. In addition to this, DKK-1 blocked epithelial to mesenchymal transition and increased levels of the cell adhesion protein E-cadherin. We provide evidence that WNT signaling is active in the setting of experimental peritoneal fibrosis and WNT1 correlates with patient peritoneal membrane solute transport in PD patients. Intervention in this pathway is a possible therapy for peritoneal membrane injury.

An allometric approach of tumor-angiogenesis.

Science.gov (United States)

Szasz, Oliver; Vincze, Gyula; Szigeti, Gyula Peter; Benyo, Zoltan; Szasz, Andras

2018-07-01

Angiogenesis is one of the main supporting factors of tumor-progression. It is a complex set of interactions together with hypoxia and inflammation, regulating tumor growth. The objective of this study is to examine the effect of angiogenesis with an allometric approach applied to angiogenesis and the regulating factors. The results show that allometry has the potential to describe this aspect, including the sigmoid-like transport function. There are particular conditions under which the complex control maximizes the relative tumor mass. Linear growth of malignancy diameter with an allometric approach was proven. Copyright © 2018. Published by Elsevier Ltd.

Altered extracellular matrix remodeling and angiogenesis in sponge granulomas of thrombospondin 2-null mice.

Science.gov (United States)

Kyriakides, T R; Zhu, Y H; Yang, Z; Huynh, G; Bornstein, P

2001-10-01

The matricellular angiogenesis inhibitor, thrombospondin (TSP) 2, has been shown to be an important modulator of wound healing and the foreign body response. Specifically, TSP2-null mice display improved healing with minimal scarring and form well-vascularized foreign body capsules. In this study we performed subcutaneous implantation of sponges and investigated the resulting angiogenic and fibrogenic responses. Histological and immunohistochemical analysis of sponges, excised at 7, 14, and 21 days after implantation, revealed significant differences between TSP2-null and wild-type mice. Most notably, TSP2-null mice exhibited increased angiogenesis and fibrotic encapsulation of the sponge. However, invasion of dense tissue was compromised, even though its overall density was increased. Furthermore, histomorphometry and biochemical assays demonstrated a significant increase in the extracellular distribution of matrix metalloproteinase (MMP) 2, but no change in the levels of active transforming growth factor-beta(1). The alterations in neovascularization, dense tissue invasion, and MMP2 in TSP2-null mice coincided with the deposition of TSP2 in the extracellular matrix of wild-type animals. These observations support the proposed role of TSP2 as a modulator of angiogenesis and matrix remodeling during tissue repair. In addition, they provide in vivo evidence for a newly proposed function of TSP2 as a modulator of extracellular MMP2 levels.

Green tea and its anti-angiogenesis effects.

Science.gov (United States)

Rashidi, Bahman; Malekzadeh, Mehrnoush; Goodarzi, Mohammad; Masoudifar, Aria; Mirzaei, Hamed

2017-05-01

The development of new blood vessels from a pre-existing vasculature (also known as angiogenesis) is required for many physiological processes including embryogenesis and post-natal growth. However, pathological angiogenesis is also a hallmark of cancer and many ischaemic and inflammatory diseases. The pro-angiogenic members of the VEGF family (vascular endothelial growth factor family), VEGF-A, VEGF-B, VEGF-C, VEGF-D and placental growth factor (PlGF), and the related receptors, VEGFR-1, VEGFR-2 and VEGFR-3 have a central and decisive role in angiogenesis. Indeed, they are the targets for anti-angiogenic drugs currently approved. Green tea (from the Camellia sinensis plant) is one of the most popular beverages in the world. It is able to inhibit angiogenesis by different mechanisms such as microRNAs (miRNAs). Green tea and its polyphenolic substances (like catechins) show chemo-preventive and chemotherapeutic features in various types of cancer and experimental models for human cancers. The tea catechins, including (-)-epigallocatechin-3-gallate (EGCG), have multiple effects on the cellular proteome and signalome. Note that the polyphenolic compounds from green tea are able to change the miRNA expression profile associated with angiogenesis in various cancer types. This review focuses on the ability of the green tea constituents to suppress angiogenesis signaling and it summarizes the mechanisms by which EGCG might inhibit the VEGF family. We also highlighted the miRNAs affected by green tea which are involved in anti-angiogenesis. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Hacking macrophage-associated immunosuppression for regulating glioblastoma angiogenesis.

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Cui, Xin; Morales, Renee-Tyler Tan; Qian, Weiyi; Wang, Haoyu; Gagner, Jean-Pierre; Dolgalev, Igor; Placantonakis, Dimitris; Zagzag, David; Cimmino, Luisa; Snuderl, Matija; Lam, Raymond H W; Chen, Weiqiang

2018-04-01

Glioblastoma (GBM) is the most lethal primary adult brain tumor and its pathology is hallmarked by distorted neovascularization, diffuse tumor-associated macrophage infiltration, and potent immunosuppression. Reconstituting organotypic tumor angiogenesis models with biomimetic cell heterogeneity and interactions, pro-/anti-inflammatory milieu and extracellular matrix (ECM) mechanics is critical for preclinical anti-angiogenic therapeutic screening. However, current in vitro systems do not accurately mirror in vivo human brain tumor microenvironment. Here, we engineered a three-dimensional (3D), microfluidic angiogenesis model with controllable and biomimetic immunosuppressive conditions, immune-vascular and cell-matrix interactions. We demonstrate in vitro, GL261 and CT-2A GBM-like tumors steer macrophage polarization towards a M2-like phenotype for fostering an immunosuppressive and proangiogenic niche, which is consistent with human brain tumors. We distinguished that GBM and M2-like immunosuppressive macrophages promote angiogenesis, while M1-like pro-inflammatory macrophages suppress angiogenesis, which we coin "inflammation-driven angiogenesis." We observed soluble immunosuppressive cytokines, predominantly TGF-β1, and surface integrin (α v β 3 ) endothelial-macrophage interactions are required in inflammation-driven angiogenesis. We demonstrated tuning cell-adhesion receptors using an integrin (α v β 3 )-specific collagen hydrogel regulated inflammation-driven angiogenesis through Src-PI3K-YAP signaling, highlighting the importance of altered cell-ECM interactions in inflammation. To validate the preclinical applications of our 3D organoid model and mechanistic findings of inflammation-driven angiogenesis, we screened a novel dual integrin (α v β 3 ) and cytokine receptor (TGFβ-R1) blockade that suppresses GBM tumor neovascularization by simultaneously targeting macrophage-associated immunosuppression, endothelial-macrophage interactions, and

Angiogenesis measured by expression of CD34 antigen in lymph nodes of patients with non-Hodgkin's lymphoma.

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Kazimierz Kuliczkowski

2005-02-01

Full Text Available Angiogenesis is important in development, maintenance and progression of haematological malignancies. Some clinical observations have indicated that in non-Hodgkin's lymphoma (nHL tumour microvessel density (MVD may correlate with tumour staging and outcome. The aim of the study was to examine relationship between MVD as a parameter of tumour angiogenesis measured by expression of CD34 and the grade of nHL histological malignancy as determined by REAL classification. 40 lymph node samples of patients with newly diagnosed nHL (17 women, 23 men; aged 48-70 yrs, median age 64 yrs; stage III and IV and treated at the Department of Haematology, Wrocław Medical University in 1999-2002 were fixed in 10% buffered formalin and embedded in paraffin. In all the studied cases, sections were incubated with antibodies against CD34. The slides were stained with hematoxylin and eosin and evaluated histopathologically. Patients were divided into two groups according to histological malignancy: indolent nHL (19 patients and aggressive nHL (21 patients. Mean MVD measured by expression of CD34 in aggressive and indolent nHL groups amounted to 19.45 +/- 11.24 vessels/0.375 mm2 and 21.7 +/- 12.4 vessels/0.375 mm2, respectively. Statistical analysis of microvessel staining demonstrated no correlation between tumour MVD and grade of histological malignancy in lymph nodes of nHL patients. Nevertheless, angiogenesis observed in nHL provides rationale for use of angiogenesis inhibitors in lymphoma therapy.

Advances and challenges in skeletal muscle angiogenesis

DEFF Research Database (Denmark)

Olfert, I Mark; Baum, Oliver; Hellsten, Ylva

2016-01-01

The role of capillaries is to serve as the interface for delivery of oxygen and removal of metabolites to/from tissues. During the past decade there has been a proliferation of studies that have advanced our understanding of angiogenesis demonstrating tissue capillary supply is under strict control...... rearrangement of capillaries) that identify areas of future research with the greatest potential to expand our understanding of how angiogenesis is normally regulated, and that may also help to better understand conditions of uncontrolled (pathologic) angiogenesis....

Anti-VEGF strategies - from antibodies to tyrosine kinase inhibitors: background and clinical development in human cancer.

LENUS (Irish Health Repository)

Korpanty, Grzegorz

2012-01-01

Tumour angiogenesis (formation of new blood vessels supporting tumour growth and metastasis) is a result of complex interactions between the tumour and the surrounding microenvironment. Targeting tumours with anti-angiogenic therapy remains an exciting area of preclinical and clinical studies. Although many significant advances have been achieved and the clinical use of anti-angiogenic drugs is now well recognized in many solid malignancies, these therapies fall short of their anticipated clinical benefits and leave many unanswered questions like exact mechanism of action, patients\\' selection and monitoring response to anti-angiogenic drugs. Tumour angiogenesis is controlled by complex signaling cascades and ongoing research into molecular mechanisms of tumour angiogenesis not only helps to understand its basic mechanisms but hopefully will identify new therapeutic targets. In 2012, both monoclonal antibodies and small molecule tyrosine kinase inhibitors remain the two major clinically useful therapeutic options that interfere with tumour angiogenesis in many solid malignancies.

Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model.

Science.gov (United States)

Li, Zhenyuan; Yan, Hao; Yuan, Jiangzi; Cao, Liou; Lin, Aiwu; Dai, Huili; Ni, Zhaohui; Qian, Jiaqi; Fang, Wei

2018-04-01

Molecular mechanisms of peritoneal dialysis (PD) ultrafiltration failure, peritoneal neo-angiogenesis, and fibrosis remain to be determined. We aimed to determine the role of heparin-binding EGF-like growth factor (HB-EGF) inhibition on angiogenesis of peritoneal membrane in a PD rat model. 32 male Wistar rats were assigned into (1) control group; (2) uremic non-PD group: subtotal nephrectomy-induced uremic rats without PD; (3) uremic rats subjected to PD: uremic rats that were dialyzed with Dianeal ® for 4 weeks; (4) CRM 197 group: dialyzed uremic rats were supplemented with CRM197, a specific HB-EGF inhibitor. Peritoneal transport function was examined by peritoneal equilibration test. Expression of HB-EGF and EGFR in peritoneal samples were examined by real-time PCR, immunohistochemical staining, and western blot. Progressive angiogenesis and fibrosis were observed in uremic PD rats, and there were associated with decreased net ultrafiltration (nUF), increased permeability of peritoneal membrane, and reduced expression of HB-EGF and EGFR protein and mRNA in uremic PD rats compared to uremic non-PD or control groups (both p CRM197 significantly induced peritoneal membrane permeability, decreased nUF, increased higher vessel density, and reduced pericyte count compared to that of uremic PD rats. The levels of HB-EGF and EGFR expression negatively correlated with vessel density in peritoneal membrane (both p < 0.001). PD therapy was associated with peritoneal angiogenesis, functional deterioration, and downregulation of HB-EGF/EGFR. Pharmacological inhibition of HB-EGF promoted PD-induced peritoneal angiogenesis and fibrosis and ultrafiltration decline, suggesting that HB-EGF downregulation contributes to peritoneal functional deterioration in the uremic PD rat model.

Progesterone in Breast Cancer Angiogenesis

OpenAIRE

Botelho, Monica C.; Soares, Raquel; Alves, Helena

2015-01-01

The involvement of steroid hormones in breast carcinogenesis is well established. Recent evidence suggests that angiogenesis can be regulated by hormones. Both oestrogen and progesterone have been implicated in the angiogenic process of hormone-dependent cancers, such as breast cancer. Vascular Endothelial Growth Factor (VEGF) is a growth factor involved in angiogenesis in breast cancer that is up-regulated by estrogens. In our study we evaluated the role of progesterone in the expression of ...

Effective treatment of diverse medulloblastoma models with mebendazole and its impact on tumor angiogenesis.

Science.gov (United States)

Bai, Ren-Yuan; Staedtke, Verena; Rudin, Charles M; Bunz, Fred; Riggins, Gregory J

2015-04-01

Medulloblastoma is the most common malignant brain tumor in children. Current standard treatments cure 40%-60% of patients, while the majority of survivors suffer long-term neurological sequelae. The identification of 4 molecular groups of medulloblastoma improved the clinical management with the development of targeted therapies; however, the tumor acquires resistance quickly. Mebendazole (MBZ) has a long safety record as antiparasitic in children and has been recently implicated in inhibition of various tyrosine kinases in vitro. Here, we investigated the efficacy of MBZ in various medulloblastoma subtypes and MBZ's impact on vascular endothelial growth factor receptor 2 (VEGFR2) and tumor angiogenesis. The inhibition of MBZ on VEGFR2 kinase was investigated in an autophosphorylation assay and a cell-free kinase assay. Mice bearing orthotopic PTCH1-mutant medulloblastoma allografts, a group 3 medulloblastoma xenograft, and a PTCH1-mutant medulloblastoma with acquired resistance to the smoothened inhibitor vismodegib were treated with MBZ. The survival benefit and the impact on tumor angiogenesis and VEGFR2 kinase function were analyzed. We determined that MBZ interferes with VEGFR2 kinase by competing with ATP. MBZ selectively inhibited tumor angiogenesis but not the normal brain vasculatures in orthotopic medulloblastoma models and suppressed VEGFR2 kinase in vivo. MBZ significantly extended the survival of medulloblastoma models derived from different molecular backgrounds. Our findings support testing of MBZ as a possible low-toxicity therapy for medulloblastomas of various molecular subtypes, including tumors with acquired vismodegib resistance. Its antitumor mechanism may be partially explained by inhibition of tumor angiogenesis. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics.

Directory of Open Access Journals (Sweden)

Ehud Segal

Full Text Available There is an immense clinical need for novel therapeutics for the treatment of angiogenesis-dependent calcified neoplasms such as osteosarcomas and bone metastases. We developed a new therapeutic strategy to target bone metastases and calcified neoplasms using combined polymer-bound angiogenesis inhibitors. Using an advanced "living polymerization" technique, the reversible addition-fragmentation chain transfer (RAFT, we conjugated the aminobisphosphonate alendronate (ALN, and the potent anti-angiogenic agent TNP-470 with N-(2-hydroxypropylmethacrylamide (HPMA copolymer through a Glycine-Glycine-Proline-Norleucine linker, cleaved by cathepsin K, a cysteine protease overexpressed at resorption sites in bone tissues. In this approach, dual targeting is achieved. Passive accumulation is possible due to the increase in molecular weight following polymer conjugation of the drugs, thus extravasating from the tumor leaky vessels and not from normal healthy vessels. Active targeting to the calcified tissues is achieved by ALN's affinity to bone mineral.The anti-angiogenic and antitumor potency of HPMA copolymer-ALN-TNP-470 conjugate was evaluated both in vitro and in vivo. We show that free and conjugated ALN-TNP-470 have synergistic anti-angiogenic and antitumor activity by inhibiting proliferation, migration and capillary-like tube formation of endothelial and human osteosarcoma cells in vitro. Evaluation of anti-angiogenic, antitumor activity and body distribution of HPMA copolymer-ALN-TNP-470 conjugate was performed on severe combined immunodeficiency (SCID male mice inoculated with mCherry-labeled MG-63-Ras human osteosarcoma and by modified Miles permeability assay. Our targeted bi-specific conjugate reduced VEGF-induced vascular hyperpermeability by 92% and remarkably inhibited osteosarcoma growth in mice by 96%.This is the first report to describe a new concept of a narrowly-dispersed combined polymer therapeutic designed to target both tumor and

Molecular targeting of angiogenesis for imaging and therapy

International Nuclear Information System (INIS)

Brack, Simon S.; Neri, Dario; Dinkelborg, Ludger M.

2004-01-01

Angiogenesis, i.e. the proliferation of new blood vessels from pre-existing ones, is an underlying process in many human diseases, including cancer, blinding ocular disorders and rheumatoid arthritis. The ability to selectively target and interfere with neovascularisation would potentially be useful in the diagnosis and treatment of angiogenesis-related diseases. This review presents the authors' views on some of the most relevant markers of angiogenesis described to date, as well as on specific ligands which have been characterised in pre-clinical animal models and/or clinical studies. Furthermore, we present an overview on technologies which are likely to have an impact on the way molecular targeting of angiogenesis is performed in the future. (orig.)

N-methyl-N-nitro-N-nitrosoguanidine-mediated ING4 downregulation contributed to the angiogenesis of transformed human gastric epithelial cells.

Science.gov (United States)

Chen, Yansu; Fu, Rui; Xu, Mengdie; Huang, Yefei; Sun, Guixiang; Xu, Lichun

2018-04-15

Angiogenesis is associated with the progression and mortality of gastric cancer. Epidemiological evidences indicate that long-term N-nitroso compounds (NOCs) exposure predominantly contributes to the mortality of gastric cancer. Therefore, further reduced mortality of gastric cancer demands to explore the exact mechanisms of NOCs induced angiogenesis. As a tumor suppressor gene, inhibitor of growth protein 4 (ING4) plays an important role in pathological angiogenesis. In this study, we will investigate ING4 expression level in human gastric epithelial cells after the long-term low dose exposure of N-methyl-N-nitro-N-nitrosoguanidine (MNNG) and the pathological impact of MNNG-reduced ING4 on angiogenesis of transformed cells. The soft agar colony formation assay, Western blotting, immunofluorescence and wound healing assay were used to evaluate the characteristics of transformed cells. HUVEC growth and tube formation assays were performed to test the angiogenic abilities. EMSA, luciferase reporter gene assay, real-time PCR and Western blotting were used to explore the exact mechanism. By establishing transformed human gastric epithelial cells via chronic low dose treatment, a gradually ING4 downregulation was observed in the later-stage of MNNG-induced cell transformation. Moreover, we demonstrated that MNNG exposure-reduced ING4 expression significantly resulted into aggravating angiogenesis through increasing the phosphorylation level of NF-κB p65 and subsequently DAN binding activity and regulating the expressions of NF-κB p65 downstream pro-angiogenic genes, MMP-2 and MMP-9. Our findings provided a significant mechanistic insight into angiogenesis of MNNG-transformed human gastric epithelial cell and supported the concept that ING4 may be a relevant therapeutic target for gastric cancer. Copyright © 2018 Elsevier Inc. All rights reserved.

CS5931, a Novel Polypeptide in Ciona savignyi, Represses Angiogenesis via Inhibiting Vascular Endothelial Growth Factor (VEGF and Matrix Metalloproteinases (MMPs

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Ge Liu

2014-03-01

Full Text Available CS5931 is a novel polypeptide from Ciona savignyi with anticancer activities. Previous study in our laboratory has shown that CS5931 can induce cell death via mitochondrial apoptotic pathway. In the present study, we found that the polypeptide could inhibit angiogenesis both in vitro and in vivo. CS5931 inhibited the proliferation, migration and formation of capillary-like structures of HUVECs (Human Umbilical Vein Endothelial Cell in a dose-dependent manner. Additionally, CS5931 repressed spontaneous angiogenesis of the zebrafish vessels. Further studies showed that CS5931 also blocked vascular endothelial growth factor (VEGF production but without any effect on its mRNA expression. Moreover, CS5931 reduced the expression of matrix metalloproteinases (MMP-2 and MMP-9 both on protein and mRNA levels in HUVEC cells. We demonstrated that CS5931 possessed strong anti-angiogenic activity both in vitro and in vivo, possible via VEGF and MMPs. This study indicates that CS5931 has the potential to be developed as a novel therapeutic agent as an inhibitor of angiogenesis for the treatment of cancer.

COX-2, VEGF and tumour angiogenesis.

LENUS (Irish Health Repository)

Toomey, D P

2009-06-01

Epidemiological evidence suggests a protective effective of regular NSAID use against developing cancer. Cyclooxygenase-2, a target of NSAIDs, is upregulated in many cancers and has been associated with increased VEGF production and angiogenesis. Angiogenesis is the formation of new vessels from existing vasculature and as an essential process for tumour development represents an important therapeutic target. Following an extensive review of the literature this article details the current knowledge on the role of COX-2 in tumorigenesis focusing on its relationship to angiogenesis and VEGF production by tumour cells. While COX-2 is clearly detrimental to prognosis and NSAIDs have a beneficial effect, the possibility of COX-2 independent effects being partly or wholly responsible for this benefit cannot be excluded.

Effect of paricalcitol and GcMAF on angiogenesis and human peripheral blood mononuclear cell proliferation and signaling.

Science.gov (United States)

Pacini, Stefania; Morucci, Gabriele; Punzi, Tiziana; Gulisano, Massimo; Ruggiero, Marco; Amato, Marcello; Aterini, Stefano

2012-01-01

In addition to its role in calcium homeostasis and bone mineralization, vitamin D is involved in immune defence, cardiovascular function, inflammation and angiogenesis, and these pleiotropic effects are of interested in the treatment of chronic kidney disease. Here we investigated the effects of paricalcitol, a nonhypercalcemic vitamin D analogue, on human peripheral blood mononuclear cell proliferation and signaling, and on angiogenesis. These effects were compared with those of a known inhibitor of angiogenesis pertaining to the vitamin D axis, the vitamin D-binding protein-derived Gc-macrophage activating factor (GcMAF). Since the effects of vitamin D receptor agonists are associated with polymorphisms of the gene coding for the receptor, we measured the effects of both compounds on mononuclear cells harvested from subjects harboring different BsmI polymorphisms. Paricalcitol inhibited mononuclear cell viability with the bb genotype showing the highest effect. GcMAF, on the contrary, stimulated cell proliferation, with the bb genotype showing the highest stimulatory effect. Both compounds stimulated 3'-5'-cyclic adenosine monophosphate formation in mononuclear cells with the highest effect on the bb genotype. Paricalcitol and GcMAF inhibited the angiogenesis induced by proinflammatory prostaglandin E1. Polymorphisms of the vitamin D receptor gene, known to be associated with the highest responses to vitamin D receptor agonists, are also associated with the highest responses to GcMAF. These results highlight the role of the vitamin D axis in chronic kidney disease, an axis which includes vitamin D, its receptor and vitamin D-binding protein-derived GcMAF.

Diet-derived polyphenols inhibit angiogenesis by modulating the interleukin-6/STAT3 pathway

International Nuclear Information System (INIS)

Lamy, Sylvie; Akla, Naoufal; Ouanouki, Amira; Lord-Dufour, Simon; Béliveau, Richard

2012-01-01

Several epidemiological studies have indicated that abundant consumption of foods from plant origin is associated with a reduced risk of developing several types of cancers. This chemopreventive effect is related to the high content of these foods in phytochemicals, such as polyphenols, that interfere with several processes involved in cancer progression including tumor cell growth, survival and angiogenesis. In addition to the low intake of plant-based foods, increased body mass and physical inactivity have recently emerged as other important lifestyle factors influencing cancer risk, leading to the generation of low-grade chronic inflammatory conditions which are a key process involved in tumor progression. The objectives of the current study are to investigate the inhibitory effects of these polyphenols on angiogenesis triggered by an inflammatory cytokine (IL-6) and to determine the mechanisms underlying this action. We found that, among the tested polyphenols, apigenin and luteolin were the most potent angiogenesis inhibitors through their inhibitory effect on the inflammatory cytokine IL-6/STAT3 pathway. These effects resulted in modulation of the activation of extracellular signal-regulated kinase-1/2 signaling triggered by IL-6, as well as in a marked reduction in the proliferation, migration and morphogenic differentiation of endothelial cells. Interestingly, these polyphenols also modulated the expression of IL-6 signal transducing receptor (IL-6Rα) and the secretion of the extracellular matrix degrading enzyme MMP-2 as well as the expression of suppressor of cytokine signaling (SOCS3) protein. Overall, these results may provide important new information on the role of diet in cancer prevention.

Diet-derived polyphenols inhibit angiogenesis by modulating the interleukin-6/STAT3 pathway

Energy Technology Data Exchange (ETDEWEB)

Lamy, Sylvie; Akla, Naoufal; Ouanouki, Amira; Lord-Dufour, Simon; Beliveau, Richard, E-mail: oncomol@nobel.si.uqam.ca

2012-08-01

Several epidemiological studies have indicated that abundant consumption of foods from plant origin is associated with a reduced risk of developing several types of cancers. This chemopreventive effect is related to the high content of these foods in phytochemicals, such as polyphenols, that interfere with several processes involved in cancer progression including tumor cell growth, survival and angiogenesis. In addition to the low intake of plant-based foods, increased body mass and physical inactivity have recently emerged as other important lifestyle factors influencing cancer risk, leading to the generation of low-grade chronic inflammatory conditions which are a key process involved in tumor progression. The objectives of the current study are to investigate the inhibitory effects of these polyphenols on angiogenesis triggered by an inflammatory cytokine (IL-6) and to determine the mechanisms underlying this action. We found that, among the tested polyphenols, apigenin and luteolin were the most potent angiogenesis inhibitors through their inhibitory effect on the inflammatory cytokine IL-6/STAT3 pathway. These effects resulted in modulation of the activation of extracellular signal-regulated kinase-1/2 signaling triggered by IL-6, as well as in a marked reduction in the proliferation, migration and morphogenic differentiation of endothelial cells. Interestingly, these polyphenols also modulated the expression of IL-6 signal transducing receptor (IL-6R{alpha}) and the secretion of the extracellular matrix degrading enzyme MMP-2 as well as the expression of suppressor of cytokine signaling (SOCS3) protein. Overall, these results may provide important new information on the role of diet in cancer prevention.

Human trophoblast-derived hydrogen sulfide stimulates placental artery endothelial cell angiogenesis.

Science.gov (United States)

Chen, Dong-Bao; Feng, Lin; Hodges, Jennifer K; Lechuga, Thomas J; Zhang, Honghai

2017-09-01

Endogenous hydrogen sulfide (H2S), mainly synthesized by cystathionine β-synthase (CBS) and cystathionine γ-lyase (CTH), has been implicated in regulating placental angiogenesis; however, the underlying mechanisms are unknown. This study was to test a hypothesis that trophoblasts synthesize H2S to promote placental angiogenesis. Human choriocarcinoma-derived BeWo cells expressed both CBS and CTH proteins, while the first trimester villous trophoblast-originated HTR-8/SVneo cells expressed CTH protein only. The H2S producing ability of BeWo cells was significantly inhibited by either inhibitors of CBS (carboxymethyl hydroxylamine hemihydrochloride, CHH) or CTH (β-cyano-L-alanine, BCA) and that in HTR-8/SVneo cells was inhibited by CHH only. H2S donors stimulated cell proliferation, migration, and tube formation in ovine placental artery endothelial cells (oFPAECs) as effectively as vascular endothelial growth factor. Co-culture with BeWo and HTR-8/SVneo cells stimulated oFPAEC migration, which was inhibited by CHH or BCA in BeWo but CHH only in HTR-8/SVneo cells. Primary human villous trophoblasts (HVT) were more potent than trophoblast cell lines in stimulating oFPAEC migration that was inhibited by CHH and CHH/BCA combination in accordance with its H2S synthesizing activity linked to CBS and CTH expression patterns. H2S donors activated endothelial nitric oxide synthase (NOS3), v-AKT murine thymoma viral oncogene homolog 1 (AKT1), and extracellular signal-activated kinase 1/2 (mitogen-activated protein kinase 3/1, MAPK3/1) in oFPAECs. H2S donor-induced NOS3 activation was blocked by AKT1 but not MAPK3/1 inhibition. In keeping with our previous studies showing a crucial role of AKT1, MAPK3/1, and NOS3/NO in placental angiogenesis, these data show that trophoblast-derived endogenous H2S stimulates placental angiogenesis, involving activation of AKT1, NOS3/NO, and MAPK3/1. © The Authors 2017. Published by Oxford University Press on behalf of Society for the Study

Heritability of circulating growth factors involved in the angiogenesis in healthy human population.

Science.gov (United States)

Pantsulaia, I; Trofimov, S; Kobyliansky, E; Livshits, G

2004-09-21

The present study examined the extent of genetic and environmental influences on the populational variation of circulating growth factors (VEGF, EGF) involved in angiogenesis in healthy and ethnically homogeneous Caucasian families. The plasma levels of each of the studied biochemical indices were determined by enzyme-linked immunoassay in 478 healthy individuals aged 18-75 years. Quantitative genetic analysis showed that the VEGF and EGF variation was appreciably attributable to genetic effects, with heritability estimates of 79.9% and 48.4%, respectively. Yet, common environmental factors, shared by members of the same household, also played a significant role (P growth factor-beta 1 (TGF-beta 1) or tissue inhibitors of matrix metalloproteinases 1 (TIMP-1), likewise relevant for angiogenesis. Bivariate analysis revealed significant phenotypic correlations (P < 0.002) between all pairs of variables, thus indicating the possible existence of common genetic and environmental factors. The analysis suggested that the pleiotropic genetic effects were consistently the primary (or even the sole) source of correlation between all pairs of studied molecules. The results of our study affirm the existence of specific and common genetic pathways that commonly determine the greater part of the circulating variation of these molecules.

Transcriptional changes associated with resistance to inhibitors of epidermal growth factor receptor revealed using metaanalysis

International Nuclear Information System (INIS)

Younis, Sidra; Javed, Qamar; Blumenberg, Miroslav

2015-01-01

EGFR is important in maintaining metabolic homeostasis in healthy cells, but in tumors it activates downstream signaling pathways, causing proliferation, angiogenesis, invasion and metastasis. Consequently, EGFR is targeted in cancers using reversible, irreversible or antibody inhibitors. Unfortunately, tumors develop inhibitor resistance by mutations or overexpressing EGFR, or its ligand, or activating secondary, EGFR-independent pathways. Here we present a global metaanalysis comparing transcriptional profiles from matched pairs of EGFR inhibitor-sensitive vs. -resistant cell lines, using 15 datasets comprising 274 microarrays. We also analyzed separately pairs of cell lines derived using reversible, irreversible or antibody inhibitors. The metaanalysis identifies commonalities in cell lines resistant to EGFR inhibitors: in sensitive cell lines, the ontological categories involving the ErbB receptors pathways, cell adhesion and lipid metabolism are overexpressed; however, resistance to EGFR inhibitors is associated with overexpression of genes for ErbB receptors-independent oncogenic pathways, regulation of cell motility, energy metabolism, immunity especially inflammatory cytokines biosynthesis, cell cycle and responses to exogenous and endogenous stimuli. Specifically in Gefitinib-resistant cell lines, the immunity-associated genes are overexpressed, whereas in Erlotinib-resistant ones so are the mitochondrial genes and processes. Unexpectedly, lines selected using EGFR-targeting antibodies overexpress different gene ontologies from ones selected using kinase inhibitors. Specifically, they have reduced expression of genes for proliferation, chemotaxis, immunity and angiogenesis. This metaanalysis suggests that ‘combination therapies’ can improve cancer treatment outcomes. Potentially, use of mitochondrial blockers with Erlotinib, immunity blockers with Gefitinib, tyrosine kinase inhibitors with antibody inhibitors, may have better chance of avoiding

Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer

DEFF Research Database (Denmark)

Chang, Joan; Lucas, Morghan C; Leonte, Lidia Elena

2017-01-01

inhibitor in the MDA-MB-231 human model of breast cancer. We confirmed a functional role for LOXL2 activity in the progression of primary breast cancer. Inhibition of LOXL2 activity inhibited the growth of primary tumors and reduced primary tumor angiogenesis. Dual inhibition of LOXL2 and LOX showed...... a greater effect and also led to a lower overall metastatic burden in the lung and liver. Our data provides the first evidence to support a role for LOXL2 specific small molecule inhibitors as a potential therapy in breast cancer....

Oxidized LDL-induced angiogenesis involves sphingosine 1-phosphate: prevention by anti-S1P antibody.

Science.gov (United States)

Camaré, Caroline; Trayssac, Magali; Garmy-Susini, Barbara; Mucher, Elodie; Sabbadini, Roger; Salvayre, Robert; Negre-Salvayre, Anne

2015-01-01

Neovascularization occurring in atherosclerotic lesions may promote plaque expansion, intraplaque haemorrhage and rupture. Oxidized LDL (oxLDL) are atherogenic, but their angiogenic effect is controversial; both angiogenic and anti-angiogenic effects have been reported. The angiogenic mechanism of oxLDL is partly understood, but the role of the angiogenic sphingolipid, sphingosine 1-phosphate (S1P), in this process is not known. Thus, we investigated whether S1P is involved in the oxLDL-induced angiogenesis and whether an anti-S1P monoclonal antibody can prevent this effect. Angiogenesis was assessed by capillary tube formation by human microvascular endothelial cells (HMEC-1) cultured on Matrigel and in vivo by the Matrigel plug assay in C57BL/6 mice. Human oxLDL exhibited a biphasic angiogenic effect on HMEC-1; low concentrations were angiogenic, higher concentrations were cytotoxic. The angiogenic response to oxLDL was blocked by the sphingosine kinase (SPHK) inhibitor, dimethylsphingosine, by SPHK1-siRNA and by an anti-S1P monoclonal antibody. Moreover, inhibition of oxLDL uptake and subsequent redox signalling by anti-CD36 and anti-LOX-1 receptor antibodies and by N-acetylcysteine, respectively, blocked SPHK1 activation and tube formation. In vivo, in the Matrigel plug assay, low concentrations of human oxLDL or murine oxVLDL also triggered angiogenesis, which was prevented by i.p. injection of the anti-S1P antibody. These data highlight the role of S1P in angiogenesis induced by oxLDL both in HMEC-1 cultured on Matrigel and in vivo in the Matrigel plug model in mice, and demonstrate that the anti-S1P antibody effectively blocks the angiogenic effect of oxLDL. © 2014 The British Pharmacological Society.

The controversial origin of pericytes during angiogenesis - Implications for cell-based therapeutic angiogenesis and cell-based therapies.

Science.gov (United States)

Blocki, Anna; Beyer, Sebastian; Jung, Friedrich; Raghunath, Michael

2018-01-01

Pericytes reside within the basement membrane of small vessels and are often in direct cellular contact with endothelial cells, fulfilling important functions during blood vessel formation and homeostasis. Recently, these pericytes have been also identified as mesenchymal stem cells. Mesenchymal stem cells, and especially their specialized subpopulation of pericytes, represent promising candidates for therapeutic angiogenesis applications, and have already been widely applied in pre-clinical and clinical trials. However, cell-based therapies of ischemic diseases (especially of myocardial infarction) have not resulted in significant long-term improvement. Interestingly, pericytes from a hematopoietic origin were observed in embryonic skin and a pericyte sub-population expressing leukocyte and monocyte markers was described during adult angiogenesis in vivo. Since mesenchymal stem cells do not express hematopoietic markers, the latter cell type might represent an alternative pericyte population relevant to angiogenesis. Therefore, we sourced blood-derived angiogenic cells (BDACs) from monocytes that closely resembled hematopoietic pericytes, which had only been observed in vivo thus far. BDACs displayed many pericytic features and exhibited enhanced revascularization and functional tissue regeneration in a pre-clinical model of critical limb ischemia. Comparison between BDACs and mesenchymal pericytes indicated that BDACs (while resembling hematopoietic pericytes) enhanced early stages of angiogenesis, such as endothelial cell sprouting. In contrast, mesenchymal pericytes were responsible for blood vessel maturation and homeostasis, while reducing endothelial sprouting.Since the formation of new blood vessels is crucial during therapeutic angiogenesis or during integration of implants into the host tissue, hematopoietic pericytes (and therefore BDACs) might offer an advantageous addition or even an alternative for cell-based therapies.

Diversity of radioprobes targeted to tumor angiogenesis on molecular functional imaging

International Nuclear Information System (INIS)

Lu Xia; Zhang Huabei

2013-01-01

Molecular functional imaging could visualize, characterize, and measure the bio- logical processes including tumor angiogenesis at the molecular and cellular levels in humans and other living systems. The molecular probes labeled by a variety of radionuclide used in the field of the nuclear medicine play pivotal roles in molecular imaging of tumor angiogenesis. However, the regulatory role of different probes in tumor angiogenesis has not been systematically illustrated. The current status of tumor angiogenesis imaging with radiolabeled probes of peptide, monoclonal antibody as well as its fragment, especially nanoparticle-based probes to gain insights into the robust tumor angiogenesis development were summarized. It was recognized that only the probes such as nanoparticle-based probes, which truly target the tumor vasculature rather than tumor cells because of poor extravasation, are really tumor angiogenesis imaging agent. The research of molecular probe targeted to angiogenesis would meet its flourish just after the outstanding improvements in the in vivo stability and biocompatibility, tumor-targeting efficacy, and pharmacokinetics of tumor angiogenesis imaging probes are made. Translation to clinical applications will also be critical for the maximize benefits of these novel agents. The future of tumor angiogenesis imaging lies in liable imaging probes and multiple imaging modalities, imaging of protein-protein interactions, and quantitative molecular imaging. (authors)

Fascin 1 is dispensable for developmental and tumour angiogenesis

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Yafeng Ma

2013-09-01

The actin bundling protein fascin 1 is not expressed in adult epithelial tissues, but during development it is transiently expressed in many different cell types, and later in adults it is expressed in a subset of immune cells, nervous tissues, endothelial cells, smooth muscle cells and pericytes. In contrast to the wealth of knowledge about the role of fascin 1 in cancer cell migration and invasion, little is known about the involvement of fascin 1 in angiogenesis. We speculated that as angiogenesis involves migration and invasion of tissues by endothelial cells, fascin 1 might have a role in both normal and tumour angiogenesis. Here, we provide evidence that loss of fascin 1 causes relatively minor reductions to angiogenesis during embryonic, postnatal and cancerous development by examining E12.5 hindbrains, postnatal retinas and B16F0 tumour cell allografts in fascin 1-null mice. We also find that in fascin 1 null tissues, endothelial cells display reduced filopodia formation during sprouting. We thus propose that fascin 1 expression promotes angiogenesis via filopodia formation, but is largely dispensable for both normal and tumour angiogenesis.

HDAC inhibitors: modulating leukocyte differentiation, survival, proliferation and inflammation.

Science.gov (United States)

Sweet, Matthew J; Shakespear, Melanie R; Kamal, Nabilah A; Fairlie, David P

2012-01-01

Therapeutic effects of histone deacetylase (HDAC) inhibitors in cancer models were first linked to their ability to cause growth arrest and apoptosis of tumor cells. It is now clear that these agents also have pleiotropic effects on angiogenesis and the immune system, and some of these properties are likely to contribute to their anti-cancer activities. It is also emerging that inhibitors of specific HDACs affect the differentiation, survival and/or proliferation of distinct immune cell populations. This is true for innate immune cells such as macrophages, as well as cells of the acquired immune system, for example, T-regulatory cells. These effects may contribute to therapeutic profiles in some autoimmune and chronic inflammatory disease models. Here, we review our current understanding of how classical HDACs (HDACs 1-11) and their inhibitors impact on differentiation, survival and proliferation of distinct leukocyte populations, as well as the likely relevance of these effects to autoimmune and inflammatory disease processes. The ability of HDAC inhibitors to modulate leukocyte survival may have implications for the rationale of developing selective inhibitors as anti-inflammatory drugs.

Angiogenesis Inhibitors

Science.gov (United States)

... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... as vascular endothelial growth factor (VEGF) , bind to receptors on the surface of normal endothelial cells. When ...

Intra-laboratory validation of a human cell based in vitro angiogenesis assay for testing angiogenesis modulators

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Jertta-Riina Sarkanen

2011-01-01

Full Text Available The developed standardized human cell based in vitro angiogenesis assay was intra-laboratory validated to verify that the method is reliable and relevant for routine testing of modulators of angiogenesis e.g. pharmaceuticals and industrial chemicals. This assay is based on the earlier published method but it was improved and shown to be more sensitive and rapid than the previous assay. The performance of the assay was assessed by using 6 reference chemicals, which are widely used pharmaceuticals that inhibit angiogenesis: acetyl salicylic acid, erlotinib, 2-methoxyestradiol, levamisole, thalidomide, and anti-vascular endothelial growth factor. In the intra-laboratory validation, the sensitivity of the assay (upper and lower limits of detection and linearity of response in tubule formation, batch to batch variation in tubule formation between different Master cell bank batches, and precision as well as the reliability of the assay (reproducibility and repeatability were tested. The pre-set acceptance criteria for the intra-laboratory validation study were met. The relevance of the assay in man was investigated by comparing the effects of reference chemicals and their concentrations to the published human data. The comparison showed a good concordance, which indicates that this human cell based angiogenesis model predicts well the effects in man and has the potential to be used to supplement and/or replace of animal tests.

Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

Science.gov (United States)

Zeng, Yi; Zhang, Le; Hu, Zhiping

2016-01-01

Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

Vasculogenesis and Angiogenesis: Molecular and Cellular Controls

Science.gov (United States)

Kubis, N.; Levy, B.I.

2003-01-01

Summary Angiogenesis characterizes embryonic development, but also occurs in adulthood in physiological situations such as adaptation to muscle exercise, and in pathological conditions like cancer. Major advances have been made in understanding the molecular mechanisms responsible for vasculogenesis and angiogenesis, largely due to the use of “knock-out mice”, i.e. mice in which the gene coding for the protein under investigation has been inactivated. Interestingly, the same growth factors and their receptors are equally involved in the different aspects of vasculogenesis and angiogenesis during development and in adulthood. This review aims to describe in detail their respective roles and how interactions between them lead to a newly formed vessel. PMID:20591248

Diet-derived polyphenols inhibit angiogenesis by modulating the interleukin-6/STAT3 pathway.

Science.gov (United States)

Lamy, Sylvie; Akla, Naoufal; Ouanouki, Amira; Lord-Dufour, Simon; Béliveau, Richard

2012-08-01

Several epidemiological studies have indicated that abundant consumption of foods from plant origin is associated with a reduced risk of developing several types of cancers. This chemopreventive effect is related to the high content of these foods in phytochemicals, such as polyphenols, that interfere with several processes involved in cancer progression including tumor cell growth, survival and angiogenesis. In addition to the low intake of plant-based foods, increased body mass and physical inactivity have recently emerged as other important lifestyle factors influencing cancer risk, leading to the generation of low-grade chronic inflammatory conditions which are a key process involved in tumor progression. The objectives of the current study are to investigate the inhibitory effects of these polyphenols on angiogenesis triggered by an inflammatory cytokine (IL-6) and to determine the mechanisms underlying this action. We found that, among the tested polyphenols, apigenin and luteolin were the most potent angiogenesis inhibitors through their inhibitory effect on the inflammatory cytokine IL-6/STAT3 pathway. These effects resulted in modulation of the activation of extracellular signal-regulated kinase-1/2 signaling triggered by IL-6, as well as in a marked reduction in the proliferation, migration and morphogenic differentiation of endothelial cells. Interestingly, these polyphenols also modulated the expression of IL-6 signal transducing receptor (IL-6Rα) and the secretion of the extracellular matrix degrading enzyme MMP-2 as well as the expression of suppressor of cytokine signaling (SOCS3) protein. Overall, these results may provide important new information on the role of diet in cancer prevention. Copyright © 2012 Elsevier Inc. All rights reserved.

ARTERIAL HYPERTENSION DURING THERAPY OF ONCOLOGICAL DISEASES WITH ANGIOGENESIS INHIBITORS: SERIOUS IMPEDIMENT OR CONTROLLED REACTION?

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Zh. D. Kobalava

2017-01-01

Full Text Available Vascular endothelial growth factor signaling pathway (VSP inhibitors are drugs for which arterial hypertension (AH is a class effect, occurring with a frequency of up to 73 % of treated patients. Blockade of vascular endothelial growth factor or its receptor is accompanied by inhibition of the synthesis of nitric oxide, which is considered a major pathogenic mechanism for the development of AH. VSP-inhibitors therapy will be as safe as possible, if the patient prior to treatment will take a minimum assessment, allowing to identify the category of patients with high/very high cardiovascular risk. Risk evaluation is necessary not to abandon an effective therapy of VSP-inhibitors, and to provide a systematic approach to reduce the likelihood of potential cardiovascular toxicity. Blood pressure during VSP-inhibitors therapy is characterized by a rapid rise after the first dose of target therapy, as a rule, in the first cycle of treatment, ranging from no increase to double the systolic blood pressure. Usually iatrogenic AH spontaneously resolves after stopping chemotherapy. Timely prescribed antihypertensive therapy help to avoids dose reduction or interruption of the course of VSP-inhibitors, which significantly improves the survival of patients.

Signaling and molecular basis of bone marrow niche angiogenesis in leukemia

NARCIS (Netherlands)

Shirzad, R.; Shahrabi, S.; Ahmadzadeh, A.; Kampen, K. R.; Shahjahani, M.; Saki, N.

2016-01-01

Angiogenesis, the process of blood vessel formation, is necessary for tissue survival in normal and pathologic conditions. Increased angiogenesis in BM niche is correlated with leukemia progression and resistance to treatment. Angiogenesis can interfere with disease progression and several

Angiogenesis and anti-angiogenesis: Perspectives for the treatment of solid tumors

NARCIS (Netherlands)

Hinsbergh, V.W.M. van; Collen, A.; Koolwijk, P.

1999-01-01

Angiogenesis is the formation of new blood vessels from preexisting ones. Many solid tumors depend on an extensive newly formed vascular network to become nourished and to expand. Tumor cells induce the formation of an extensive but aberrant vascular network by the secretion of angiogenic factors. A

Comparison of three rapamycin dosing schedules in A/J Tsc2+/- mice and improved survival with angiogenesis inhibitor or asparaginase treatment in mice with subcutaneous tuberous sclerosis related tumors

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Dabora Sandra L

2010-02-01

Full Text Available Abstract Background Tuberous Sclerosis Complex (TSC is an autosomal dominant tumor disorder characterized by the growth of hamartomas in various organs including the kidney, brain, skin, lungs, and heart. Rapamycin has been shown to reduce the size of kidney angiomyolipomas associated with TSC; however, tumor regression is incomplete and kidney angiomyolipomas regrow after cessation of treatment. Mouse models of TSC2 related tumors are useful for evaluating new approaches to drug therapy for TSC. Methods In cohorts of Tsc2+/- mice, we compared kidney cystadenoma severity in A/J and C57BL/6 mouse strains at both 9 and 12 months of age. We also investigated age related kidney tumor progression and compared three different rapamycin treatment schedules in cohorts of A/J Tsc2+/- mice. In addition, we used nude mice bearing Tsc2-/- subcutaneous tumors to evaluate the therapeutic utility of sunitinib, bevacizumab, vincristine, and asparaginase. Results TSC related kidney disease severity is 5-10 fold higher in A/J Tsc2+/- mice compared with C57BL/6 Tsc2+/- mice. Similar to kidney angiomyolipomas associated with TSC, the severity of kidney cystadenomas increases with age in A/J Tsc2+/- mice. When rapamycin dosing schedules were compared in A/J Tsc2+/- cohorts, we observed a 66% reduction in kidney tumor burden in mice treated daily for 4 weeks, an 82% reduction in mice treated daily for 4 weeks followed by weekly for 8 weeks, and an 81% reduction in mice treated weekly for 12 weeks. In the Tsc2-/- subcutaneous tumor mouse model, vincristine is not effective, but angiogenesis inhibitors (sunitinib and bevacizumab and asparaginase are effective as single agents. However, these drugs are not as effective as rapamycin in that they increased median survival only by 24-27%, while rapamycin increased median survival by 173%. Conclusions Our results indicate that the A/J Tsc2+/- mouse model is an improved, higher through-put mouse model for future TSC

Adaptation in Response of Excitation and Inhibition Factors of Angiogenesis after 4 Weeks of Progressive Resistant Training in Sedentary Men

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s. Karami

2016-09-01

Full Text Available Aims: The sport activity is an important factor affecting the capillary density and angiogenesis. Nitric oxide (NO and vascular endothelial growth factor (VEGF are the most important stimulative regulators in the angiogenesis. In addition, endostatin is one of the inhibitors of angiogenesis. The aim of this study was to investigate the adaptation in the responses of the angiogenesis inhibition and stimulating factors after 4-week increasing resistive exercises in the sedentary men. Materials & Methods: In the semi-experimental study, 20 healthy and inactive male students, aged between 20 and 25 years, who were residents of Tehran University Dormitory, were studied in the first semester of the academic year 2015-16. The subjects, selected via available sampling method, were divided into two groups including experimental and control groups (n=10 per group. 4-week resistive exercises were done three sessions per week. Blood-sampling was done before and 48 hours after the last exercise session. VEGF, NO, and endostatin were then measured. Data was analyzed by SPSS 18 software using independent and dependent T tests, as well as Pearson correlation coefficient test. Findings: In experimental group, VEGF and No significantly increased at the posttest stage than the pretest (p=0.001. Nevertheless, no significant difference was observed in control group (p>0.05. In both experimental and control groups, endostatin level did not significantly increase at the posttest stage than the pretest (p>0.05. In addition, VEGF and NO were the only variables that were significantly correlated (p=0.016; r=0.82. Conclusion: 4-week increasing resistive exercises in the sedentary men significantly affect the angiogenes stimulating factors, i. e. VEGF and NO, while such exercises do not significantly affect the angiogenesis inhibition factor, i. e. endostatin.

An angiotensin-converting enzyme inhibitor in the combination treatment of rheumatoid arthritis

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E. B. Komarova

2017-01-01

Full Text Available Angiotensin-converting enzyme (ACE inhibitors have anti-inflammatory and antiproliferative properties and can affect the processes of angiogenesis, by reducing the effects of angiotensin II (ATII. The use of ACE inhibitors in the combination therapy of rheumatoid arthritis (RA can be also effective for monitoring disease activity and for reducing a cardiovascular risk.Objective: to evaluate the efficacy of an ACE inhibitor in the combination therapy of RA.Patients and methods. Eighty-four patients with RA and endothelial dysfunction were examined; the mean age was 40.12±10.2 years; the mean disease duration was 4.22±3.43 years. All the patients had a blood level of ATII of >9 pg/ml. Enzyme immunoassay was used to measure the levels of tumor necrosis factor-α (TNF-α (Vector-Best, Russia, intercellular adhesion molecules 1 (ICAM-1 (Diaclone, France, vascular endothelial growth factor (VEGF and ATII (Diagnostic, Canada. Wrist ultrasonography using the Doppler ultrasound apparatus ESAOTE MyLAB40 was carried out to assess synovial vascularization. The patients were divided into two groups. Group 1 included 43 patients who were assigned to receive standard therapy for RA according to the rheumatic disease treatment protocols; Group 2 comprised 41 patients who received the standard therapy plus ACE inhibitors 2.5–5 mg/day.Results. The use of ACE inhibitors in the 12-month combination therapy of RA patients led to an improvement in the endothelial regulation of vascular tone, to a decrease in the blood concentration of ICAM-1, to a reduction in the intensity of synovial angiogenesis and in the blood level of VEGF by 39%, and a more significant drop in the levels of CRP and TNF-? and in DAS28 by 1.2 scores as compared to those in the standard therapy.

Mesoscopic and continuum modelling of angiogenesis

KAUST Repository

Spill, F.; Guerrero, P.; Alarcon, T.; Maini, P. K.; Byrne, H. M.

2014-01-01

Angiogenesis is the formation of new blood vessels from pre-existing ones in response to chemical signals secreted by, for example, a wound or a tumour. In this paper, we propose a mesoscopic lattice-based model of angiogenesis, in which processes that include proliferation and cell movement are considered as stochastic events. By studying the dependence of the model on the lattice spacing and the number of cells involved, we are able to derive the deterministic continuum limit of our equations and compare it to similar existing models of angiogenesis. We further identify conditions under which the use of continuum models is justified, and others for which stochastic or discrete effects dominate. We also compare different stochastic models for the movement of endothelial tip cells which have the same macroscopic, deterministic behaviour, but lead to markedly different behaviour in terms of production of new vessel cells. © 2014 Springer-Verlag Berlin Heidelberg.

Mesoscopic and continuum modelling of angiogenesis

KAUST Repository

Spill, F.

2014-03-11

Angiogenesis is the formation of new blood vessels from pre-existing ones in response to chemical signals secreted by, for example, a wound or a tumour. In this paper, we propose a mesoscopic lattice-based model of angiogenesis, in which processes that include proliferation and cell movement are considered as stochastic events. By studying the dependence of the model on the lattice spacing and the number of cells involved, we are able to derive the deterministic continuum limit of our equations and compare it to similar existing models of angiogenesis. We further identify conditions under which the use of continuum models is justified, and others for which stochastic or discrete effects dominate. We also compare different stochastic models for the movement of endothelial tip cells which have the same macroscopic, deterministic behaviour, but lead to markedly different behaviour in terms of production of new vessel cells. © 2014 Springer-Verlag Berlin Heidelberg.

A Role for PPAR/ in Ocular Angiogenesis

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David Bishop-Bailey

2008-01-01

Full Text Available The uses of highly selective PPAR/ ligands and PPAR/ knockout mice have shown a direct ability of PPAR/ to regulate angiogenesis in vitro and in vivo in animal models. PPAR/ ligands induce the proangiogenic growth factor VEGF in many cells and tissues, though its actions in the eye are not known. However, virtually, all tissue components of the eye express PPAR/. Both angiogenesis and in particular VEGF are not only critical for the development of the retina, but they are also a central component in many common pathologies of the eye, including diabetic retinopathy and age-related macular degeneration, the most common causes of blindness in the Western world. This review, therefore, will discuss the recent evidence of PPAR/-mediated angiogenesis and VEGF release in the context of ocular disorders.

Pilot Evaluation of Angiogenesis Signaling Factor Response after Transcatheter Arterial Embolization for Hepatocellular Carcinoma.

Science.gov (United States)

Ronald, James; Nixon, Andrew B; Marin, Daniele; Gupta, Rajan T; Janas, Gemini; Chen, Willa; Suhocki, Paul V; Pabon-Ramos, Waleska; Sopko, David R; Starr, Mark D; Brady, John C; Hurwitz, Herbert I; Kim, Charles Y

2017-10-01

Purpose To identify changes in a broad panel of circulating angiogenesis factors after bland transcatheter arterial embolization (TAE), a purely ischemic treatment for hepatocellular carcinoma (HCC). Materials and Methods This prospective HIPAA-compliant study was approved by the institutional review board. Informed written consent was obtained from all participants prior to entry into the study. Twenty-five patients (21 men; mean age, 61 years; range, 30-81 years) with Liver Imaging Reporting and Data System category 5 or biopsy-proven HCC and who were undergoing TAE were enrolled from October 15, 2014, through December 2, 2015. Nineteen plasma angiogenesis factors (angiopoietin 2; hepatocyte growth factor; platelet-derived growth factor AA and BB; placental growth factor; vascular endothelial growth factor A and D; vascular endothelial growth factor receptor 1, 2, and 3; osteopontin; transforming growth factor β1 and β2; thrombospondin 2; intercellular adhesion molecule 1; interleukin 6 [IL-6]; stromal cell-derived factor 1; tissue inhibitor of metalloproteinases 1; and vascular cell adhesion molecule 1 [VCAM-1]) were measured by using enzyme-linked immunosorbent assays at 1 day, 2 weeks, and 5 weeks after TAE and were compared with baseline levels by using paired Wilcoxon tests. Tumor response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Angiogenesis factor levels were compared between responders and nonresponders by mRECIST criteria by using unpaired Wilcoxon tests. Results All procedures were technically successful with no complications. Fourteen angiogenesis factors showed statistically significant changes following TAE, but most changes were transient. IL-6 was upregulated only 1 day after the procedure, but showed the largest increases of any factor. Osteopontin and VCAM-1 demonstrated sustained upregulation at all time points following TAE. At 3-month follow-up imaging, 11 patients had responses to TAE

Mediators of ocular angiogenesis

Indian Academy of Sciences (India)

2016-08-26

Aug 26, 2016 ... Keywords. ocular angiogenesis; corneal neovascularization; retinal neovascularization; diabetic retinopathy; age-related macular degeneration; retinopathy of prematurity; VEGF; PEDF; Flt-1; Flk-1; endostatin; angiopoietin; erythropoietin; Tie2; inflammation; complement; gene therapy; TLR-3; Robo4.

High-grade ovarian cancer secreting effective exosomes in tumor angiogenesis.

Science.gov (United States)

Yi, Huan; Ye, Jun; Yang, Xiao-Mei; Zhang, Li-Wen; Zhang, Zhi-Gang; Chen, Ya-Ping

2015-01-01

Ovarian cancer, the most lethal gynecological cancer, related closely to tumor stage. High-grade ovarian cancer always results in a late diagnose and high recurrence, which reduce survival within five years. Until recently, curable therapy is still under research and anti-angiogenesis proves a promising way. Tumor-derived exosomes are essential in tumor migration and metastases such as angiogenesis is enhanced by exosomes. In our study, we have made comparison between high-grade and unlikely high-grade serous ovarian cancer cells on exosomal function of endothelial cells proliferation, migration and tube formation. Exosomes derived from high-grade ovarian cancer have a profound impact on angiogenesis with comparison to unlikely high-grade ovarian cancer. Proteomic profiles revealed some potential proteins involved in exosomal function of angiogenesis such as ATF2, MTA1, ROCK1/2 and so on. Therefore, exosomes plays an influential role in angiogenesis in ovarian serous cancer and also function more effectively in high-grade ovarian cancer cells.

Angiogenesis-Related Pathways in the Pathogenesis of Ovarian Cancer

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Aristotle Bamias

2013-07-01

Full Text Available Ovarian Cancer represents the most fatal type of gynecological malignancies. A number of processes are involved in the pathogenesis of ovarian cancer, especially within the tumor microenvironment. Angiogenesis represents a hallmark phenomenon in cancer, and it is responsible for tumor spread and metastasis in ovarian cancer, among other tumor types, as it leads to new blood vessel formation. In recent years angiogenesis has been given considerable attention in order to identify targets for developing effective anti-tumor therapies. Growth factors have been identified to play key roles in driving angiogenesis and, thus, the formation of new blood vessels that assist in “feeding” cancer. Such molecules include the vascular endothelial growth factor (VEGF, the platelet derived growth factor (PDGF, the fibroblast growth factor (FGF, and the angiopoietin/Tie2 receptor complex. These proteins are key players in complex molecular pathways within the tumor cell and they have been in the spotlight of the development of anti-angiogenic molecules that may act as stand-alone therapeutics, or in concert with standard treatment regimes such as chemotherapy. The pathways involved in angiogenesis and molecules that have been developed in order to combat angiogenesis are described in this paper.

The role of cyclooxygenase-2 in the malignant tissue and possible applicability of cyclooxygenase-2 inhibitors in the therapy of cancer

International Nuclear Information System (INIS)

Legan, M.

2003-01-01

Cyclooxygenase-2 (COX-2), an inducible prostaglandin (PG) synthase, is elevated in many types of malignant and pre-malignant tissues. This enzyme is localized in neoplastic (epithelial) cells, microvascular endothelial cells, and stromal fibroblasts. Through the released PG it enhances carcinogenesis with increasing angiogenesis, inhibiting apoptosis, activating matrix metalloproteinases, suppressing of cell mediated antitumor immune response and protection against damage by cytotoxic agents. Evidences from in vitro studies, studies on animal models as well as first clinical outcomes suggest that the inhibition of COX-2 may suppress carcinogenesis by affecting a number of pathways: inhibiting angiogenesis, invasiveness of tumors and promoting apoptosis. References forecast that COX-2 inhibitors, mostly COX-2 selective inhibitors, may get a role in the therapy of cancer as an adjuvant therapy or as an co-chemotherapeutic agent. The purpose of the present article is to summarize the most important facts about the role of COX-2 in the malignant tissue and discuss possible ways for potential therapeutic place of COX-2 inhibitors in clinical practice. (author)

Oxalomalate reduces expression and secretion of vascular endothelial growth factor in the retinal pigment epithelium and inhibits angiogenesis: Implications for age-related macular degeneration

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Sung Hwan Kim

2016-12-01

Full Text Available Clinical and experimental observations indicate a critical role for vascular endothelial growth factor (VEGF, secreted by the retinal pigment epithelium (RPE, in pathological angiogenesis and the development of choroidal neovascularization (CNV in age-related macular degeneration (AMD. RPE-mediated VEGF expression, leading to angiogenesis, is a major signaling mechanism underlying ocular neovascular disease. Inhibiting this signaling pathway with a therapeutic molecule is a promising anti-angiogenic strategy to treat this disease with potentially fewer side effects. Oxalomalate (OMA is a competitive inhibitor of NADP+-dependent isocitrate dehydrogenase (IDH, which plays an important role in cellular signaling pathways regulated by reactive oxygen species (ROS. Here, we have investigated the inhibitory effect of OMA on the expression of VEGF, and the associated underlying mechanism of action, using in vitro and in vivo RPE cell models of AMD. We found that OMA reduced the expression and secretion of VEGF in RPE cells, and consequently inhibited CNV formation. This function of OMA was linked to its capacity to activate the pVHL-mediated HIF-1α degradation in these cells, partly via a ROS-dependent ATM signaling axis, through inhibition of IDH enzymes. These findings reveal a novel role for OMA in inhibiting RPE-derived VEGF expression and angiogenesis, and suggest unique therapeutic strategies for treating pathological angiogenesis and AMD development.

Angiogenesis in vestibular schwannomas

DEFF Research Database (Denmark)

Møller, Martin Nue; Werther, Kim; Nalla, Amarnadh

2010-01-01

Vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMPs) are potent mediators of tumor angiogenesis. It has been demonstrated that vestibular schwannoma VEGF expression correlates with tumor growth pattern, whereas knowledge on the expression of MMPs is lacking. This study...

Human embryo-conditioned medium stimulates in vitro endometrial angiogenesis

NARCIS (Netherlands)

Kapiteijn, K.; Koolwijk, P.; Weiden, R.M.F. van der; Nieuw Amerongen, G. van; Plaisier, M.; Hinsbergh, V.W.M. van; Helmerhorst, F.M.

2006-01-01

Objective: Successful implantation and placentation depend on the interaction between the endometrium and the embryo. Angiogenesis is crucial at this time. In this article we investigate the direct influence of the human embryo on in vitro endometrial angiogenesis. Design: In vitro study. Setting:

The vascular permeabilizing factors histamine and serotonin induce angiogenesis through TR3/Nur77 and subsequently truncate it through thrombospondin-1

Science.gov (United States)

Qin, Liuliang; Zhao, Dezheng; Xu, Jianfeng; Ren, Xianghui; Terwilliger, Ernest F.; Parangi, Sareh; Lawler, Jack; Dvorak, Harold F.

2013-01-01

Angiogenesis plays an important role in cancer and in many other human diseases. Vascular endothelial growth factor-A (VEGF-A), the best known angiogenic factor, was originally discovered as a potent vascular permeability factor (VPF), suggesting that other vascular permeabilizing agents, such as histamine and serotonin, might also have angiogenic activity. We recently demonstrated that, like VEGF-A, histamine and serotonin up-regulate the orphan nuclear receptor and transcription factor TR3 (mouse homolog Nur77) and that TR3/Nur77 is essential for their vascular permeabilizing activities. We now report that histamine and serotonin are also angiogenic factors that, at low micromolar concentrations, induce endothelial cell proliferation, migration and tube formation in vitro, and angiogenesis in vivo. All of these responses are mediated through specific histamine and serotonin receptors, are independent of VEGF-A, and are directly dependent on TR3/Nur77. Initially, the angiogenic response closely resembled that induced by VEGF-A, with generation of “mother” vessels. However, after ∼10 days, mother vessels began to regress as histamine and serotonin, unlike VEGF-A, up-regulated the potent angiogenesis inhibitor thrombospondin-1, thereby triggering a negative feedback loop. Thus, histamine and serotonin induce an angiogenic response that fits the time scale of acute inflammation. PMID:23315169

Evaluation of Functionalized Porous Titanium Implants for Enhancing Angiogenesis in Vitro

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Laura Roland

2016-04-01

Full Text Available Implant constructs supporting angiogenesis are favorable for treating critically-sized bone defects, as ingrowth of capillaries towards the center of large defects is often insufficient. Consequently, the insufficient nutritional supply of these regions leads to impaired bone healing. Implants with specially designed angiogenic supporting geometry and functionalized with proangiogenic cytokines can enhance angiogenesis. In this study, Vascular Endothelial Growth Factor (VEGF and High Mobility Group Box 1 (HMGB1 were used for incorporation into poly-ε-caprolactone (PCL-coated porous titanium implants. Bioactivity of released factors and influence on angiogenesis of functionalized implants were evaluated using a migration assay and angiogenesis assays. Both implants released angiogenic factors, inducing migration of endothelial cells. Also, VEGF-functionalized PCL-coated titanium implants enhanced angiogenesis in vitro. Both factors were rapidly released in high doses from the implant coating during the first 72 h.

Role of anti-angiogenesis therapy in the management of hepatocellular carcinoma: The jury is still out

Institute of Scientific and Technical Information of China (English)

Hong; Sun; Man-Sheng; Zhu; Wen-Rui; Wu; Xiang-De; Shi; Lei-Bo; Xu

2014-01-01

As the leading cause of disease-related deaths,cancer is a major public health threat worldwide.Surgical resection is still the first-line therapy for patients with early-stage cancers.However,postoperative relapse and metastasis remain the cause of 90%of deaths of patients with solid organ malignancies,including hepatocellular carcinoma(HCC).With the rapid development of molecular biology techniques in recent years,molecularly targeted therapies using monoclonal antibodies,small molecules,and vaccines have become a milestone in cancer therapeutic by significantly improv-ing the survival of cancer patients,and have opened a window of hope for patients with advanced cancer.Hypervascularization is a major characteristic of HCC.It has been reported that anti-angiogenic treatments,which inhibit blood vessel formation,are highly effective for treating HCC.However,the efficacy and safety of anti-angiogenesis therapies remain controversial.Sorafenib is an oral multikinase inhibitor with antiproliferative and anti-angiogenic effects and is the first molecular target drug approved for the treatment of advanced HCC.While sorafenib has shown promising therapeutic effects,substantial evidence of primary and acquired resistance to sorafenib has been reported.Numerous clinical trials have been conducted to evaluate a large number of molecularly targeted drugs for treating HCC,but most drugs exhibited less efficacy and/or higher toxicity compared to sorafenib.Therefore,understanding the mechanism(s)underlying sorafenib resistance of cancer cells is highlighted for efficiently treating HCC.This concise review aims to provide an overview of anti-angiogenesis therapy in the management of HCC and to discuss the common mechanisms of resistance to anti-angiogenesis therapies.

Design and synthesis of imidazopyridine analogues as inhibitors of phosphoinositide 3-kinase signaling and angiogenesis.

Science.gov (United States)

Kim, Okseon; Jeong, Yujeong; Lee, Hyunseung; Hong, Sun-Sun; Hong, Sungwoo

2011-04-14

Phosphatidylinositol 3-kinase α (PI3Kα) is an important regulator of intracellular signaling pathways, controlling remarkably diverse arrays of physiological processes. Because the PI3K pathway is frequently up-regulated in human cancers, the inhibition of PI3Kα can be a promising approach to cancer therapy. In this study, we have designed and synthesized a new series of imidazo[1,2-a]pyridine derivatives as PI3Kα inhibitors through the fragment-growing strategy. By varying groups at the 3- and 6-positions of imidazo[1,2-a]pyridines, we studied the structure-activity relationships (SAR) profiles and identified a series of potent PI3Kα inhibitors. Representative derivatives showed good activity in cellular proliferation and apoptosis assays. Moreover, these inhibitors exhibited noteworthy antiangiogenic activity.

Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer.

Science.gov (United States)

Sunamura, Makoto; Duda, Dan G; Ghattas, Maivel H; Lozonschi, Lucian; Motoi, Fuyuhiko; Yamauchi, Jun-Ichiro; Matsuno, Seiki; Shibahara, Shigeki; Abraham, Nader G

2003-01-01

Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.

Aspartame induces angiogenesis in vitro and in vivo models.

Science.gov (United States)

Yesildal, F; Aydin, F N; Deveci, S; Tekin, S; Aydin, I; Mammadov, R; Fermanli, O; Avcu, F; Acikel, C H; Ozgurtas, T

2015-03-01

Angiogenesis is the process of generating new blood vessels from preexisting vessels and is considered essential in many pathological conditions. The purpose of the present study is to evaluate the effect of aspartame on angiogenesis in vivo chick chorioallantoic membrane (CAM) and wound-healing models as well as in vitro 2,3-bis-2H-tetrazolium-5-carboxanilide (XTT) and tube formation assays. In CAM assay, aspartame increased angiogenesis in a concentration-dependent manner. Compared with the control group, aspartame has significantly increased vessel proliferation (p aspartame group had better healing than control group, and this was statistically significant at p aspartame on human umbilical vein endothelial cells on XTT assay in vitro, but it was not statistically significant; and there was no antiangiogenic effect of aspartame on tube formation assay in vitro. These results provide evidence that aspartame induces angiogenesis in vitro and in vivo; so regular use may have undesirable effect on susceptible cases. © The Author(s) 2015.

Insulin-like growth factor binding protein-3 induces angiogenesis through IGF-I- and SphK1-dependent mechanisms.

Science.gov (United States)

Granata, R; Trovato, L; Lupia, E; Sala, G; Settanni, F; Camussi, G; Ghidoni, R; Ghigo, E

2007-04-01

Angiogenesis is critical for development and repair, and is a prominent feature of many pathological conditions. Based on evidence that insulin-like growth factor binding protein (IGFBP)-3 enhances cell motility and activates sphingosine kinase (SphK) in human endothelial cells, we have investigated whether IGFBP-3 plays a role in promoting angiogenesis. IGFBP-3 potently induced network formation by human endothelial cells on Matrigel. Moreover, it up-regulated proangiogenic genes, such as vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP)-2 and -9. IGFBP-3 even induced membrane-type 1 MMP (MT1-MMP), which regulates MMP-2 activation. Decreasing SphK1 expression by small interfering RNA (siRNA), blocked IGFBP-3-induced network formation and inhibited VEGF, MT1-MMP but not IGF-I up-regulation. IGF-I activated SphK, leading to sphingosine-1-phosphate (S1P) formation. The IGF-I effect on SphK activity was blocked by specific inhibitors of IGF-IR, PI3K/Akt and ERK1/2 phosphorylation. The disruption of IGF-I signaling prevented the IGFBP-3 effect on tube formation, SphK activity and VEGF release. Blocking ERK1/2 signaling caused the loss of SphK activation and VEGF and IGF-I up-regulation. Finally, IGFBP-3 dose-dependently stimulated neovessel formation into subcutaneous implants of Matrigel in vivo. Thus, IGFBP-3 positively regulates angiogenesis through involvement of IGF-IR signaling and subsequent SphK/S1P activation.

Inhibition of VEGF: a novel mechanism to control angiogenesis by Withania somnifera's key metabolite Withaferin A.

Science.gov (United States)

Saha, Sanjib; Islam, Md Khirul; Shilpi, Jamil A; Hasan, Shihab

2013-01-01

Angiogenesis, or new blood vessel formation from existing one, plays both beneficial and detrimental roles in living organisms in different aspects. Vascular endothelial growth factor (VEGF), a signal protein, well established as key regulator of vasculogenesis and angiogenesis. VEGF ensures oxygen supply to the tissues when blood supply is not adequate, or tissue environment is in hypoxic condition. Limited expression of VEGF is necessary, but if it is over expressed, then it can lead to serious disease like cancer. Cancers that have ability to express VEGF are more efficient to grow and metastasize because solid cancers cannot grow larger than a limited size without adequate blood and oxygen supply. Anti-VEGF drugs are already available in the market to control angiogenesis, but they are often associated with severe side-effects like fetal bleeding and proteinuria in the large number of patients. To avoid such side-effects, new insight is required to find potential compounds as anti-VEGF from natural sources. In the present investigation, molecular docking studies were carried out to find the potentiality of Withaferin A, a key metabolite of Withania somnifera, as an inhibitor of VEGF. Molecular Docking studies were performed in DockingServer and SwissDock. Bevacizumab, a commercial anti-VEGF drug, was used as reference to compare the activity of Withaferin A. X-ray crystallographic structure of VEGF, was retrieved from Protein Data Bank (PDB), and used as drug target protein. Structure of Withaferin A and Bevacizumab was obtained from PubChem and ZINC databases. Molecular visualization was performed using UCSF Chimera. Withaferin A showed favorable binding with VEGF with low binding energy in comparison to Bevacizumab. Molecular Docking studies also revealed potential protein-ligand interactions for both Withaferin A and Bevacizumab. Conclusively our results strongly suggest that Withaferin A is a potent anti-VEGF agent as ascertained by its potential

Tip Cells in Angiogenesis

NARCIS (Netherlands)

M.G. Dallinga (Marchien); S.E.M. Boas (Sonja); I. Klaassen (Ingeborg); R.M.H. Merks (Roeland); C.J.F. van Noorden; R.O. Schlingemann (Reinier)

2015-01-01

htmlabstractIn angiogenesis, the process in which blood vessel sprouts grow out from a pre-existing vascular network, the so-called endothelial tip cells play an essential role. Tip cells are the leading cells of the sprouts; they guide following endothelial cells and sense their environment for

QUANTIFICATION OF ANGIOGENESIS IN THE CHICKEN CHORIOALLANTOIC MEMBRANE (CAM

Directory of Open Access Journals (Sweden)

Silvia Blacher

2011-05-01

Full Text Available The chick chorioallantoic membrane (CAM provides a suitable in vivo model to study angiogenesis and evaluate several pro- and anti-angiogenic factors and compounds. In the present work, new developments in image analysis are used to quantify CAM angiogenic response from optical microscopic observations, covering all vascular components, from the large supplying and feeding vessels down to the capillary plexus. To validate our methodology angiogenesis is quantified during two phases of CAM development (day 7 and 13 and after treatment with an antiangiogenic modulator of the angiogenesis. Our morphometric analysis emphasizes that an accurate quantification of the CAM vasculature needs to be performed at various scales.

Efficient inhibition of tumor angiogenesis and growth by a synthetic peptide blocking S100A4-methionine aminopeptidase 2 interaction

Directory of Open Access Journals (Sweden)

Takahiro Ochiya

Full Text Available The prometastatic calcium-binding protein, S100A4, is expressed in endothelial cells, and its downregulation markedly suppresses tumor angiogenesis in a xenograft cancer model. Given that endothelial S100A4 can be a molecular target for inhibiting tumor angiogenesis, we addressed here whether synthetic peptide capable of blocking S100A4-effector protein interaction could be a novel antiangiogenic agent. To examine this hypothesis, we focused on the S100A4-binding domain of methionine aminopeptidase 2, an effector protein, which plays a role in endothelial cell growth. Overexpression of the domain in mouse endothelial MSS31 cells reduced DNA synthesis, and the corresponding synthetic peptide (named NBD indeed interacted with S100A4 and inhibited capillary formation in vitro and new blood vessel formation in vivo. Intriguingly, a single intra-tumor administration of the NBD peptide in human prostate cancer xenografts significantly reduced vascularity, resulting in tumor regression. Mechanistically, the NBD peptide enhanced assembly of nonmuscle myosin IIA filaments along with Ser1943 phosphorylation, stimulated formation of focal adhesions without phosphorylation of focal adhesion kinase, and provoked G1/S arrest of the cell cycle. Altogether, the NBD peptide is a potent inhibitor for tumor angiogenesis, and is the first example of an anticancer peptide drug developed on the basis of an endothelial S100A4-targeted strategy.

Sphingosine-1-phosphate induces human endothelial VEGF and MMP-2 production via transcription factor ZNF580: Novel insights into angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Sun, Hui-Yan, E-mail: shy35309@sohu.com [Department of Physiology and Pathophysiology, Medical College of Chinese People' s Armed Police Forces, Tianjin 300162 (China); Wei, Shu-Ping, E-mail: weishuping_83@163.com [Department of Physiology and Pathophysiology, Medical College of Chinese People' s Armed Police Forces, Tianjin 300162 (China); Xu, Rui-Cheng, E-mail: xu_rc@sohu.com [Department of Physiology and Pathophysiology, Medical College of Chinese People' s Armed Police Forces, Tianjin 300162 (China); Xu, Peng-Xiao, E-mail: xupengxiao1228@sina.com [Department of Physiology and Pathophysiology, Medical College of Chinese People' s Armed Police Forces, Tianjin 300162 (China); Zhang, Wen-Cheng, E-mail: wenchengzhang@yahoo.com [Department of Physiology and Pathophysiology, Medical College of Chinese People' s Armed Police Forces, Tianjin 300162 (China)

2010-05-07

Sphingosine-1-phosphate (S1P)-induced migration and proliferation of endothelial cells are critical for angiogenesis. C2H2-zinc finger (ZNF) proteins usually play an essential role in altering gene expression and regulating the angiogenesis. The aim of this study is to investigate whether a novel human C2H2-zinc finger gene ZNF580 (Gene ID: 51157) is involved in the migration and proliferation of endothelial cells stimulated by S1P. Our study shows that EAhy926 endothelial cells express S1P1, S1P3 and S1P5 receptors. Furthermore, S1P upregulates both ZNF580 mRNA and protein levels in a concentration- and time-dependent manner. SB203580, the specific inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK) pathway, blocks the S1P-induced upregulation of ZNF580. Moreover, overexpression/downexpression of ZNF580 in EAhy926 cells leads to the enhancement/decrease of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) expression as well as the migration and proliferation of EAhy926 endothelial cells. These results elucidate the important role that ZNF580 plays in the process of migration and proliferation of endothelial cells, which provides a foundation for a novel approach to regulate angiogenesis.

Sphingosine-1-phosphate induces human endothelial VEGF and MMP-2 production via transcription factor ZNF580: Novel insights into angiogenesis

International Nuclear Information System (INIS)

Sun, Hui-Yan; Wei, Shu-Ping; Xu, Rui-Cheng; Xu, Peng-Xiao; Zhang, Wen-Cheng

2010-01-01

Sphingosine-1-phosphate (S1P)-induced migration and proliferation of endothelial cells are critical for angiogenesis. C2H2-zinc finger (ZNF) proteins usually play an essential role in altering gene expression and regulating the angiogenesis. The aim of this study is to investigate whether a novel human C2H2-zinc finger gene ZNF580 (Gene ID: 51157) is involved in the migration and proliferation of endothelial cells stimulated by S1P. Our study shows that EAhy926 endothelial cells express S1P1, S1P3 and S1P5 receptors. Furthermore, S1P upregulates both ZNF580 mRNA and protein levels in a concentration- and time-dependent manner. SB203580, the specific inhibitor of the p38 mitogen-activated protein kinase (p38 MAPK) pathway, blocks the S1P-induced upregulation of ZNF580. Moreover, overexpression/downexpression of ZNF580 in EAhy926 cells leads to the enhancement/decrease of matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) expression as well as the migration and proliferation of EAhy926 endothelial cells. These results elucidate the important role that ZNF580 plays in the process of migration and proliferation of endothelial cells, which provides a foundation for a novel approach to regulate angiogenesis.

Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation.

Directory of Open Access Journals (Sweden)

Xinhua Chen

Full Text Available Saccharomyces boulardii (Sb can protect against intestinal injury and tumor formation, but how this probiotic yeast controls protective mucosal host responses is unclear. Angiogenesis is an integral process of inflammatory responses in inflammatory bowel diseases (IBD and required for mucosal remodeling during restitution. The aim of this study was to determine whether Sb alters VEGFR (vascular endothelial growth factor receptor signaling, a central regulator of angiogenesis.HUVEC were used to examine the effects of Sb on signaling and on capillary tube formation (using the ECMatrix™ system. The effects of Sb on VEGF-mediated angiogenesis were examined in vivo using an adenovirus expressing VEGF-A(164 in the ears of adult nude mice (NuNu. The effects of Sb on blood vessel volume branching and density in DSS-induced colitis was quantified using VESsel GENeration (VESGEN software.1 Sb treatment attenuated weight-loss (p<0.01 and histological damage (p<0.01 in DSS colitis. VESGEN analysis of angiogenesis showed significantly increased blood vessel density and volume in DSS-treated mice compared to control. Sb treatment significantly reduced the neo-vascularization associated with acute DSS colitis and accelerated mucosal recovery restoration of the lamina propria capillary network to a normal morphology. 2 Sb inhibited VEGF-induced angiogenesis in vivo in the mouse ear model. 3 Sb also significantly inhibited angiogenesis in vitro in the capillary tube assay in a dose-dependent manner (p<0.01. 4 In HUVEC, Sb reduced basal VEGFR-2 phosphorylation, VEGFR-2 phosphorylation in response to VEGF as well as activation of the downstream kinases PLCγ and Erk1/2.Our findings indicate that the probiotic yeast S boulardii can modulate angiogenesis to limit intestinal inflammation and promote mucosal tissue repair by regulating VEGFR signaling.

Cobalt (III) complexes as novel matrix metalloproteinase-9 inhibitors

International Nuclear Information System (INIS)

Lee, Jiyoun

2012-01-01

We have synthesized a series of novel MMP-9 inhibitors containing cobalt(III) complexes. The synthesized cobalt(III) complexes are effective as enzyme inhibitors and the attachment of a biphenyl group enhanced the efficiency of enzyme inhibition up to 6-fold. When compared to the reported non-hydroxamate MMP inhibitors, the synthesized complexes showed comparable in vitro potency. The enzyme assay showed that the cobalt(III) complex can disrupt the zinc binding active site of MMP-9 and is proposed to work via a ligand exchange mechanism. Since histidine residues are essential for the catalytic activity of a large percentage of enzymes and zinc finger proteins, these cobalt(III) complexes can serve as a prototype inhibitor towards various zinc containing enzymes and proteins. Matrix metalloproteinases (MMPs) are a family of zinc binding endopeptidases that play crucial roles in various physiological processes and diseases such as embryogenic growth, angiogenesis, arthritis, skin ulceration, liver fibrosis and tumor metastasis. Because of their implications in a wide range of diseases, MMPs are considered as intriguing drug targets. The majority of MMP inhibitors are organic small molecules containing a hydroxamate functionality for the zinc binding group. This hydroxamate group binds to a zinc(II) center in a bidentate fashion and creates a distorted trigonal bipyramidal geometry

Cobalt (III) complexes as novel matrix metalloproteinase-9 inhibitors

Energy Technology Data Exchange (ETDEWEB)

Lee, Jiyoun [Sungshin Women' s Univ., Seoul (Korea, Republic of)

2012-04-15

We have synthesized a series of novel MMP-9 inhibitors containing cobalt(III) complexes. The synthesized cobalt(III) complexes are effective as enzyme inhibitors and the attachment of a biphenyl group enhanced the efficiency of enzyme inhibition up to 6-fold. When compared to the reported non-hydroxamate MMP inhibitors, the synthesized complexes showed comparable in vitro potency. The enzyme assay showed that the cobalt(III) complex can disrupt the zinc binding active site of MMP-9 and is proposed to work via a ligand exchange mechanism. Since histidine residues are essential for the catalytic activity of a large percentage of enzymes and zinc finger proteins, these cobalt(III) complexes can serve as a prototype inhibitor towards various zinc containing enzymes and proteins. Matrix metalloproteinases (MMPs) are a family of zinc binding endopeptidases that play crucial roles in various physiological processes and diseases such as embryogenic growth, angiogenesis, arthritis, skin ulceration, liver fibrosis and tumor metastasis. Because of their implications in a wide range of diseases, MMPs are considered as intriguing drug targets. The majority of MMP inhibitors are organic small molecules containing a hydroxamate functionality for the zinc binding group. This hydroxamate group binds to a zinc(II) center in a bidentate fashion and creates a distorted trigonal bipyramidal geometry.

Angiogenesis and vascular targeting: Relevance for hyperthermia

DEFF Research Database (Denmark)

Horsman, Michael R

2008-01-01

The creation of a functional blood supply from the normal tissue vasculature via the process of angiogenesis is critical for the continued growth and development of solid tumours. This importance has led to the concept of targeting the tumour vasculature as a therapeutic strategy, and two major...... types of vascular targeting agents (VTAs) have developed; those that inhibit the angiogenic process-angiogenesis inhibiting agents (AIAs)-and those that specifically damage the already established neovasculature-vascular disrupting agents (VDAs). The tumour vasculature also plays a critical role...

Overexpression of decorin promoted angiogenesis in diabetic cardiomyopathy via IGF1R-AKT-VEGF signaling.

Science.gov (United States)

Lai, Jinsheng; Chen, Fuqiong; Chen, Jing; Ruan, Guoran; He, Mengying; Chen, Chen; Tang, Jiarong; Wang, Dao Wen

2017-03-14

Microcirculatory dysfunction is believed to play an important role in diabetic cardiomyopathy. The small leucine-rich proteoglycan decorin is generally considered a pro-angiogenic factor. Here, we investigate whether overexpression of decorin ameliorates diabetic cardiomyopathy and its effects on angiogenesis in vivo and in vitro. Diabetes was induced through intraperitoneal injection with streptozotocin combined with a high-fat diet, and decorin was overexpressed via recombinant adeno-associated virus in Wistar rats. Six months later, cardiac function was determined using an echocardiography and cardiac catheter system. The results showed that cardiac function was decreased in diabetic rats and restored by overexpression of decorin. In addition, overexpression of decorin upregulated the expression of VEGF and attenuated the reduction in the cardiac capillary density. In the in vitro study, high glucose induced apoptosis and inhibited the capabilities of tube formation, migration and proliferation, which were all ameliorated by decorin overexpression. Meanwhile, decorin overexpression increased the expression of VEGF and IGF1R, as well as the phosphorylation level of AKT and AP-1. Nonetheless, all of these effects were abolished by pretreatment with the IGF1R antibody or AKT inhibitor. In conclusion, overexpression of decorin ameliorated diabetic cardiomyopathy and promoted angiogenesis through the IGF1R-AKT-VEGF signaling pathway in vivo and in vitro.

VEGF blockade inhibits angiogenesis and reepithelialization of endometrium

OpenAIRE

Fan, Xiujun; Krieg, Sacha; Kuo, Calvin J.; Wiegand, Stanley J.; Rabinovitch, Marlene; Druzin, Maurice L.; Brenner, Robert M.; Giudice, Linda C.; Nayak, Nihar R.

2008-01-01

Despite extensive literature on vascular endothelial growth factor (VEGF) expression and regulation by steroid hormones, the lack of clear understanding of the mechanisms of angiogenesis in the endometrium is a major limitation for use of antiangiogenic therapy targeting endometrial vessels. In the current work, we used the rhesus macaque as a primate model and the decidualized mouse uterus as a murine model to examine angiogenesis during endometrial breakdown and regeneration. We found that ...

Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

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Yanli Li

2015-08-01

Full Text Available The mechanism of birth defects induced by folate deficiency was focused on mainly in fetal development. Little is known about the effect of folate deficiency on the maternal uterus, especially on decidual angiogenesis after implantation which establishes vessel networks to support embryo development. The aim of this study was to investigate the effects of folate deficiency on decidual angiogenesis. Serum folate levels were measured by electrochemiluminescence. The status of decidual angiogenesis was examined by cluster designation 34 (CD34 immunohistochemistry and the expression of angiogenic factors, including vascular endothelial growth factor A (VEGFA, placental growth factor (PLGF, and VEGF receptor 2 (VEGFR2 were also tested. Serum levels of homocysteine (Hcy, follicle stimulating hormone (FSH, luteinizing hormone (LH, prolactin (PRL, progesterone (P4, and estradiol (E2 were detected by Enzyme-linked immunosorbent assay. The folate-deficient mice had a lower folate level and a higher Hcy level. Folate deficiency restrained decidual angiogenesis with significant abnormalities in vascular density and the enlargement and elongation of the vascular sinus. It also showed a reduction in the expressions of VEGFA, VEGFR2, and PLGF. In addition, the serum levels of P4, E2, LH, and PRL were reduced in folate-deficient mice, and the expression of progesterone receptor (PR and estrogen receptor α (ERα were abnormal. These results indicated that folate deficiency could impaire decidual angiogenesis and it may be related to the vasculotoxic properties of Hcy and the imbalance of the reproductive hormone.

Endothelial-Rac1 is not required for tumor angiogenesis unless alphavbeta3-integrin is absent.

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Gabriela D'Amico

2010-03-01

Full Text Available Endothelial cell migration is an essential aspect of tumor angiogenesis. Rac1 activity is needed for cell migration in vitro implying a requirement for this molecule in angiogenesis in vivo. However, a precise role for Rac1 in tumor angiogenesis has never been addressed. Here we show that depletion of endothelial Rac1 expression in adult mice, unexpectedly, has no effect on tumor growth or tumor angiogenesis. In addition, repression of Rac1 expression does not inhibit VEGF-mediated angiogenesis in vivo or ex vivo, nor does it affect chemotactic migratory responses to VEGF in 3-dimensions. In contrast, the requirement for Rac1 in tumor growth and angiogenesis becomes important when endothelial beta3-integrin levels are reduced or absent: the enhanced tumor growth, tumor angiogenesis and VEGF-mediated responses in beta3-null mice are all Rac1-dependent. These data indicate that in the presence of alphavbeta3-integrin Rac1 is not required for tumor angiogenesis.

Cranial vasculature in zebrafish forms by angioblast cluster-derived angiogenesis.

Science.gov (United States)

Proulx, Kira; Lu, Annie; Sumanas, Saulius

2010-12-01

Formation of embryonic vasculature involves vasculogenesis as endothelial cells differentiate and aggregate into vascular cords and angiogenesis which includes branching from the existing vessels. In the zebrafish which has emerged as an advantageous model to study vasculogenesis, cranial vasculature is thought to originate by a combination of vasculogenesis and angiogenesis, but how these processes are coordinated is not well understood. To determine how angioblasts assemble into cranial vasculature, we generated an etsrp:GFP transgenic line in which GFP reporter is expressed under the promoter control of an early regulator of vascular and myeloid development, etsrp/etv2. By utilizing time-lapse imaging we show that cranial vessels originate by angiogenesis from angioblast clusters, which themselves form by the mechanism of vasculogenesis. The two major pairs of bilateral clusters include the rostral organizing center (ROC) which gives rise to the most rostral cranial vessels and the midbrain organizing center (MOC) which gives rise to the posterior cranial vessels and to the myeloid and endocardial lineages. In Etsrp knockdown embryos initial cranial vasculogenesis proceeds normally but endothelial and myeloid progenitors fail to initiate differentiation, migration and angiogenesis. Such angioblast cluster-derived angiogenesis is likely to be involved during vasculature formation in other vertebrate systems as well. Copyright © 2010 Elsevier Inc. All rights reserved.

The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis

International Nuclear Information System (INIS)

Baek, Yi-Yong; Lee, Dong-Keon; So, Ju-Hoon; Kim, Cheol-Hee; Jeoung, Dooil; Lee, Hansoo; Choe, Jongseon; Won, Moo-Ho; Ha, Kwon-Soo; Kwon, Young-Guen; Kim, Young-Myeong

2015-01-01

Kringle 5, derived from plasminogen, is highly capable of inhibiting angiogenesis. Here, we have designed and synthesized 10 tetrapeptides, based on the amino acid properties of the core tetrapeptide Lys-Leu-Tyr-Asp (KLYD) originating from anti-angiogenic kringle 5 of human plasminogen. Of these, Arg-Leu-Tyr-Glu (RLYE) effectively inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration and tube formation, with an IC 50 of 0.06–0.08 nM, which was about ten-fold lower than that of the control peptide KLYD (0.79 nM), as well as suppressed developmental angiogenesis in a zebrafish model. Furthermore, this peptide effectively inhibited the cellular events that precede angiogenesis, such as ERK and eNOS phosphorylation and nitric oxide production, in endothelial cells stimulated with VEGF. Collectively, these data demonstrate that RLYE is a potent anti-angiogenic peptide that targets the VEGF signaling pathway. - Highlights: • The tetrapeptide RLYE inhibited VEGF-induced angiogenesis in vitro. • RLYE also suppressed neovascularization in a zebrafish model. • Its effect was correlated with inhibition of VEGF-induced ERK and eNOS activation. • RLYE may be used as a therapeutic drug for angiogenesis-related diseases

The tetrapeptide Arg-Leu-Tyr-Glu inhibits VEGF-induced angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Baek, Yi-Yong; Lee, Dong-Keon [Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); So, Ju-Hoon; Kim, Cheol-Hee [Department of Biology, Chungnam National University, Daejeon, 305-764 (Korea, Republic of); Jeoung, Dooil [Department of Biochemistry, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Lee, Hansoo [Department of Life Sciences, College of Natural Sciences, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Choe, Jongseon [Department of Immunology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Won, Moo-Ho [Department of Neurobiology, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Ha, Kwon-Soo [Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of); Kwon, Young-Guen [Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-752 (Korea, Republic of); Kim, Young-Myeong, E-mail: ymkim@kangwon.ac.kr [Department of Molecular and Cellular Biochemistry, School of Medicine, Kangwon National University, Chuncheon, Gangwon-do, 200-702 (Korea, Republic of)

2015-08-07

Kringle 5, derived from plasminogen, is highly capable of inhibiting angiogenesis. Here, we have designed and synthesized 10 tetrapeptides, based on the amino acid properties of the core tetrapeptide Lys-Leu-Tyr-Asp (KLYD) originating from anti-angiogenic kringle 5 of human plasminogen. Of these, Arg-Leu-Tyr-Glu (RLYE) effectively inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation, migration and tube formation, with an IC{sub 50} of 0.06–0.08 nM, which was about ten-fold lower than that of the control peptide KLYD (0.79 nM), as well as suppressed developmental angiogenesis in a zebrafish model. Furthermore, this peptide effectively inhibited the cellular events that precede angiogenesis, such as ERK and eNOS phosphorylation and nitric oxide production, in endothelial cells stimulated with VEGF. Collectively, these data demonstrate that RLYE is a potent anti-angiogenic peptide that targets the VEGF signaling pathway. - Highlights: • The tetrapeptide RLYE inhibited VEGF-induced angiogenesis in vitro. • RLYE also suppressed neovascularization in a zebrafish model. • Its effect was correlated with inhibition of VEGF-induced ERK and eNOS activation. • RLYE may be used as a therapeutic drug for angiogenesis-related diseases.

IQGAP1-dependent signaling pathway regulates endothelial cell proliferation and angiogenesis.

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Rosana D Meyer

Full Text Available Vascular endothelial growth factor receptor-2 (VEGFR-2 signaling is an obligate requirement for normal development and pathological angiogenesis such as cancer and age-related macular degeneration. Although autophosphorylation of tyrosine 1173 (Y1173 of VEGFR-2 is considered a focal point for its angiogenic signal relay, however, the mechanism of phosphorylation of Y1173, signaling proteins that are recruited to this residue and their role in angiogenesis is not fully understood.In this study we demonstrate that c-Src kinase directly through its Src homology 2 (SH2 domain and indirectly via c-Cbl binds to phospho-Y1057 of VEGFR-2. Activation of c-Src kinase by a positive feedback mechanism phosphorylates VEGFR-2 at multi-docking site, Y1173. c-Src also catalyzes tyrosine phosphorylation of IQGAP1 and acts as an adaptor to bridge IQGAP1 to VEGFR-2. In turn, IQGAP1 activates b-Raf and mediates proliferation of endothelial cells. Silencing expression of IQGAP1 and b-Raf revealed that their activity is essential for VEGF to stimulate angiogenesis in an in vivo angiogenesis model of chicken chorioallantoic membrane (CAM.Angiogenesis contributes to the pathology of numerous human diseases ranging from cancer to age-related macular degeneration. Determining molecular mechanism of tyrosine phosphorylation of VEGFR-2 and identification of molecules that are relaying its angiogenic signaling may identify novel targets for therapeutic intervention against angiogenesis-associated diseases. Our study shows that recruitment and activation of c-Src by VEGFR-2 plays a pivotal role in relaying angiogenic signaling of VEGFR-2; it phosphorylates VEGFR-2 at Y1173, facilitates association and activation of IQGAP1 and other signaling proteins to VEGFR-2. IQGAP1-dependent signaling, in part, is critically required for endothelial cell proliferation, a key step in angiogenesis. Thus, Y1057 of VEGFR-2 serves to regulate VEGFR-2 function in a combinatorial manner by

Leptin and its cardiovascular effects: Focus on angiogenesis

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Zoya Tahergorabi

2015-01-01

Full Text Available Leptin is an endocrine hormone synthesized by adipocytes. It plays a key role in the energy homeostasis in central and peripheral tissues and has additional roles are attributed to it, such as the regulation of reproduction, immune function, bone homeostasis, and angiogenesis. The plasma concentration of leptin significantly increases in obese individuals. In the present review, we give an introduction concerning leptin, its receptors, signaling pathways, and its effect on cardiovascular system, especially on angiogenesis.

[Research progress of dipeptidyl peptidase 4 inhibitors on healing of chronic diabetic foot ulcers].

Science.gov (United States)

Gao, Yunyi; Liang, Yujie; Ran, Xingwu

2018-05-01

To review the effect of dipeptidyl peptidase 4 (DPP-4) inhibitors on the wound healing and its mechanisms in chronic diabetic foot ulcers. The latest literature concerning DPP-4 inhibitors for chronic diabetic foot ulcers was extensively reviewed, as well as the potential benefit and mechanism of DPP-4 inhibitors on wound healing of diabetic foot ulcers was analyzed thoroughly. DPP-4 inhibitors can accelerated the ulcer healing. The mechanisms probably include inhibiting the expression of the matrix metalloproteinase (MMP) and restoring the balance of the wound MMP and the tissue inhibitors of MMP; promoting recruitment of endothelial progenitor cells and augmenting angiogenesis; optimizing extracellular matrix construction and the immune response to persistent hypoxia in chronic diabetes wounds, and so on. At present, clinical researches show that DPP-4 inhibitors may be considered as an adjuvant treatment for chronic diabetic foot ulcers. DPP-4 inhibitors show promise in the local wound healing of chronic diabetic foot ulcers. However, more strictly designed, adequately powered, long-term follow-up, and high-quality randomized control trials are needed to further verify their efficacy and safety for chronic diabetic foot ulcers.

Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells

International Nuclear Information System (INIS)

Chuang, Cheng-Hung; Liu, Chia-Hua; Lu, Ta-Jung; Hu, Miao-Lin

2014-01-01

Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression. - Graphical abstract: Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells. Brief summary In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. - Highlights: • The anti-angiogenic effect and the mechanistic action of α-TEA were investigated. • α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo. • α-TEA down

Suppression of alpha-tocopherol ether-linked acetic acid in VEGF-induced angiogenesis and the possible mechanisms in human umbilical vein endothelial cells

Energy Technology Data Exchange (ETDEWEB)

Chuang, Cheng-Hung, E-mail: chchuang@hk.edu.tw [Department of Nutrition, Master Program of Biomedical Nutrition, Hungkuang University, 1018 Sec. 6 Taiwan Boulevard, Taichung 43302, Taiwan, ROC (China); Liu, Chia-Hua [Department of Food Science and Biotechnology, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China); Lu, Ta-Jung [Department of Chemistry, Institute of Technology and Innovation Management, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China); Hu, Miao-Lin, E-mail: mlhuhu@dragon.nchu.edu.tw [Department of Food Science and Biotechnology, National Chung-Hsing University, 250 Kuo Kuang Road, Taichung 40227, Taiwan, ROC (China)

2014-12-15

Alpha-tocopherol ether-linked acetic acid (α-TEA) has been reported to exhibit both anti-tumor and anti-metastatic activities in cell culture and animal studies. However, it is unclear whether α-TEA possesses anti-angiogenic effects. In this study, we investigated the effect of α-TEA on vascular endothelial growth factor (VEGF)-induced angiogenesis and matrix metalloproteinase (MMP) expression both in vitro and ex vivo. We found that the α-TEA inhibited tube formation, invasion, and migration in human umbilical vein endothelial cells (HUVECs) and that such actions were accompanied by reduced expression of MMP-2. α-TEA also inhibited ex vivo angiogenesis, as indicated by chicken egg chorioallantoic membrane assay. We further showed that α-TEA attenuated protein expression of VEGF receptor-2 (VEGFR-2)-mediated p38 mitogen-activated protein kinase (p38), phosphorylated p38, and focal adhesion kinase (FAK). Moreover, α-TEA (30 μM) significantly up-regulated protein expression of tissue inhibitors of MMP (TIMP)-2 (by 138%) and the metastasis suppressor gene nm23-H1 (by 54%). These results demonstrate that the anti-angiogenic effect of α-TEA both in vitro and ex vivo and its possible mechanistic action appears to involve the inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways and through up-regulation of TIMP-2 and nm23-H1 expression. - Graphical abstract: Possible mechanisms of α-TEA on inhibited angiogenesis of human umbilical vein endothelial cells. Brief summary In the present study, we have demonstrated that VEGF-mediated angiogenesis is significantly inhibited by α-TEA, and that this effect involves inhibition of MMP-2 level through VEGFR-2-mediated FAK and p38 signaling pathways related to invasion and migration. - Highlights: • The anti-angiogenic effect and the mechanistic action of α-TEA were investigated. • α-TEA significantly inhibited VEGF-mediated angiogenesis both in vitro and ex vivo. • α-TEA down

Protein Kinase B (Akt) Promotes Pathological Angiogenesis in Murine Model of Oxygen-Induced Retinopathy

International Nuclear Information System (INIS)

Wang, Peng; Tian, Xiao-Feng; Rong, Jun-Bo; Liu, Dan; Yi, Guo-Guo; Tan, Qian

2011-01-01

Akt, or protein kinase B, is an important signaling molecule that modulates many cellular processes such as cell growth, survival, and metabolism. However, the vivo roles and effectors of Akt in retinal angiogenesis are not explicitly clear. We therefore detected the expression of Akt using Western blotting or RT-PCR technologies in an animal model of oxygen-induced retinopathy, and investigated the effects of recombinant Akt on inhibiting vessels loss and Akt inhibitor on suppressing experimental retinal neovascularization in this model. We showed that in the hyperoxic phase of oxygen-induced retinopathy, the expression of Akt was greatly suppressed. In the hypoxic phase, the expression of Akt was increased dramatically. No significant differences were found in normoxic groups. Compared with control groups, administration of the recombinant Akt in the first phase of retinopathy markedly reduced capillary-free areas, while the administration of the Akt inhibitor in the second phase of retinopathy significantly decreased retinal neovascularization but capillary-free areas. These results indicate that Akt play a critical role in the pathological process (vessels loss and neovascularization) of mouse model of oxygen-induced retinopathy, which may provide a valubale therapeutic tool for ischemic-induced retinal diseases

Angiogenesis and lymphangiogenesis are downregulated in primary breast cancer

Science.gov (United States)

Boneberg, E-M; Legler, D F; Hoefer, M M; Öhlschlegel, C; Steininger, H; Füzesi, L; Beer, G M; Dupont-Lampert, V; Otto, F; Senn, H-J; Fürstenberger, G

2009-01-01

Background: Angiogenesis and lymphangiogenesis are considered to play key roles in tumour growth, progression and metastasis. However, targeting tumour angiogenesis in clinical trials showed only modest efficacy. We therefore scrutinised the concept of tumour angiogenesis and lymphangiogenesis by analysing the expression of crucial markers involved in these processes in primary breast cancer. Methods: We analysed the expression of angiogenic, lymphangiogenic or antiangiogenic factors, their respective receptors and specific markers for endothelial and lymphendothelial cells by quantitative real-time RT-PCR in primary breast cancer and compared the expression profiles to non-cancerous, tumour-adjacent tissues and breast tissues from healthy women. Results: We found decreased mRNA amounts of major angiogenic and lymphangiogenic factors in tumour compared to healthy tissues, whereas antiangiogenic factors were upregulated. Concomitantly, angiogenic and lymphangiogenic receptors were downregulated in breast tumours. This antiangiogenic, antilymphangiogenic microenvironment was even more pronounced in aggressive tumours and accompanied by reduced amounts of endothelial and lymphatic endothelial cell markers. Conclusion: Primary breast tumours are not a site of highly active angiogenesis and lymphangiogenesis. Selection for tumour cells that survive with minimal vascular supply may account for this observation in clinical apparent tumours. PMID:19672262

Gamma-secretase inhibitor treatment promotes VEGF-A-driven blood vessel growth and vascular leakage but disrupts neovascular perfusion.

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Mattias Kalén

Full Text Available The Notch signaling pathway is essential for normal development due to its role in control of cell differentiation, proliferation and survival. It is also critically involved in tumorigenesis and cancer progression. A key enzyme in the activation of Notch signaling is the gamma-secretase protein complex and therefore, gamma-secretase inhibitors (GSIs--originally developed for Alzheimer's disease--are now being evaluated in clinical trials for human malignancies. It is also clear that Notch plays an important role in angiogenesis driven by Vascular Endothelial Growth Factor A (VEGF-A--a process instrumental for tumor growth and metastasis. The effect of GSIs on tumor vasculature has not been conclusively determined. Here we report that Compound X (CX, a GSI previously reported to potently inhibit Notch signaling in vitro and in vivo, promotes angiogenic sprouting in vitro and during developmental angiogenesis in mice. Furthermore, CX treatment suppresses tumor growth in a mouse model of renal carcinoma, leads to the formation of abnormal vessels and an increased tumor vascular density. Using a rabbit model of VEGF-A-driven angiogenesis in skeletal muscle, we demonstrate that CX treatment promotes abnormal blood vessel growth characterized by vessel occlusion, disrupted blood flow, and increased vascular leakage. Based on these findings, we propose a model for how GSIs and other Notch inhibitors disrupt tumor blood vessel perfusion, which might be useful for understanding this new class of anti-cancer agents.

Sympathetic nerves: How do they affect angiogenesis, particularly during wound healing of soft tissues?

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Pan, Liangli; Tang, Jianbing; Liu, Hongwei; Cheng, Biao

2016-01-01

Angiogenesis is essential for wound healing, and angiogenesis impairment can result in chronic ulcers. Studies have shown that the sympathetic nervous system has an important role in angiogenesis. In recent years, researchers have focused on the roles of sympathetic nerves in tumor angiogenesis. In fact, sympathetic nerves can affect angiogenesis in the wound healing of soft tissues, and may have a similar mechanism of action as that seen in tumorigenesis. Sympathetic nerves act primarily through interactions between the neurotransmitters released from nerve endings and receptors present in target organs. Among this, activation or inhibition of adrenergic receptors (mainly β-adrenergic receptors) influence formation of new blood vessels considerably. As sympathetic nerves locate near pericytes in microvessel, go along the capillaries and there are adrenergic receptors present in endothelial cells and pericytes, sympathetic nerves may participate in angiogenesis by influencing the endothelial cells and pericytes of new capillaries. Studying the roles of sympathetic nerves on the angiogenesis of wound healing can contribute to understanding the mechanisms of tissue repair, tissue regeneration, and tumorigenesis, thereby providing new therapeutic perspectives.

Angiogenesis Dysregulation in Term Asphyxiated Newborns Treated with Hypothermia

Science.gov (United States)

Shaikh, Henna; Boudes, Elodie; Khoja, Zehra; Shevell, Michael; Wintermark, Pia

2015-01-01

Background Neonatal encephalopathy following birth asphyxia is a major predictor of long-term neurological impairment. Therapeutic hypothermia is currently the standard of care to prevent brain injury in asphyxiated newborns but is not protective in all cases. More robust and versatile treatment options are needed. Angiogenesis is a demonstrated therapeutic target in adult stroke. However, no systematic study examines the expression of angiogenesis-related markers following birth asphyxia in human newborns. Objective This study aimed to evaluate the expression of angiogenesis-related protein markers in asphyxiated newborns developing and not developing brain injury compared to healthy control newborns. Design/Methods Twelve asphyxiated newborns treated with hypothermia were prospectively enrolled; six developed eventual brain injury and six did not. Four healthy control newborns were also included. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study the plasma concentration of 49 angiogenesis-related proteins. Mean protein concentrations were compared between each group of newborns. Results Compared to healthy newborns, asphyxiated newborns not developing brain injury showed up-regulation of pro-angiogenic proteins, including fatty acid binding protein-4, glucose-6-phosphate isomerase, neuropilin-1, and receptor tyrosine-protein kinase erbB-3; this up-regulation was not evident in asphyxiated newborns eventually developing brain injury. Also, asphyxiated newborns developing brain injury showed a decreased expression of anti-angiogenic proteins, including insulin-growth factor binding proteins -1, -4, and -6, compared to healthy newborns. Conclusions These findings suggest that angiogenesis pathways are dysregulated following birth asphyxia and are putatively involved in brain injury pathology and recovery. PMID:25996847

Angiogenesis dysregulation in term asphyxiated newborns treated with hypothermia.

Directory of Open Access Journals (Sweden)

Henna Shaikh

Full Text Available Neonatal encephalopathy following birth asphyxia is a major predictor of long-term neurological impairment. Therapeutic hypothermia is currently the standard of care to prevent brain injury in asphyxiated newborns but is not protective in all cases. More robust and versatile treatment options are needed. Angiogenesis is a demonstrated therapeutic target in adult stroke. However, no systematic study examines the expression of angiogenesis-related markers following birth asphyxia in human newborns.This study aimed to evaluate the expression of angiogenesis-related protein markers in asphyxiated newborns developing and not developing brain injury compared to healthy control newborns.Twelve asphyxiated newborns treated with hypothermia were prospectively enrolled; six developed eventual brain injury and six did not. Four healthy control newborns were also included. We used Rules-Based Medicine multi-analyte profiling and protein array technologies to study the plasma concentration of 49 angiogenesis-related proteins. Mean protein concentrations were compared between each group of newborns.Compared to healthy newborns, asphyxiated newborns not developing brain injury showed up-regulation of pro-angiogenic proteins, including fatty acid binding protein-4, glucose-6-phosphate isomerase, neuropilin-1, and receptor tyrosine-protein kinase erbB-3; this up-regulation was not evident in asphyxiated newborns eventually developing brain injury. Also, asphyxiated newborns developing brain injury showed a decreased expression of anti-angiogenic proteins, including insulin-growth factor binding proteins -1, -4, and -6, compared to healthy newborns.These findings suggest that angiogenesis pathways are dysregulated following birth asphyxia and are putatively involved in brain injury pathology and recovery.

JS-K has Potent Anti-Angiogenic Activity in vitro and Inhibits Tumor Angiogenesis in a Multiple Myeloma Model in vivo

Science.gov (United States)

Kaur, Gurmeet; Kiziltepe, Tanyel; Anderson, Kenneth C.; Kutok, Jeffery L.; Jia, Lee; Boucher, Kenneth M.; Saavedra, Joseph E.; Keefer, Larry K.; Shami, Paul J.

2009-01-01

Glutathione S-Transferases (GST) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases NO on metabolism by GST. O2-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent anti-neoplastic activity. We studied the effect of JS-K on angiogenesis. JS-K inhibited the proliferation of HUVEC’s with a 50% inhibitory concentration (IC50) of 0.432, 0.466, and 0.505 µM at 24, 48, and 72 hours, respectively. In the cord formation assay, JS-K led to a decrease in the number of cord junctions and cord length with an IC50 of 0.637 and 0.696 µM, respectively. JS-K inhibited cell migration at 5 hours using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 µM. In the chick aortic ring assay using VEGF or FGF-b for vessel growth stimulation, 0.5 µM JS-K completely inhibited vessel growth. JS-K inhibited tumor angiogenesis in vivo in NIH III mice implanted subcutaneously with OPM1 multiple myeloma cells. JS-K is a potent inhibitor of angiogenesis in vitro and tumor vessel growth in vivo. As such, it establishes a new class of anti-neoplastic agents that target the malignant cells directly as well as their microenvironment. PMID:20723011

Syndecan-4 shedding impairs macrovascular angiogenesis in diabetes mellitus

Energy Technology Data Exchange (ETDEWEB)

Li, Ran; Xie, Jun; Wu, Han; Li, Guannan; Chen, Jianzhou; Chen, Qinhua; Wang, Lian; Xu, Biao, E-mail: xubiao@medmail.com.cn

2016-05-20

Purpose: Syndecan-4 (synd4) is a ubiquitous heparan sulfate proteoglycan cell surface receptor that modulates cell proliferation, migration, mechanotransduction, and endocytosis. The extracellular domain of synd4 sheds heavily in acute inflammation, but the shedding of synd4 in chronic inflammation, such as diabetes mellitus (DM), is still undefined. We investigated the alterations of synd4 endothelial expression in DM and the influence of impaired synd4 signaling on angiogenesis in human umbilical vein endothelial cells (HUVECs), diabetic rats, synd4 null mice, and db/db mice. Material and methods: HUVECs were incubated with advanced glycation end products (AGEs). Western blot analysis was used to determine synd4 protein expression and ELISA was used to detect soluble synd4 fragments. The concentration of synd4 in the aortic endothelia of diabetic rats was detected by immunohistochemical staining. Aortic ring assays were performed to study the process of angiogenesis in the diabetic rats and in synd4 null and db/db mice. Recombinant adenoviruses containing the synd4 gene or null were constructed to enhance synd4 aortic expression in db/db mice. Results: Western blot analysis showed decreased expression of the synd4 extracellular domain in HUVECs, and ELISA detected increased soluble fragments of synd4 in the media. Synd4 endothelial expression in the aortas of diabetic rats was decreased. Aortic ring assay indicated impaired angiogenesis in synd4 null and db/db mice, which was partially reversed by synd4 overexpression in db/db mice. Conclusion: Synd4 shedding from vascular endothelial cells played an important role in the diabetes-related impairment of angiogenesis. -- Highlights: •Synd4 shedding from endothelial cells is accelerated under the stimulation of AGEs. •Extracellular domain of synd4 is diminished in the endothelium of DM rats. •Aortic rings of synd4 null mice showed impaired angiogenesis. •Overexpression of synd4 partly rescues macrovascular

Angiogenesis in Schistosoma haematobium-associated urinary bladder cancer.

Science.gov (United States)

Dematei, Anderson; Fernandes, Rúben; Soares, Raquel; Alves, Helena; Richter, Joachim; Botelho, Monica C

2017-12-01

Schistosoma haematobium, a parasitic flatworm that infects more than 100 million people, mostly in the developing world, is the causative agent of urogenital schistosomiasis, and is associated with a high incidence of squamous cell carcinoma (SCC) of the bladder. During infection, eggs are deposited in the bladder causing an intense inflammatory reaction. Angiogenesis is defined as the formation of new blood vessels from preexisting ones and is recognized as a key event in cell proliferation and carcinogenesis and spread of malignant lesions. A growing amount of evidence points to angiogenesis playing a key role in schistosomiasis-associated bladder cancer. Thus, identifying biomarkers of this process plays an important role in the study of cancer. Here, we review recent findings on the role of angiogenesis in bladder cancer and the growth factors that induce and assist in their development, particularly SCC of the bladder associated to urogenital schistosomiasis. © 2017 APMIS. Published by John Wiley & Sons Ltd.

miR-21 Is Linked to Glioma Angiogenesis

DEFF Research Database (Denmark)

Hermansen, Simon Kjær; Nielsen, Boye Schnack; Aaberg-Jessen, Charlotte

2016-01-01

MicroRNA-21 (miR-21) is the most consistently over-expressed microRNA (miRNA) in malignant gliomas. We have previously reported that miR-21 is upregulated in glioma vessels and subsets of glioma cells. To better understand the role of miR-21 in glioma angiogenesis and to characterize miR-21......-localized with the hypoxia- and angiogenesis-associated markers HIF-1α (p=0.0020) and VEGF (p=0.0096), whereas the putative miR-21 target, PTEN, was expressed independently of miR-21. Expression of stem cell markers Oct4, Sox2 and CD133 was not associated with miR-21. In six glioblastoma cultures, miR-21 did not correlate...... with the six markers. These findings suggest that miR-21 is linked to glioma angiogenesis, that miR-21 is unlikely to regulate PTEN, and that miR-21-positive tumor cells do not possess stem cell characteristics....

Solena amplexicaulis induces cell cycle arrest, apoptosis and inhibits angiogenesis in hepatocarcinoma cells and HUVECs.

Science.gov (United States)

Ren, Jie; Xu, Yuan Yuan; Jiang, He Fei; Yang, Meng; Huang, Qian Hui; Yang, Jie; Hu, Kun; Wei, Kun

2014-01-01

Solena amplexicaulis (Lam.) Gandhi (SA) has been used as a traditional medicine for the treatment of dysentery, multiple abscess, gastralgia, urethritis, and eczema in the minority area of China. This study was aimed to examine the cell proliferation inhibitory activity of the SA extract (SACE) and its mechanism of action in human hepatoma cell line (HepG2) and evaluate its anti-angiogenesis activity in human umbilical vein endothelial cell line (HUVEC). SACE could inhibit the growth of HepG2 cells in a dose- and time-dependent manner. FCM analysis showed that SACE could induce G2/M phase arrest, cell apoptosis, the mitochondrial membrane potential loss (ΔΨm) and increase the production of intracellular ROS of HepG2 cells. After treatment with SACE, topical morphological changes of apoptotic body formation, obvious increase of apoptosis-related protein expressions, such as Bax, cytochrome c, caspase-3, PARP-1, and decrease of Bcl-2, procaspase-9 protein expressions were observed at the same time. Moreover, SACE caused the significant inhibition of endothelial cell migration and tube formation in HUVEC cells. The results suggested that SACE could act as an angiogenesis inhibitor and induce cell apoptosis via a caspase-dependent mitochondrial pathway. Therefore, SACE could be a potent candidate for the prevention and treatment of liver cancer.

Mechanical strain stimulates vasculogenesis and expression of angiogenesis guidance molecules of embryonic stem cells through elevation of intracellular calcium, reactive oxygen species and nitric oxide generation.

Science.gov (United States)

Sharifpanah, Fatemeh; Behr, Sascha; Wartenberg, Maria; Sauer, Heinrich

2016-12-01

Differentiation of embryonic stem (ES) cells may be regulated by mechanical strain. Herein, signaling molecules underlying mechanical stimulation of vasculogenesis and expression of angiogenesis guidance cues were investigated in ES cell-derived embryoid bodies. Treatment of embryoid bodies with 10% static mechanical strain using a Flexercell strain system significantly increased CD31-positive vascular structures and the angiogenesis guidance molecules plexinB1, ephrin B2, neuropilin1 (NRP1), semaphorin 4D (sem4D) and robo4 as well as vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2) and platelet-derived growth factor-BB (PDGF-BB) as evaluated by Western blot and real time RT-PCR. In contrast ephrin type 4 receptor B (EphB4) expression was down-regulated upon mechanical strain, indicating an arterial-type differentiation. Robo1 protein expression was modestly increased with no change in mRNA expression. Mechanical strain increased intracellular calcium as well as reactive oxygen species (ROS) and nitric oxide (NO). Mechanical strain-induced vasculogenesis was abolished by the NOS inhibitor L-NAME, the NADPH oxidase inhibitor VAS2870, upon chelation of intracellular calcium by BAPTA as well as upon siRNA inactivation of ephrin B2, NRP1 and robo4. BAPTA blunted the strain-induced expression of angiogenic growth factors, the increase in NO and ROS as well as the expression of NRP1, sem4D and plexinB1, whereas ephrin B2, EphB4 as well as robo1 and robo4 expression were not impaired. Mechanical strain stimulates vasculogenesis of ES cells by the intracellular messengers ROS, NO and calcium as well as by upregulation of angiogenesis guidance molecules and the angiogenic growth factors VEGF, FGF-2 and PDGF-BB. Copyright © 2016 Elsevier B.V. All rights reserved.

Angiogenesis in Balb/c mice under beta-carotene supplementation in diet

NARCIS (Netherlands)

Razny, U.; Polus, P.; Kiec-wilk, B.; Wator, L.; Hartwich, J.; Keijer, J.

2010-01-01

Angiogenesis is a process of new blood vessel formation from pre-existing ones. The most important steps in angiogenesis include detachment, proliferation, migration, homing and differentiation of vascular wall cells, which are mainly endothelial cells and their progenitors. The study focused on the

Angiogenesis for tumor vascular normalization of Endostar on hepatoma 22 tumor-bearing mice is involved in the immune response.

Science.gov (United States)

Xu, Qingyu; Gu, Junfei; Lv, You; Yuan, Jiarui; Yang, Nan; Chen, Juan; Wang, Chunfei; Hou, Xuefeng; Jia, Xiaobin; Feng, Liang; Yin, Guowen

2018-03-01

Tumor vascular normalization involved in immune response is beneficial to the chemotherapy of tumors. Recombinant human endostatin (Endostar), an angiogenesis inhibitor, has been demonstrated to be effective in hepatocellular cancer (HCC). However, its vascular normalization in HCC and the role of the immune response in angiogenesis were unclear. In the present study, effects of Endostar on tumor vascular normalization were evaluated in hepatoma 22 (H22) tumor-bearing mice. Endostar was able to inhibit the proliferation and infiltration of tumor cells and improve α-fetoprotein, tumor necrosis factor-α and cyclic adenosine 5'-phosphate levels in the serum of H22-bearing mice, as well as the protein expression levels of the immune factors interferon-γ and cluster of differentiation (CD)86 in liver tissue. Endostar also exhibited more marked downregulation of the levels of vascular endothelial growth factor, CD31, matrix metalloproteinase (MMP)-2, MMP-9 and interleukin-17 during day 3-9 treatment, resulting in short-term normalization of tumor blood vessels. The period of vascular normalization was 3-9 days. The results of the present study demonstrated that Endostar was able to induce the period of vascular normalization, contributing to a more efficacious means of HCC treatment combined with other chemotherapy, and this effect was associated with the immune response. It may be concluded that Endostar inhibited immunity-associated angiogenesis behaviors of vascular endothelial cells in response to HCC. The results of the present study provided more reasonable possibility for the combination therapy of Endostar for the treatment of HCC.

Effects of amelogenins on angiogenesis-associated processes of endothelial cells

DEFF Research Database (Denmark)

Almqvist, S; Kleinman, H K; Werthén, M

2011-01-01

To study the effects of an amelogenin mixture on integrin-dependent adhesion, DNA synthesis and apoptosis of cultured human dermal microvascular endothelial cells and angiogenesis in an organotypic assay.......To study the effects of an amelogenin mixture on integrin-dependent adhesion, DNA synthesis and apoptosis of cultured human dermal microvascular endothelial cells and angiogenesis in an organotypic assay....

Gli3 Regulation of Myogenesis Is Necessary for Ischemia-Induced Angiogenesis

Science.gov (United States)

Renault, Marie-Ange; Vandierdonck, Soizic; Chapouly, Candice; Yu, Yang; Qin, Gangjian; Metras, Alexandre; Couffinhal, Thierry; Losordo, Douglas W.; Yao, Qinyu; Reynaud, Annabel; Jaspard-Vinassa, Béatrice; Belloc, Isabelle; Desgranges, Claude; Gadeau, Alain-Pierre

2015-01-01

Rationale A better understanding of the mechanism underlying skeletal muscle repair is required to develop therapies that promote tissue regeneration in adults. Hedgehog signaling has been shown previously to be involved in myogenesis and angiogenesis: 2 crucial processes for muscle development and regeneration. Objective The objective of this study was to identify the role of the hedgehog transcription factor Gli3 in the crosstalk between angiogenesis and myogenesis in adults. Methods and Results Using conditional knockout mice, we found that Gli3 deficiency in endothelial cells did not affect ischemic muscle repair, whereas in myocytes, Gli3 deficiency resulted in severely delayed ischemia-induced myogenesis. Moreover, angiogenesis was also significantly impaired in HSA-CreERT2; Gli3Flox/Flox mice, demonstrating that impaired myogenesis indirectly affects ischemia-induced angiogenesis. The role of Gli3 in myocytes was then further investigated. We found that Gli3 promotes myoblast differentiation through myogenic factor 5 regulation. In addition, we found that Gli3 regulates several proangiogenic factors, including thymidine phosphorylase and angiopoietin-1 both in vitro and in vivo, which indirectly promote endothelial cell proliferation and arteriole formation. In addition, we found that Gli3 is upregulated in proliferating myoblasts by the cell cycle–associated transcription factor E2F1. Conclusions This study shows for the first time that Gli3-regulated postnatal myogenesis is necessary for muscle repair–associated angiogenesis. Most importantly, it implies that myogenesis drives angiogenesis in the setting of skeletal muscle repair and identifies Gli3 as a potential target for regenerative medicine. PMID:24044950

Dimethyl phenyl piperazine iodide (DMPP) induces glioma regression by inhibiting angiogenesis

International Nuclear Information System (INIS)

He, Yan-qing; Li, Yan; Wang, Xiao-yu; He, Xiao-dong; Jun, Li; Chuai, Manli; Lee, Kenneth Ka Ho; Wang, Ju; Wang, Li-jing; Yang, Xuesong

2014-01-01

1,1-Dimethyl-4-phenyl piperazine iodide (DMPP) is a synthetic nicotinic acetylcholine receptor (nAChR) agonist that could reduce airway inflammation. In this study, we demonstrated that DMPP could dramatically inhibit glioma size maintained on the chick embryonic chorioallantoic membrane (CAM). We first performed MTT and BrdU incorporation experiments on U87 glioma cells in vitro to understand the mechanism involved. We established that DMPP did not significantly affect U87 cell proliferation and survival. We speculated that DMPP directly caused the tumor to regress by affecting the vasculature in and around the implanted tumor on our chick CAM model. Hence, we conducted detailed analysis of DMPP's inhibitory effects on angiogenesis. Three vasculogenesis and angiogenesis in vivo models were used in the study which included (1) early chick blood islands formation, (2) chick yolk-sac membrane (YSW) and (3) CAM models. The results revealed that DMPP directly suppressed all developmental stages involved in vasculogenesis and angiogenesis – possibly by acting through Ang-1 and HIF-2α signaling. In sum, our results show that DMPP could induce glioma regression grown on CAM by inhibiting vasculogenesis and angiogenesis. - Highlights: ●We demonstrated that DMPP inhibited the growth of glioma cells on chick CAM. ●DMPP did not significantly affect the proliferation and survival of U87 cells. ●We revealed that DMPP suppressed vasculogenesis and angiogenesis in chick embryo. ●Angiogenesis in chick CAM was inhibited by DMPP via most probably Ang-1 and HIF-2α. ●DMPP could be potentially developed as an anti-tumor drug in the future

Endogenous Sonic Hedgehog limits inflammation and angiogenesis in the ischaemic skeletal muscle of mice.

Science.gov (United States)

Caradu, Caroline; Guy, Alexandre; James, Chloé; Reynaud, Annabel; Gadeau, Alain-Pierre; Renault, Marie-Ange

2018-04-01

Hedgehog (Hh) signalling has been shown to be re-activated in ischaemic tissues and participate in ischaemia-induced angiogenesis. Sonic Hedgehog (Shh) is upregulated by more than 80-fold in the ischaemic skeletal muscle, however its specific role in ischaemia-induced angiogenesis has not yet been fully investigated. The purpose of the present study was to investigate the role of endogenous Shh in ischaemia-induced angiogenesis. To this aim, we used inducible Shh knock-out (KO) mice and unexpectedly found that capillary density was significantly increased in re-generating muscle of Shh deficient mice 5 days after hind limb ischaemia was induced, demonstrating that endogenous Shh does not promote angiogenesis but more likely limits it. Myosin and MyoD expression were equivalent in Shh deficient mice and control mice, indicating that endogenous Shh is not required for ischaemia-induced myogenesis. Additionally, we observed a significant increase in macrophage infiltration in the ischaemic muscle of Shh deficient mice. Our data indicate that this was due to an increase in chemokine expression by myoblasts in the setting of impaired Hh signalling, using tissue specific Smoothened conditional KO mice. The increased macrophage infiltration in mice deficient for Hh signalling in myocytes was associated with increased VEGFA expression and a transiently increased angiogenesis, demonstrating that Shh limits inflammation and angiogenesis indirectly by signalling to myocytes. Although ectopic administration of Shh has previously been shown to promote ischaemia-induced angiogenesis, the present study reveals that endogenous Shh does not promote ischaemia-induced angiogenesis. On the contrary, the absence of Shh leads to aberrant ischaemic tissue inflammation and a transiently increased angiogenesis.

An interesting case of angiogenesis in cavernous hemangioma

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Dipankar Das

2016-01-01

Full Text Available Cavernous hemangioma is the most common orbital tumor in adult. There is lot of literatures for clinicopathological features of this tumor. These tumors had been studied for the model of angiogenesis in many of the experimental setups. We present a case of 34-year-old male with this tumor in the left eye with computerized tomography evidence. Postsurgical laboratory findings gave interesting evidence of tumor angiogenesis with tumor endothelial cells and sprouting of the small vessels endothelial cells. Podosome rosette could be conceptualized from the characteristic patterns seen in the tumor.

The Harvard angiogenesis story.

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Miller, Joan W

2014-01-01

I shall discuss the work of researchers at Harvard Medical School who came together in the early 1990s. Scattered across various Harvard-affiliated hospitals and research centers, these individuals were unified by their interest in ocular neovascularization. Together and separately, they investigated models of ocular neovascularization, exploring tumor angiogenesis in eye development and disease. Copyright © 2014 The Author. Published by Elsevier Inc. All rights reserved.

Inhibitory effects of vitamin K3 on DNA polymerase and angiogenesis.

Science.gov (United States)

Matsubara, Kiminori; Kayashima, Tomoko; Mori, Masaharu; Yoshida, Hiromi; Mizushina, Yoshiyuki

2008-09-01

Vitamins play essential roles in cellular reactions and maintain human health. Recent studies have revealed that some vitamins including D3, B6 and K2 and their derivatives have an anti-cancer effect. As a mechanism, their inhibitory effect on cancer-related angiogenesis has been demonstrated. Vitamin K2 (menaquinones) has an anti-cancer effect in particular for hepatic cancer and inhibits angiogenesis. In the current study, we demonstrated that sole vitamin K3 (menadione) selectively inhibits the in vitro activity of eukaryotic DNA polymerase gamma, which is a mitochondrial DNA polymerase, and suppresses angiogenesis in a rat aortic ring model. The anti-angiogenic effect of vitamin K3 has been shown in angiogenesis models using human umbilical vein endothelial cells (HUVECs) with regard to HUVEC growth, tube formation on reconstituted basement membrane and chemotaxis. These results suggest that vitamin K3 may be a potential anti-cancer agent like vitamin K2.

Dimethyl phenyl piperazine iodide (DMPP) induces glioma regression by inhibiting angiogenesis

Energy Technology Data Exchange (ETDEWEB)

He, Yan-qing; Li, Yan; Wang, Xiao-yu [Key Laboratory for Regenerative Medicine of the Ministry of Education, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou 510632 (China); He, Xiao-dong [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510006 (China); Jun, Li [Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Centre of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632 (China); Chuai, Manli [Division of Cell and Developmental Biology, University of Dundee, Dundee, DD1 5EH (United Kingdom); Lee, Kenneth Ka Ho [Key Laboratory for Regenerative Medicine of the Ministry of Education, School of Biomedical Sciences, Chinese University of Hong Kong, Shatin (Hong Kong); Wang, Ju [Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Centre of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632 (China); Wang, Li-jing, E-mail: wanglijing62@163.com [Institute of Vascular Biological Sciences, Guangdong Pharmaceutical University, Guangzhou 510006 (China); Yang, Xuesong, E-mail: yang_xuesong@126.com [Key Laboratory for Regenerative Medicine of the Ministry of Education, Division of Histology and Embryology, Medical College, Jinan University, Guangzhou 510632 (China)

2014-01-15

1,1-Dimethyl-4-phenyl piperazine iodide (DMPP) is a synthetic nicotinic acetylcholine receptor (nAChR) agonist that could reduce airway inflammation. In this study, we demonstrated that DMPP could dramatically inhibit glioma size maintained on the chick embryonic chorioallantoic membrane (CAM). We first performed MTT and BrdU incorporation experiments on U87 glioma cells in vitro to understand the mechanism involved. We established that DMPP did not significantly affect U87 cell proliferation and survival. We speculated that DMPP directly caused the tumor to regress by affecting the vasculature in and around the implanted tumor on our chick CAM model. Hence, we conducted detailed analysis of DMPP's inhibitory effects on angiogenesis. Three vasculogenesis and angiogenesis in vivo models were used in the study which included (1) early chick blood islands formation, (2) chick yolk-sac membrane (YSW) and (3) CAM models. The results revealed that DMPP directly suppressed all developmental stages involved in vasculogenesis and angiogenesis – possibly by acting through Ang-1 and HIF-2α signaling. In sum, our results show that DMPP could induce glioma regression grown on CAM by inhibiting vasculogenesis and angiogenesis. - Highlights: ●We demonstrated that DMPP inhibited the growth of glioma cells on chick CAM. ●DMPP did not significantly affect the proliferation and survival of U87 cells. ●We revealed that DMPP suppressed vasculogenesis and angiogenesis in chick embryo. ●Angiogenesis in chick CAM was inhibited by DMPP via most probably Ang-1 and HIF-2α. ●DMPP could be potentially developed as an anti-tumor drug in the future.

10-Hydroxy-2-decenoic Acid, a Major Fatty Acid from Royal Jelly, Inhibits VEGF-Induced Angiogenesis in Human Umbilical Vein Endothelial Cells

Directory of Open Access Journals (Sweden)

Hiroshi Izuta

2009-01-01

Full Text Available Vascular endothelial growth factor (VEGF is reported to be a potent pro-angiogenic factor that plays a pivotal role in both physiological and pathological angiogenesis. Royal jelly (RJ is a honeybee product containing various proteins, sugars, lipids, vitamins and free amino acids. 10-Hydroxy-2-decenoic acid (10HDA, a major fatty acid component of RJ, is known to have various pharmacological effects; its antitumor activity being especially noteworthy. However, the mechanism underlying this effect is unclear. We examined the effect of 10HDA on VEGF-induced proliferation, migration and tube formation in human umbilical vein endothelial cells (HUVECs. Our findings showed that, 10HDA at 20 µM or more significantly inhibited such proliferation, migration and tube formation. Similarly, 10 µM GM6001, a matrix metalloprotease inhibitor, prevented VEGF-induced migration and tube formation. These findings indicate that 10HDA exerts an inhibitory effect on VEGF-induced angiogenesis, partly by inhibiting both cell proliferation and migration. Further experiments will be needed to clarify the detailed mechanism.

Bone marrow-derived cells are differentially involved in pathological and physiological retinal angiogenesis in mice

Energy Technology Data Exchange (ETDEWEB)

Zou, He [Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507 (Japan); Otani, Atsushi, E-mail: otan@kuhp.kyoto-u.ac.jp [Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507 (Japan); Oishi, Akio; Yodoi, Yuko; Kameda, Takanori; Kojima, Hiroshi; Yoshimura, Nagahisa [Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507 (Japan)

2010-01-08

Purpose: Bone marrow-derived cells have been shown to play roles in angiogenesis. Although these cells have been shown to promote angiogenesis, it is not yet clear whether these cells affect all types of angiogenesis. This study investigated the involvement of bone marrow-derived cells in pathological and physiological angiogenesis in the murine retina. Materials and methods: The oxygen-induced retinopathy (OIR) model was used as a retinal angiogenesis model in newborn mice. To block the influence of bone marrow-derived cells, the mice were irradiated with a 4-Gy dose of radiation from a {sup 137}Cs source. Irradiation was performed in four different conditions with radio dense 2-cm thick lead disks; (1) H group, the head were covered with these discs to protect the eyes from radiation; (2) A group, all of the body was covered with these discs; (3) N group, mice were completely unshielded; (4) C group, mice were put in the irradiator but were not irradiated. On P17, the retinal areas showing pathological and physiological retinal angiogenesis were measured and compared to the retinas of nonirradiated mice. Results: Although irradiation induced leukocyte depletion, it did not affect the number of other cell types or body weight. Retinal nonperfusion areas were significantly larger in irradiated mice than in control mice (P < 0.05), indicating that physiological angiogenesis was impaired. However, the formation of tuft-like angiogenesis processes was more prominent in the irradiated mice (P < 0.05), indicating that pathological angiogenesis was intact. Conclusions: Bone marrow-derived cells seem to be differentially involved in the formation of physiological and pathological retinal vessels. Pathological angiogenesis in the murine retina does not require functional bone marrow-derived cells, but these cells are important for the formation of physiological vessels. Our results add a new insight into the pathology of retinal angiogenesis and bolster the hypothesis that

Bone marrow-derived cells are differentially involved in pathological and physiological retinal angiogenesis in mice

International Nuclear Information System (INIS)

Zou, He; Otani, Atsushi; Oishi, Akio; Yodoi, Yuko; Kameda, Takanori; Kojima, Hiroshi; Yoshimura, Nagahisa

2010-01-01

Purpose: Bone marrow-derived cells have been shown to play roles in angiogenesis. Although these cells have been shown to promote angiogenesis, it is not yet clear whether these cells affect all types of angiogenesis. This study investigated the involvement of bone marrow-derived cells in pathological and physiological angiogenesis in the murine retina. Materials and methods: The oxygen-induced retinopathy (OIR) model was used as a retinal angiogenesis model in newborn mice. To block the influence of bone marrow-derived cells, the mice were irradiated with a 4-Gy dose of radiation from a 137 Cs source. Irradiation was performed in four different conditions with radio dense 2-cm thick lead disks; (1) H group, the head were covered with these discs to protect the eyes from radiation; (2) A group, all of the body was covered with these discs; (3) N group, mice were completely unshielded; (4) C group, mice were put in the irradiator but were not irradiated. On P17, the retinal areas showing pathological and physiological retinal angiogenesis were measured and compared to the retinas of nonirradiated mice. Results: Although irradiation induced leukocyte depletion, it did not affect the number of other cell types or body weight. Retinal nonperfusion areas were significantly larger in irradiated mice than in control mice (P < 0.05), indicating that physiological angiogenesis was impaired. However, the formation of tuft-like angiogenesis processes was more prominent in the irradiated mice (P < 0.05), indicating that pathological angiogenesis was intact. Conclusions: Bone marrow-derived cells seem to be differentially involved in the formation of physiological and pathological retinal vessels. Pathological angiogenesis in the murine retina does not require functional bone marrow-derived cells, but these cells are important for the formation of physiological vessels. Our results add a new insight into the pathology of retinal angiogenesis and bolster the hypothesis that bone

A computational model of in vitro angiogenesis based on extracellular matrix fibre orientation.

Science.gov (United States)

Edgar, Lowell T; Sibole, Scott C; Underwood, Clayton J; Guilkey, James E; Weiss, Jeffrey A

2013-01-01

Recent interest in the process of vascularisation within the biomedical community has motivated numerous new research efforts focusing on the process of angiogenesis. Although the role of chemical factors during angiogenesis has been well documented, the role of mechanical factors, such as the interaction between angiogenic vessels and the extracellular matrix, remains poorly understood. In vitro methods for studying angiogenesis exist; however, measurements available using such techniques often suffer from limited spatial and temporal resolutions. For this reason, computational models have been extensively employed to investigate various aspects of angiogenesis. This paper outlines the formulation and validation of a simple and robust computational model developed to accurately simulate angiogenesis based on length, branching and orientation morphometrics collected from vascularised tissue constructs. Microvessels were represented as a series of connected line segments. The morphology of the vessels was determined by a linear combination of the collagen fibre orientation, the vessel density gradient and a random walk component. Excellent agreement was observed between computational and experimental morphometric data over time. Computational predictions of microvessel orientation within an anisotropic matrix correlated well with experimental data. The accuracy of this modelling approach makes it a valuable platform for investigating the role of mechanical interactions during angiogenesis.

Angiogenesis gene expression in murine endothelial cells during post-pneumonectomy lung growth

Directory of Open Access Journals (Sweden)

Konerding Moritz A

2011-07-01

Full Text Available Abstract Although blood vessel growth occurs readily in the systemic bronchial circulation, angiogenesis in the pulmonary circulation is rare. Compensatory lung growth after pneumonectomy is an experimental model with presumed alveolar capillary angiogenesis. To investigate the genes participating in murine neoalveolarization, we studied the expression of angiogenesis genes in lung endothelial cells. After left pneumonectomy, the remaining right lung was examined on days 3, 6, 14 and 21days after surgery and compared to both no surgery and sham thoracotomy controls. The lungs were enzymatically digested and CD31+ endothelial cells were isolated using flow cytometry cell sorting. The transcriptional profile of the CD31+ endothelial cells was assessed using quantitative real-time polymerase chain reaction (PCR arrays. Focusing on 84 angiogenesis-associated genes, we identified 22 genes with greater than 4-fold regulation and significantly enhanced transcription (p

Peptide-coated gold nanoparticles for modulation of angiogenesis in vivo

Directory of Open Access Journals (Sweden)

Roma-Rodrigues C

2016-06-01

Full Text Available Catarina Roma-Rodrigues,1 Amelie Heuer-Jungemann,2 Alexandra R Fernandes,1 Antonios G Kanaras,2 Pedro V Baptista1 1UCIBIO, Departamento de Ciências da Vida, Faculdade de Ciências e Tecnologia, Universidade NOVA de Lisboa, Caparica, Portugal; 2Institute for Life Sciences, Physics and Astronomy, Faculty of Physical Sciences and Engineering, University of Southampton, Southampton, UK Abstract: In this work, peptides designed to selectively interact with cellular receptors involved in the regulation of angiogenesis were anchored to oligo-ethylene glycol-capped gold nanoparticles (AuNPs and used to evaluate the modulation of vascular development using an ex ovo chick chorioallantoic membrane assay. These nanoparticles alter the balance between naturally secreted pro- and antiangiogenic factors, under various biological conditions, without causing toxicity. Exposure of chorioallantoic membranes to AuNP–peptide activators of angiogenesis accelerated the formation of new arterioles when compared to scrambled peptide-coated nanoparticles. On the other hand, antiangiogenic AuNP–peptide conjugates were able to selectively inhibit angiogenesis in vivo. We demonstrated that AuNP vectorization is crucial for enhancing the effect of active peptides. Our data showed for the first time the effective control of activation or inhibition of blood vessel formation in chick embryo via AuNP-based formulations suitable for the selective modulation of angiogenesis, which is of paramount importance in applications where promotion of vascular growth is desirable (eg, wound healing or ought to be contravened, as in cancer development. Keywords: angiogenesis activators, antiangiogenic, CAM assay, gold nanoparticles, peptide-coated gold nanoparticles, vascular development

JS-K has potent anti-angiogenic activity in vitro and inhibits tumour angiogenesis in a multiple myeloma model in vivo.

Science.gov (United States)

Kiziltepe, Tanyel; Anderson, Kenneth C; Kutok, Jeffery L; Jia, Lee; Boucher, Kenneth M; Saavedra, Joseph E; Keefer, Larry K; Shami, Paul J

2010-01-01

Glutathione S-transferases (GSTs) play an important role in multidrug resistance and are upregulated in multiple cancers. We have designed a prodrug class that releases nitric oxide on metabolism by GST. O(2)-(2,4-Dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent antineoplastic activity. We studied the effect of JS-K on angiogenesis in human umbilical vein endothelial cells (HUVECs), OPM1 multiple myeloma cells, chick aortic rings and in mice. JS-K inhibited the proliferation of HUVECs with a 50% inhibitory concentration (IC50) of 0.432, 0.466 and 0.505 microm at 24, 48 and 72 h, respectively. In the cord formation assay, JS-K led to a decrease in the number of cord junctions and cord length with an IC50 of 0.637 and 0.696 microm, respectively. JS-K inhibited cell migration at 5 h using VEGF as a chemoattractant. Migration inhibition occurred with an IC50 of 0.493 microm. In the chick aortic ring assay using VEGF or FGF-2 for vessel growth stimulation, 0.5 microm JS-K completely inhibited vessel growth. JS-K inhibited tumour angiogenesis in vivo in NIH III mice implanted subcutaneously with OPM1 multiple myeloma cells. JS-K is a potent inhibitor of angiogenesis in vitro and tumour vessel growth in vivo. As such, it establishes a new class of antineoplastic agent that targets the malignant cells directly as well as their microenvironment.

Perlecan and tumor angiogenesis

DEFF Research Database (Denmark)

Jiang, Xinnong; Couchman, John R

2003-01-01

Perlecan is a major heparan sulfate proteoglycan (HSPG) of basement membranes (BMs) and connective tissues. The core protein of perlecan is divided into five domains based on sequence homology to other known proteins. Commonly, the N-terminal domain I of mammalian perlecan is substituted with thr...... have unwanted promoting effects on tumor cell proliferation and tumor angiogenesis. Understanding of these attributes at the molecular level may offer opportunities for therapeutic intervention....

PEG-b-PCL polymeric nano-micelle inhibits vascular angiogenesis by activating p53-dependent apoptosis in zebrafish.

Science.gov (United States)

Zhou, Tian; Dong, Qinglei; Shen, Yang; Wu, Wei; Wu, Haide; Luo, Xianglin; Liao, Xiaoling; Wang, Guixue

Micro/nanoparticles could cause adverse effects on cardiovascular system and increase the risk for cardiovascular disease-related events. Nanoparticles prepared from poly(ethylene glycol) (PEG)- b -poly( ε -caprolactone) (PCL), namely PEG- b -PCL, a widely studied biodegradable copolymer, are promising carriers for the drug delivery systems. However, it is unknown whether polymeric PEG- b -PCL nano-micelles give rise to potential complications of the cardiovascular system. Zebrafish were used as an in vivo model to evaluate the effects of PEG- b -PCL nano-micelle on cardiovascular development. The results showed that PEG- b -PCL nano-micelle caused embryo mortality as well as embryonic and larval malformations in a dose-dependent manner. To determine PEG- b -PCL nano-micelle effects on embryonic angiogenesis, a critical process in zebrafish cardiovascular development, growth of intersegmental vessels (ISVs) and caudal vessels (CVs) in flk1-GFP transgenic zebrafish embryos using fluorescent stereomicroscopy were examined. The expression of fetal liver kinase 1 (flk1), an angiogenic factor, by real-time quantitative polymerase chain reaction (qPCR) and in situ whole-mount hybridization were also analyzed. PEG- b -PCL nano-micelle decreased growth of ISVs and CVs, as well as reduced flk1 expression in a concentration-dependent manner. Parallel to the inhibitory effects on angiogenesis, PEG- b -PCL nano-micelle exposure upregulated p53 pro-apoptotic pathway and induced cellular apoptosis in angiogenic regions by qPCR and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay. This study further showed that inhibiting p53 activity, either by pharmacological inhibitor or RNA interference, could abrogate the apoptosis and angiogenic defects caused by PEG- b -PCL nano-micelles, indicating that PEG- b -PCL nano-micelle inhibits angiogenesis by activating p53-mediated apoptosis. This study indicates that polymeric PEG- b -PCL nano-micelle could

Prognostic implication of apoptosis and angiogenesis in cervical uteri cancer

International Nuclear Information System (INIS)

Zaghloul, Mohamed S.; El Naggar, Mervat; El Deeb, Amany; Khaled, Hussein; Mokhtar, Nadia

2000-01-01

Purpose: A retrospective study was performed to investigate the relationship between spontaneous apoptosis and angiogenesis uterine cervix squamous cell carcinoma patients. The prognostic value of each (and both) of these biologic parameters was also tested. Methods and Materials: The pathologic materials of 40 cervical uteri squamous cell carcinoma patients were examined and immunohistochemically stained to determine the tumor angiogenesis (tumor microvascular score), using factor VIII-related antigen, and their tumor apoptotic index (AI), using the TdT-mediated dUTP nick end-labeling (TUNEL) method. Three patients were Stage I, 18 were Stage II, 15 were Stage III, and 4 were Stage IV (FIGO classification). All patients were treated with radical radiotherapy and all had follow-up for more than 2 years. Results: The mean AI was 15.1 ± 12.8, with a median of 8.3. The mean tumor microvascular score was 3 9.7 ± 14.4, with a median of 3 8. The patients' age and tumor grade did not seem to significantly affect the prognosis. On the other hand, AI and angiogenesis (tumor microvascular score) were of high prognostic significance. The 3-year disease-free survival (DFS) rate for the patients having AI above the median was 78% (confidence interval [CI] 69-87%), compared to 32% (CI 22-42%) for those having AI below the median. The DFS was 18% (CI 9-27%) for patients having an angiogenesis score above the median, while it was 86% (CI 78-94%) for those patients having a score below the median. Conclusion: Determination of both tumor microvascular score and AI can identify patients with the best prognosis of 100% DFS (with low angiogenesis score and high AI). Women with a high score and low AI had the worst prognosis (DFS = 3%, CI 1-5%). Moreover, high AI can compensate partially for the aggressive behavior of tumors showing a high rate of angiogenesis.

Design, synthesis and optimization of bis-amide derivatives as CSF1R inhibitors.

Science.gov (United States)

Ramachandran, Sreekanth A; Jadhavar, Pradeep S; Miglani, Sandeep K; Singh, Manvendra P; Kalane, Deepak P; Agarwal, Anil K; Sathe, Balaji D; Mukherjee, Kakoli; Gupta, Ashu; Haldar, Srijan; Raja, Mohd; Singh, Siddhartha; Pham, Son M; Chakravarty, Sarvajit; Quinn, Kevin; Belmar, Sebastian; Alfaro, Ivan E; Higgs, Christopher; Bernales, Sebastian; Herrera, Francisco J; Rai, Roopa

2017-05-15

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cell-oriented modeling of angiogenesis.

Science.gov (United States)

Guidolin, Diego; Rebuffat, Piera; Albertin, Giovanna

2011-01-01

Due to its significant involvement in various physiological and pathological conditions, angiogenesis (the development of new blood vessels from an existing vasculature) represents an important area of the actual biological research and a field in which mathematical modeling proved particularly useful in supporting the experimental work. In this paper, we focus on a specific modeling strategy, known as "cell-centered" approach. This type of mathematical models work at a "mesoscopic scale," assuming the cell as the natural level of abstraction for computational modeling of development. They treat cells phenomenologically, considering their essential behaviors to study how tissue structure and organization emerge from the collective dynamics of multiple cells. The main contributions of the cell-oriented approach to the study of the angiogenic process will be described. From one side, they have generated "basic science understanding" about the process of capillary assembly during development, growth, and pathology. On the other side, models were also developed supporting "applied biomedical research" for the purpose of identifying new therapeutic targets and clinically relevant approaches for either inhibiting or stimulating angiogenesis.

Scutellarin promotes in vitro angiogenesis in human umbilical vein endothelial cells

International Nuclear Information System (INIS)

Gao, Zhong-Xiu-Zi; Huang, Da-Yong; Li, Hai-Xia; Zhang, Li-Na; Lv, Yan-Hong; Cui, Hai-Dong; Zheng, Jin-Hua

2010-01-01

Research highlights: → It has been shown that scutellarin exhibits a variety of pharmacological actions, including anti-oxidative, anti-inflammatory, vasodilator as well as cardiovascular and cerebrovascular ischemia protective effects, indicating beneficial vascular effects of scutellarin. Therefore, it is speculated that scutellarin may be able to stimulate angiogenesis, which could be beneficial in the treatment of ischemic disease, wound healing and tissue regeneration. → The purpose of the present study was to elucidate the direct angiogenic actions of scutellarin on human umbilical vein endothelial cells (HUVECs) in vitro. → Our results showed that scutellarin to directly induce in vitro angiogenesis, which is closely correlated with upregulated MMP-2 expression, suggesting a potential for increasing angiogenesis. -- Abstract: Angiogenesis is critical to a wide range of physiological and pathological processes. Scutellarin, a major flavonoid of a Chinese herbal medicine Erigeron breviscapus (Vant.) Hand. Mazz. has been shown to offer beneficial effects on cardiovascular and cerebrovascular functions. However, scutellarin's effects on angiogenesis and underlying mechanisms are not fully elucidated. Here, we studied angiogenic effects of scutellarin on human umbilical vein endothelial cells (HUVECs) in vitro. Scutellarin was found by MTT assay to induce proliferation of HUVECs. In scutellarin-treated HUVECs, a dramatic increase in migration was measured by wound healing assay; Transwell chamber assay found significantly more invading cells in scutellarin-treated groups. Scutellarin also promoted capillary-like tube formation in HUVECs on Matrigel, and significantly upregulated platelet endothelial cell adhesion molecule-1 at both mRNA and protein levels. Scutellarin's angiogenic mechanism was investigated in vitro by measuring expression of angiogenic factors associated with cell migration and invasion. Scutellarin strongly induced MMP-2 activation and m

Scutellarin promotes in vitro angiogenesis in human umbilical vein endothelial cells

Energy Technology Data Exchange (ETDEWEB)

Gao, Zhong-Xiu-Zi [Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin (China); Huang, Da-Yong [Department of Oncology, The Second Clinical Hospital, Harbin Medical University, Harbin (China); Li, Hai-Xia; Zhang, Li-Na; Lv, Yan-Hong; Cui, Hai-Dong [Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin (China); Zheng, Jin-Hua, E-mail: jhzhenghrbmu@yahoo.cn [Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin (China)

2010-09-10

Research highlights: {yields} It has been shown that scutellarin exhibits a variety of pharmacological actions, including anti-oxidative, anti-inflammatory, vasodilator as well as cardiovascular and cerebrovascular ischemia protective effects, indicating beneficial vascular effects of scutellarin. Therefore, it is speculated that scutellarin may be able to stimulate angiogenesis, which could be beneficial in the treatment of ischemic disease, wound healing and tissue regeneration. {yields} The purpose of the present study was to elucidate the direct angiogenic actions of scutellarin on human umbilical vein endothelial cells (HUVECs) in vitro. {yields} Our results showed that scutellarin to directly induce in vitro angiogenesis, which is closely correlated with upregulated MMP-2 expression, suggesting a potential for increasing angiogenesis. -- Abstract: Angiogenesis is critical to a wide range of physiological and pathological processes. Scutellarin, a major flavonoid of a Chinese herbal medicine Erigeron breviscapus (Vant.) Hand. Mazz. has been shown to offer beneficial effects on cardiovascular and cerebrovascular functions. However, scutellarin's effects on angiogenesis and underlying mechanisms are not fully elucidated. Here, we studied angiogenic effects of scutellarin on human umbilical vein endothelial cells (HUVECs) in vitro. Scutellarin was found by MTT assay to induce proliferation of HUVECs. In scutellarin-treated HUVECs, a dramatic increase in migration was measured by wound healing assay; Transwell chamber assay found significantly more invading cells in scutellarin-treated groups. Scutellarin also promoted capillary-like tube formation in HUVECs on Matrigel, and significantly upregulated platelet endothelial cell adhesion molecule-1 at both mRNA and protein levels. Scutellarin's angiogenic mechanism was investigated in vitro by measuring expression of angiogenic factors associated with cell migration and invasion. Scutellarin strongly

Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.

Science.gov (United States)

Gao, Jin-Hang; Wen, Shi-Lei; Feng, Shi; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Liu, Rui; Tang, Shi-Hang; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Xie, Hui-Qi; Tang, Cheng-Wei

2016-10-01

Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.

Gold and silver nanoparticles conjugated with heparin derivative possess anti-angiogenesis properties

International Nuclear Information System (INIS)

Kemp, Melissa M; Linhardt, Robert J; Kumar, Ashavani; Ajayan, Pulickel; Mousa, Shaymaa; Dyskin, Evgeny; Yalcin, Murat; Mousa, Shaker A

2009-01-01

Silver and gold nanoparticles display unique physical and biological properties that have been extensively studied for biological and medical applications. Typically, gold and silver nanoparticles are prepared by chemical reductants that utilize excess toxic reactants, which need to be removed for biological purposes. We utilized a clean method involving a single synthetic step to prepare metal nanoparticles for evaluating potential effects on angiogenesis modulation. These nanoparticles were prepared by reducing silver nitrate and gold chloride with diaminopyridinyl (DAP)-derivatized heparin (HP) polysaccharides. Both gold and silver nanoparticles reduced with DAPHP exhibited effective inhibition of basic fibroblast growth factor (FGF-2)-induced angiogenesis, with an enhanced anti-angiogenesis efficacy with the conjugation to DAPHP (P<0.01) as compared to glucose conjugation. These results suggest that DAPHP-reduced silver nanoparticles and gold nanoparticles have potential in pathological angiogenesis accelerated disorders such as cancer and inflammatory diseases.

Gold and silver nanoparticles conjugated with heparin derivative possess anti-angiogenesis properties

Energy Technology Data Exchange (ETDEWEB)

Kemp, Melissa M; Linhardt, Robert J [Department of Biology, Rensselaer Polytechnic Institute, Troy, NY 12180 (United States); Kumar, Ashavani; Ajayan, Pulickel [Department of Mechanical Engineering and Materials Science, Rice University, Houston, TX 77005 (United States); Mousa, Shaymaa; Dyskin, Evgeny; Yalcin, Murat; Mousa, Shaker A, E-mail: Shaker.mousa@acphs.ed [Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Albany, NY 12208 (United States)

2009-11-11

Silver and gold nanoparticles display unique physical and biological properties that have been extensively studied for biological and medical applications. Typically, gold and silver nanoparticles are prepared by chemical reductants that utilize excess toxic reactants, which need to be removed for biological purposes. We utilized a clean method involving a single synthetic step to prepare metal nanoparticles for evaluating potential effects on angiogenesis modulation. These nanoparticles were prepared by reducing silver nitrate and gold chloride with diaminopyridinyl (DAP)-derivatized heparin (HP) polysaccharides. Both gold and silver nanoparticles reduced with DAPHP exhibited effective inhibition of basic fibroblast growth factor (FGF-2)-induced angiogenesis, with an enhanced anti-angiogenesis efficacy with the conjugation to DAPHP (P<0.01) as compared to glucose conjugation. These results suggest that DAPHP-reduced silver nanoparticles and gold nanoparticles have potential in pathological angiogenesis accelerated disorders such as cancer and inflammatory diseases.

ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFα inhibitors

DEFF Research Database (Denmark)

Pedersen, Susanne Juhl; Sørensen, Inge Juul; Garnero, Patrick

2011-01-01

To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial...... spondyloarthritis initiating tumour necrosis factor alpha (TNFa) inhibitor therapy....

Skeletal Muscle Angiogenesis and Its Relation to Insulin Sensitivity

DEFF Research Database (Denmark)

Lindqvist, Anna Maria Charlotte K

mediator of angiogenesis) are reduced in insulin resistant individuals. Exercise training can improve skeletal muscle capillarization and the angiogenic potential and physical activity has also been proven to enhance muscle insulin sensitivity. Increased skeletal muscle capillarization is associated......) or by overexpression of VEGF-A in the tibialis anterior muscle (transfection; study II) and the effect of the increased muscle capillarization on muscle insulin sensitivity was examined. In study I skeletal muscle specific angiogenesis was induced by administering an α1-adrenergic antagonist (prazosin) to healthy...

Peritoneal fluid reduces angiogenesis-related microRNA expression in cell cultures of endometrial and endometriotic tissues from women with endometriosis.

Directory of Open Access Journals (Sweden)

Aitana Braza-Boïls

Full Text Available UNLABELLED: Endometriosis, defined as the presence of endometrium outside the uterus, is one of the most frequent gynecological diseases. It has been suggested that modifications of both endometrial and peritoneal factors could be implicated in this disease. Endometriosis is a multifactorial disease in which angiogenesis and proteolysis are dysregulated. MicroRNAs (miRNAs are small non-coding RNAs that regulate the protein expression and may be the main regulators of angiogenesis. Our hypothesis is that peritoneal fluid from women with endometriosis could modify the expression of several miRNAs that regulate angiogenesis and proteolysis in the endometriosis development. The objective of this study has been to evaluate the influence of endometriotic peritoneal fluid on the expression of six miRNAs related to angiogenesis, as well as several angiogenic and proteolytic factors in endometrial and endometriotic cell cultures from women with endometriosis compared with women without endometriosis. METHODS: Endometrial and endometriotic cells were cultured and treated with endometriotic and control peritoneal fluid pools. We have studied the expression of six miRNAs (miR-16, -17-5p, -20a, -125a, -221, and -222 by RT-PCR and protein and mRNA levels of vascular endothelial growth factor-A, thrombospondin-1, urokinase plasminogen activator and plasminogen activator inhibitor-1 by ELISA and qRT-PCR respectively. RESULTS: Control and endometriotic peritoneal fluid pools induced a significant reduction of all miRNAs levels in endometrial and endometriotic cell cultures. Moreover, both peritoneal fluids induced a significant increase in VEGF-A, uPA and PAI-1 protein levels in all cell cultures without significant increase in mRNA levels. Endometrial cell cultures from patients treated with endometriotic peritoneal fluid showed lower expression of miRNAs and higher expression of VEGF-A protein levels than cultures from controls. In conclusion , this "in vitro

Sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis is involved in liver fibrosis-associated angiogenesis.

Science.gov (United States)

Yang, Le; Yue, Shi; Yang, Lin; Liu, Xin; Han, Zhen; Zhang, Yuanyuan; Li, Liying

2013-07-01

Sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) axis is involved in multiple biological processes, including liver fibrosis. Angiogenesis is an important pathophysiological process closely associated with liver fibrosis; however, the functional role of SphK/S1P/S1PR in this process remains incompletely defined. Bile duct ligation or carbon tetrachloride was used to induce liver fibrosis in mice. Human fibrotic samples were obtained from livers of patients undergoing liver transplantation. S1P levels in the liver were examined by HPLC. Expression of angiogenic markers, including angiopoietin 1, CD31, vascular cell adhesion molecule-1, and von Willebrand factor, was characterized by immunofluorescence, real-time RT-PCR, and Western blot in the fibrotic liver and primary mouse hepatic stellate cells (HSCs). SphK inhibitor (SKI) or S1PR antagonists were administered intraperitoneally in mice. S1P levels in the liver were closely correlated with mRNA expression of angiogenic markers. Ang1 is expressed in activated HSCs of the fibrotic liver and in primary HSCs. In HSCs, by using specific antagonists or siRNAs, we demonstrated S1P stimulation induced Ang1 expression via S1PR1 and S1PR3. In vivo, S1P reduction by SKI inhibited angiogenesis in fibrotic mice. Furthermore, S1PR1/3 antagonist significantly blocked upregulation of angiogenic markers in the injured liver, and attenuated the extent of liver fibrosis, while S1PR2 antagonist had no effect on angiogenesis, supporting the key role of S1PR1 and S1PR3 in angiogenesis underlying liver fibrosis process. SphK1/S1P/S1PR1/3 axis plays a crucial role in the angiogenic process required for fibrosis development, which may represent an effective therapeutic strategy for liver fibrosis. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Human IgG1 antibodies suppress angiogenesis in a target-independent manner

NARCIS (Netherlands)

Bogdanovich, Sasha; Kim, Younghee; Mizutani, Takeshi; Yasuma, Reo; Tudisco, Laura; Cicatiello, Valeria; Bastos-Carvalho, Ana; Kerur, Nagaraj; Hirano, Yoshio; Baffi, Judit Z; Tarallo, Valeria; Li, Shengjian; Yasuma, Tetsuhiro; Arpitha, Parthasarathy; Fowler, Benjamin J; Wright, Charles B; Apicella, Ivana; Greco, Adelaide; Brunetti, Arturo; Ruvo, Menotti; Sandomenico, Annamaria; Nozaki, Miho; Ijima, Ryo; Kaneko, Hiroki; Ogura, Yuichiro; Terasaki, Hiroko; Ambati, Balamurali K; Leusen, Jeanette HW; Langdon, Wallace Y; Clark, Michael R; Armour, Kathryn L; Bruhns, Pierre; Verbeek, J Sjef; Gelfand, Bradley D; De Falco, Sandro; Ambati, Jayakrishna

2016-01-01

Aberrant angiogenesis is implicated in diseases affecting nearly 10% of the world's population. The most widely used anti-angiogenic drug is bevacizumab, a humanized IgG1 monoclonal antibody that targets human VEGFA. Although bevacizumab does not recognize mouse Vegfa, it inhibits angiogenesis in

Hypoxia-Inducible Factor-1 in Physiological and Pathophysiological Angiogenesis: Applications and Therapies

Science.gov (United States)

Zimna, Agnieszka; Kurpisz, Maciej

2015-01-01

The cardiovascular system ensures the delivery of oxygen and nutrients to all cells, tissues, and organs. Under extended exposure to reduced oxygen levels, cells are able to survive through the transcriptional activation of a series of genes that participate in angiogenesis, glucose metabolism, and cell proliferation. The oxygen-sensitive transcriptional activator HIF-1 (hypoxia-inducible factor-1) is a key transcriptional mediator of the response to hypoxic conditions. The HIF-1 pathway was found to be a master regulator of angiogenesis. Whether the process is physiological or pathological, HIF-1 seems to participate in vasculature formation by synergistic correlations with other proangiogenic factors such as VEGF (vascular endothelial growth factor), PlGF (placental growth factor), or angiopoietins. Considering the important contributions of HIF-1 in angiogenesis and vasculogenesis, it should be considered a promising target for treating ischaemic diseases or cancer. In this review, we discuss the roles of HIF-1 in both physiological/pathophysiological angiogenesis and potential strategies for clinical therapy. PMID:26146622

Tumour angiogenesis pathways: related clinical issues and implications for nuclear medicine imaging

International Nuclear Information System (INIS)

Wiele, Christophe van de; De Winter, Olivier; Dierckx, Rudi Andre; Oltenfreiter, Ruth; Slegers, Guido; Signore, Alberto

2002-01-01

Tumour angiogenesis is essential for growth, invasion and metastasis. Retrospective studies suggest that it is an independent prognostic factor that merits prospective validation. Furthermore, as tumour blood vessels show many differences from normal vessels and are not genetically unstable, they form a key area for therapy development. However, as anti-angiogenic therapy is primarily cytostatic and not cytotoxic, novel tailor-made specific end-points for treatment monitoring are required. In this regard, suitable molecular parameters for imaging tumour angiogenesis by means of nuclear medicine are being explored. Here we review current knowledge on the multiple pathways controlling tumour angiogenesis and try to assess which are the most clinically relevant for nuclear medicine imaging. Parameters that may influence the imaging potential of radiopharmaceuticals for angiogenesis imaging such as molecular weight and structure, their targeted location within the tumour and their usefulness in terms of specificity and constancy of the targeted molecular pathway are discussed. (orig.)

Placental growth factor enhances angiogenesis in human intestinal microvascular endothelial cells via PI3K/Akt pathway: Potential implications of inflammation bowel disease

Energy Technology Data Exchange (ETDEWEB)

Zhou, Yi, E-mail: mondayzy@126.com; Tu, Chuantao, E-mail: tu.chuantao@zs-hospital.sh.cn; Zhao, Yuan, E-mail: zhao.yuan@zs-hospital.sh.cn; Liu, Hongchun, E-mail: liuhch@aliyun.com; Zhang, Shuncai, E-mail: zhang.shuncai@zs-hospital.sh.cn

2016-02-19

Background: Angiogenesis plays a major role in the pathogenesis of inflammatory bowel disease (IBD). Placental growth factor (PlGF) is a specific regulator of pathological angiogenesis and is upregulated in the sera of IBD patients. Therefore, the role of PlGF in IBD angiogenesis was investigated here using HIMECs. Methods: The expression of PlGF and its receptors in human intestinal microvascular endothelial cells (HIMECs) and inflamed mucosa of IBD patients were examined using quantitative PCR and western blot analysis and the role of PlGF in IBD HIMECs was further explored using small interfering RNA (siRNA). The induction of pro-inflammatory cytokine by PlGF in HIMECs was confirmed by ELISA. The capacity of PlGF to induce angiogenesis in HIMECs was tested through proliferation, cell-migration, matrigel tubule-formation assays and its underlying signaling pathway were explored by western blot analysis of ERK1/2 and PI3K/Akt phosphorylation. Results: mRNA and protein expression of PlGF and its receptor NRP-1 were significantly increased in IBD HIMECs. Inflamed mucosa of IBD patients also displayed higher expression of PIGF. The production of IL-6 and TNF-α in culture supernatant of HIMECs treated with exogenous recombinant human PlGF-1 (rhPlGF-1) were increased. Furthermore, rhPlGF-1 significantly induced HIMECs migration and tube formation in a dose-dependent manner and knockdown of endogenous PlGF in IBD HIMECs using siRNA substantially reduced these angiogenesis activities. PlGF induced PI3K/Akt phosphorylation in HIMECs and pretreatment of PlGF-stimulated HIMECs with PI3K inhibitor (LY294002) significantly inhibited the PlGF-induced cell migration and tube formation. Conclusion: Our results demonstrated the pro-inflammatory and angiogenic effects of PlGF on HIMECs in IBD through activation of PI3K/Akt signaling pathway. PlGF/PI3K/Akt signaling may serve as a potential therapeutic target for IBD. - Highlights: • Expression of PlGF and its receptor NRP-1

ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNF{alpha} inhibitors

DEFF Research Database (Denmark)

Pedersen, Susanne Juhl; Sørensen, Inge Juul; Garnero, Patrick

2011-01-01

To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial...... spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy....

Inhibitory effect of ginsenoside Rg3 combined with gemcitabine on angiogenesis and growth of lung cancer in mice

International Nuclear Information System (INIS)

Liu, Tai-Guo; Huang, Ying; Cui, Dan-Dan; Huang, Xiao-Bing; Mao, Shu-Hua; Ji, Ling-Ling; Song, Hai-Bo; Yi, Cheng

2009-01-01

Ginsenoside Rg3, a saponin extracted from ginseng, inhibits angiogenesis. The combination of low-dose chemotherapy and anti-angiogenic inhibitors suppresses growth of experimental tumors more effectively than conventional therapy or anti-angiogenic agent alone. The present study was designed to evaluate the efficacy of low-dose gemcitabine combined with ginsenoside Rg3 on angiogenesis and growth of established Lewis lung carcinoma in mice. C57L/6 mice implanted with Lewis lung carcinoma were randomized into the control, ginsenoside Rg3, gemcitabine and combination group. The quality of life and survival of mice were recorded. Tumor volume, inhibitive rate and necrosis rate were estimated. Necrosis of tumor and signals of blood flow as well as dynamic parameters of arterial blood flow in tumors such as peak systolic velocity (PSV) and resistive index (RI) were detected by color Doppler ultrasound. In addition, expression of vascular endothelial cell growth factor (VEGF) and CD31 were observed by immunohistochemstry, and microvessel density (MVD) of the tumor tissues was assessed by CD31 immunohistochemical analysis. Quality of life of mice in the ginsenoside Rg3 and combination group were better than in the control and gemcitabine group. Combined therapy with ginsenoside Rg3 and gemcitabine not only enhanced efficacy on suppression of tumor growth and prolongation of the survival, but also increased necrosis rate of tumor significantly. In addition, the combination treatment could obviously decrease VEGF expression and MVD as well as signals of blood flow and PSV in tumors. Ginsenoside Rg3 combined with gemcitabine may significantly inhibit angiogenesis and growth of lung cancer and improve survival and quality of life of tumor-bearing mice. The combination of chemotherapy and anti-angiogenic drugs may be an innovative and promising therapeutic strategy in the experimental treatment of human lung cancer

Applying nanomedicine in maladaptive inflammation and angiogenesis

NARCIS (Netherlands)

Alaarg, Amr; Pérez-Medina, Carlos; Metselaar, Josbert M.; Nahrendorf, Matthias; Fayad, Zahi A.; Storm, Gert; Mulder, Willem J. M.

2017-01-01

Inflammation and angiogenesis drive the development and progression of multiple devastating diseases such as atherosclerosis, cancer, rheumatoid arthritis, and inflammatory bowel disease. Though these diseases have very different phenotypic consequences, they possess several common

A FRET-based high throughput screening assay to identify inhibitors of anthrax protective antigen binding to capillary morphogenesis gene 2 protein.

Directory of Open Access Journals (Sweden)

Michael S Rogers

Full Text Available Anti-angiogenic therapies are effective for the treatment of cancer, a variety of ocular diseases, and have potential benefits in cardiovascular disease, arthritis, and psoriasis. We have previously shown that anthrax protective antigen (PA, a non-pathogenic component of anthrax toxin, is an inhibitor of angiogenesis, apparently as a result of interaction with the cell surface receptors capillary morphogenesis gene 2 (CMG2 protein and tumor endothelial marker 8 (TEM8. Hence, molecules that bind the anthrax toxin receptors may be effective to slow or halt pathological vascular growth. Here we describe development and testing of an effective homogeneous steady-state fluorescence resonance energy transfer (FRET high throughput screening assay designed to identify molecules that inhibit binding of PA to CMG2. Molecules identified in the screen can serve as potential lead compounds for the development of anti-angiogenic and anti-anthrax therapies. The assay to screen for inhibitors of this protein-protein interaction is sensitive and robust, with observed Z' values as high as 0.92. Preliminary screens conducted with a library of known bioactive compounds identified tannic acid and cisplatin as inhibitors of the PA-CMG2 interaction. We have confirmed that tannic acid both binds CMG2 and has anti-endothelial properties. In contrast, cisplatin appears to inhibit PA-CMG2 interaction by binding both PA and CMG2, and observed cisplatin anti-angiogenic effects are not mediated by interaction with CMG2. This work represents the first reported high throughput screening assay targeting CMG2 to identify possible inhibitors of both angiogenesis and anthrax intoxication.

Oridonin inhibits tumor growth and metastasis through anti-angiogenesis by blocking the Notch signaling.

Directory of Open Access Journals (Sweden)

Yanmin Dong

Full Text Available While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases.

[Establishment of sprouting embryoid body model mimicking early embryonic vasculogenesis in human embryo].

Science.gov (United States)

Jiang, Hua; Feng, You-Ji; Xie, Yi; Han, Jin-Lan; Wang, Zack; Chen, Tong

2008-10-14

To establish a sprouting embryoid body model mimicking early embryonic vasculogenesis in human embryo. Human embryonic stem were (hESCs) were cultured on the mouse embryo fibroblasts and then were induced to differentiate to form three-dimensional EB. The hEBs were cultured in media containing various angiogenesis-related factors: vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), endostatin, angiostatin, and platelet factor (PF)-4 of different concentrations for 3 days to observe the sprouting of the hEBs. 3, 3, 3', 3'-tetramethylindo-carbocyanine perchlorate labeled acetylated low density lipoprotein (Dil-AcLDL) was added onto the hEBs foe 4 h Immunofluorescence assay was used to observe if Dil-AcLDL was absorbed and if CD31 was expressed so as to determine the existence of embryonic endothelial cells in the sprouting structures. The ideal culturing condition was analyzed. The differentiated EBs formed sprouting structures in the collagen I matrix containing VEGF and FGF. The sprouts among individual EBs were able to link to each other and form vascular network-like structures. In the presence of VEGF and FGF, the sprouts branching from the EBs assimilated Dil-AcLDL, expressed CD31 and formed a 3-dimensional cylindrical organization. The concentrations of growth factors ideally stimulating sprouting growth were 100 ng/ml of VEGF and 50 ng/ml of FGF. The networks among the EBs were abolished by the angiostatin, endostatin, and PF4. The sprouting from hEBs accumulates embryonic endothelial cells and the sprouting network-like structures are indeed endothelial in nature. Inducing of sprouting EBs is an ideal model that mimics early embryonic vasculogenesis in humans.

Rhamnazin, a novel inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy

International Nuclear Information System (INIS)

Yu, Yao; Cai, Wei; Pei, Chong-gang; Shao, Yi

2015-01-01

Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer therapy. The identification of new drugs from natural products has a long and successful history. In this study, we described a novel VEGFR2 inhibitor, rhamnazin, which inhibits tumor angiogenesis and growth. Rhamnazin significantly inhibited proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in vitro as well as inhibited sprouts formation of rat aorta ring. In addition, it inhibited vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVECs. Moreover, rhamnazin could directly inhibit proliferation of breast cancer cells MDA-MB-231 in vitro and in vivo. Oral administration of rhamnazin at a dose of 200 mg/kg/day could markedly inhibited human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that rhamnazin inhibits angiogenesis and may be a promising anticancer drug candidate. - Highlights: • Rhamnazin inhibits the response of HUVECs to VEGF in vitro. • Rhamnazin inhibits VEGFR2 kinase activity and its downstream signaling. • Rhamnazin prevents the growth of MDA-MB-231 tumor and reduces micro-vessel density in vivo

Rhamnazin, a novel inhibitor of VEGFR2 signaling with potent antiangiogenic activity and antitumor efficacy

Energy Technology Data Exchange (ETDEWEB)

Yu, Yao [Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute, No.17 Yongwaizheng Street, Donghu District, Nanchang 330006, Jiangxi Province (China); Department of Endocrinology and Metabolism, The Third Hospital of Nanchang, Nanchang Key Laboratory of Diabetes, No.1 Qianjing Road, Xihu District, Nanchang 330009, Jiangxi Province (China); Cai, Wei [Department of Medical Genetics, College of Basic Medical Science of Nanchang University, No.461 Bayi Road, Donghu District, Nanchang 330006, Jiangxi Province (China); Pei, Chong-gang, E-mail: profchonggangpei@163.com [Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute, No.17 Yongwaizheng Street, Donghu District, Nanchang 330006, Jiangxi Province (China); Shao, Yi, E-mail: profyishao@163.com [Department of Ophthalmology, The First Affiliated Hospital of Nanchang University, Jiangxi Province Clinical Ophthalmology Institute, No.17 Yongwaizheng Street, Donghu District, Nanchang 330006, Jiangxi Province (China)

2015-03-20

Anti-angiogenesis targeting vascular endothelial growth factor receptor 2 (VEGFR2) has emerged as an important tool for cancer therapy. The identification of new drugs from natural products has a long and successful history. In this study, we described a novel VEGFR2 inhibitor, rhamnazin, which inhibits tumor angiogenesis and growth. Rhamnazin significantly inhibited proliferation, migration and tube formation of human umbilical vascular endothelial cells (HUVECs) in vitro as well as inhibited sprouts formation of rat aorta ring. In addition, it inhibited vascular endothelial growth factor (VEGF)-induced phosphorylation of VEGFR2 and its downstream signaling regulator in HUVECs. Moreover, rhamnazin could directly inhibit proliferation of breast cancer cells MDA-MB-231 in vitro and in vivo. Oral administration of rhamnazin at a dose of 200 mg/kg/day could markedly inhibited human tumor xenograft growth and decreased microvessel densities (MVD) in tumor sections. Taken together, these preclinical evaluations suggest that rhamnazin inhibits angiogenesis and may be a promising anticancer drug candidate. - Highlights: • Rhamnazin inhibits the response of HUVECs to VEGF in vitro. • Rhamnazin inhibits VEGFR2 kinase activity and its downstream signaling. • Rhamnazin prevents the growth of MDA-MB-231 tumor and reduces micro-vessel density in vivo.

A bioavailable cathepsin S nitrile inhibitor abrogates tumor development.

Science.gov (United States)

Wilkinson, Richard D A; Young, Andrew; Burden, Roberta E; Williams, Rich; Scott, Christopher J

2016-04-21

Cathepsin S has been implicated in a variety of malignancies with genetic ablation studies demonstrating a key role in tumor invasion and neo-angiogenesis. Thus, the application of cathepsin S inhibitors may have clinical utility in the treatment of cancer. In this investigation, we applied a cell-permeable dipeptidyl nitrile inhibitor of cathepsin S, originally developed to target cathepsin S in inflammatory diseases, in both in vitro and in vivo tumor models. Validation of cathepsin S selectivity was carried out by assaying fluorogenic substrate turnover using recombinant cathepsin protease. Complete kinetic analysis was carried out and true K i values calculated. Abrogation of tumour invasion using murine MC38 and human MCF7 cell lines were carried out in vitro using a transwell migration assay. Effect on endothelial tube formation was evaluated using primary HUVEC cells. The effect of inhibitor in vivo on MC38 and MCF7 tumor progression was evaluated using cells propagated in C57BL/6 and BALB/c mice respectively. Subsequent immunohistochemical staining of proliferation (Ki67) and apoptosis (TUNEL) was carried out on MCF7 tumors. We confirmed that this inhibitor was able to selectively target cathepsin S over family members K, V, L and B. The inhibitor also significantly reduced MC38 and MCF7 cell invasion and furthermore, significantly reduced HUVEC endothelial tubule formation in vitro. In vivo analysis revealed that the compound could significantly reduce tumor volume in murine MC38 syngeneic and MCF7 xenograft models. Immunohistochemical analysis of MCF7 tumors revealed cathepsin S inhibitor treatment significantly reduced proliferation and increased apoptosis. In summary, these results highlight the characterisation of this nitrile cathepsin S inhibitor using in vitro and in vivo tumor models, presenting a compound which may be used to further dissect the role of cathepsin S in cancer progression and may hold therapeutic potential.

Acute serum amyloid A induces migration, angiogenesis, and inflammation in synovial cells in vitro and in a human rheumatoid arthritis/SCID mouse chimera model.

LENUS (Irish Health Repository)

Connolly, Mary

2010-06-01

Serum amyloid A (A-SAA), an acute-phase protein with cytokine-like properties, is expressed at sites of inflammation. This study investigated the effects of A-SAA on chemokine-regulated migration and angiogenesis using rheumatoid arthritis (RA) cells and whole-tissue explants in vitro, ex vivo, and in vivo. A-SAA levels were measured by real-time PCR and ELISA. IL-8 and MCP-1 expression was examined in RA synovial fibroblasts, human microvascular endothelial cells, and RA synovial explants by ELISA. Neutrophil transendothelial cell migration, cell adhesion, invasion, and migration were examined using transwell leukocyte\\/monocyte migration assays, invasion assays, and adhesion assays with or without anti-MCP-1\\/anti-IL-8. NF-kappaB was examined using a specific inhibitor and Western blotting. An RA synovial\\/SCID mouse chimera model was used to examine the effects of A-SAA on cell migration, proliferation, and angiogenesis in vivo. High expression of A-SAA was demonstrated in RA patients (p < 0.05). A-SAA induced chemokine expression in a time- and dose-dependent manner (p < 0.05). Blockade with anti-scavenger receptor class B member 1 and lipoxin A4 (A-SAA receptors) significantly reduced chemokine expression in RA synovial tissue explants (p < 0.05). A-SAA induced cell invasion, neutrophil-transendothelial cell migration, monocyte migration, and adhesion (all p < 0.05), effects that were blocked by anti-IL-8 or anti-MCP-1. A-SAA-induced chemokine expression was mediated through NF-kappaB in RA explants (p < 0.05). Finally, in the RA synovial\\/SCID mouse chimera model, we demonstrated for the first time in vivo that A-SAA directly induces monocyte migration from the murine circulation into RA synovial grafts, synovial cell proliferation, and angiogenesis (p < 0.05). A-SAA promotes cell migrational mechanisms and angiogenesis critical to RA pathogenesis.

CRA-026440: a potent, broad-spectrum, hydroxamic histone deacetylase inhibitor with antiproliferative and antiangiogenic activity in vitro and in vivo.

Science.gov (United States)

Cao, Z Alexander; Bass, Kathryn E; Balasubramanian, Sriram; Liu, Liang; Schultz, Brian; Verner, Erik; Dai, Yuqin; Molina, Rafael A; Davis, Jack R; Misialek, Shawn; Sendzik, Martin; Orr, Christine J; Leung, Ling; Callan, Ondine; Young, Peter; Dalrymple, Stacie A; Buggy, Joseph J

2006-07-01

CRA-026440 is a novel, broad-spectrum, hydroxamic acid-based inhibitor of histone deacetylase (HDAC) that shows antitumor and antiangiogenic activities in vitro and in vivo preclinically. CRA-026440 inhibited pure recombinant isozymes HDAC1, HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-026440 resulted in the accumulation of acetylated histone and acetylated tubulin, leading to an inhibition of tumor cell growth and the induction of apoptosis. CRA-026440 inhibited ex vivo angiogenesis in a dose-dependent manner. CRA-026440 parenterally given to mice harboring HCT116 or U937 human tumor xenografts resulted in a statistically significant reduction in tumor growth. CRA-026440, when used in combination with Avastin, achieved greater preclinical efficacy in HCT 116 colorectal tumor model. Inhibition of tumor growth was accompanied by an increase in the acetylation of alpha-tubulin in peripheral blood mononuclear cells and an alteration in the expression of many genes in the tumors, including several involved in angiogenesis, apoptosis, and cell growth. These results reveal CRA-026440 to be a novel HDAC inhibitor with potent antitumor activity.

Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential.

Science.gov (United States)

Adini, Irit; Adini, Avner; Bazinet, Lauren; Watnick, Randolph S; Bielenberg, Diane R; D'Amato, Robert J

2015-02-01

The incidence of certain angiogenesis-dependent diseases is higher in Caucasians than in African Americans. Angiogenesis is amplified in wound healing and cornea models in albino C57 mice compared with black C57 mice. Moreover, mouse and human melanocytes with low pigmentation stimulate endothelial cell (EC) proliferation and migration in vitro more than melanocytes with high pigmentation. This effect is due, in part, to the secretion of an angiogenic protein called fibromodulin (FMOD) from lowly pigmented melanocytes. Herein, we expand upon the mechanism contributing to increased angiogenesis in lighter skin and report that monocyte chemotactic protein-1 (MCP-1) is secreted by nonpigmented mouse melanocytes by 5- to 10-fold more than pigmented melanocytes. MCP-1 protein stimulates EC proliferation and migration in vitro and angiogenesis in vivo. Mechanistic studies determine that FMOD is upstream of MCP-1 and promotes its secretion from both melanocytes and activated ECs via stimulation of NF-κB activity. Mice injected with FMOD-neutralizing antibodies show 2.3-fold decreased levels of circulating MCP-1. Human studies confirmed that, on average, Caucasians have 2-fold higher serum levels of MCP-1 than African Americans. Taken together, this study implicates the FMOD/MCP-1 pathway in the regulation of angiogenesis by local melanocytes and suggests that melanogenic activity may protect against aberrant angiogenic diseases. © FASEB.

Monitoring angiogenesis using a human compatible calibration for broadband near-infrared spectroscopy

Science.gov (United States)

Yang, Runze; Zhang, Qiong; Wu, Ying; Dunn, Jeff F.

2013-01-01

Angiogenesis is a hallmark of many conditions, including cancer, stroke, vascular disease, diabetes, and high-altitude exposure. We have previously shown that one can study angiogenesis in animal models by using total hemoglobin (tHb) as a marker of cerebral blood volume (CBV), measured using broadband near-infrared spectroscopy (bNIRS). However, the method was not suitable for patients as global anoxia was used for the calibration. Here we determine if angiogenesis could be detected using a calibration method that could be applied to patients. CBV, as a marker of angiogenesis, is quantified in a rat cortex before and after hypoxia acclimation. Rats are acclimated at 370-mmHg pressure for three weeks, while rats in the control group are housed under the same conditions, but under normal pressure. CBV increased in each animal in the acclimation group. The mean CBV (%volume/volume) is 3.49%±0.43% (mean±SD) before acclimation for the experimental group, and 4.76%±0.29% after acclimation. The CBV for the control group is 3.28%±0.75%, and 3.09%±0.48% for the two measurements. This demonstrates that angiogenesis can be monitored noninvasively over time using a bNIRS system with a calibration method that is compatible with human use and less stressful for studies using animals.

Hypoxia-Inducible Factor-1 as Regulator of Angiogenesis in Rheumatoid Arthritis - Therapeutic Implications

NARCIS (Netherlands)

Westra, J.; Molema, G.; Kallenberg, C. G. M.

Angiogenesis plays an important role in the pathogenesis of inflammatory diseases, including rheumatoid arthritis ( RA). The site and extent of inflammation and subsequent joint destruction in the rheumatoid synovium is dependent on the development of new vasculature. Inhibition of angiogenesis,

Ghrelin did not change coronary angiogenesis in diet-induced obese mice.

Science.gov (United States)

Khazaei, M; Tahergorabi, Z

2017-02-28

Ghrelin is a 28 amino acids peptide that initially was recognized as an endogenous ligand for growth hormone secretagogue receptor (GHSR). Recently, a number of studies demonstrated that ghrelin is a cardiovascular hormone with a series cardiovascular effect. The main objective of this study was to investigate the effect of systemic ghrelin administration on angiogenesis in the heart and its correlation with serum leptin levels in normal and diet-induced obese mice. 24 male C57BL/6 mice were randomly divided into four groups: normal diet (ND) or control, ND+ghrelin, high-fat-diet (HFD) or obese and HFD+ghrelin (n=6/group). Obese and control groups received HFD or ND, respectively, for 14 weeks. Then, the ghrelin was injected subcutaneously 100µg/kg twice daily. After 10 days, the animals were sacrificed, blood samples were taken and the hearts were removed. The angiogenic response in the heart was assessed by immunohisochemical staining. HFD significantly increased angiogenesis in the heart expressed as the number of CD31 positive cells than standard diet. Ghrelin did not alter angiogenesis in the heart in both obese and control groups, however, it reduced serum nitric oxide (NO) and leptin levels in obese mice. There was a strong positive correlation between the number of CD31 positive cells and serum leptin concentration (r=0.74). Leptin as an angiogenic factor has a positive correlation with angiogenesis in the heart. Although systemic administration of ghrelin reduced serum leptin and NO levels in obese mice, however, it could not alter coronary angiogenesis.

Cell-Oriented Modeling of Angiogenesis

Directory of Open Access Journals (Sweden)

Diego Guidolin

2011-01-01

Full Text Available Due to its significant involvement in various physiological and pathological conditions, angiogenesis (the development of new blood vessels from an existing vasculature represents an important area of the actual biological research and a field in which mathematical modeling proved particularly useful in supporting the experimental work. In this paper, we focus on a specific modeling strategy, known as “cell-centered” approach. This type of mathematical models work at a “mesoscopic scale,” assuming the cell as the natural level of abstraction for computational modeling of development. They treat cells phenomenologically, considering their essential behaviors to study how tissue structure and organization emerge from the collective dynamics of multiple cells. The main contributions of the cell-oriented approach to the study of the angiogenic process will be described. From one side, they have generated “basic science understanding” about the process of capillary assembly during development, growth, and pathology. On the other side, models were also developed supporting “applied biomedical research” for the purpose of identifying new therapeutic targets and clinically relevant approaches for either inhibiting or stimulating angiogenesis.

An IP-10 (CXCL10)-Derived Peptide Inhibits Angiogenesis

Science.gov (United States)

Yates-Binder, Cecelia C.; Rodgers, Margaret; Jaynes, Jesse; Wells, Alan; Bodnar, Richard J.; Turner, Timothy

2012-01-01

Angiogenesis plays a critical role in processes such as organ development, wound healing, and tumor growth. It requires well-orchestrated integration of soluble and matrix factors and timely recognition of such signals to regulate this process. Previous work has shown that newly forming vessels express the chemokine receptor CXC receptor 3 (CXCR3) and, activation by its ligand IP-10 (CXCL10), both inhibits development of new vasculature and causes regression of newly formed vessels. To identify and develop new therapeutic agents to limit or reverse pathological angiogenesis, we identified a 21 amino acid fragment of IP-10, spanning the α-helical domain residues 77–98, that mimic the actions of the whole IP-10 molecule on endothelial cells. Treatment of the endothelial cells with the 22 amino acid fragment referred to as IP-10p significantly inhibited VEGF-induced endothelial motility and tube formation in vitro, properties critical for angiogenesis. Using a Matrigel plug assay in vivo, we demonstrate that IP-10p both prevented vessel formation and induced involution of nascent vessels. CXCR3 neutralizing antibody was able to block the inhibitory effects of the IP-10p, demonstrating specificity of the peptide. Inhibition of endothelial function by IP-10p was similar to that described for IP-10, secondary to CXCR3-mediated increase in cAMP production, activation of PKA inhibiting cell migration, and inhibition of VEGF-mediated m-calpain activation. IP-10p provides a novel therapeutic agent that inhibits endothelial cell function thus, allowing for the modulation of angiogenesis. PMID:22815829

Dendritic cells regulate angiogenesis associated with liver fibrogenesis.

Science.gov (United States)

Blois, Sandra M; Piccioni, Flavia; Freitag, Nancy; Tirado-González, Irene; Moschansky, Petra; Lloyd, Rodrigo; Hensel-Wiegel, Karin; Rose, Matthias; Garcia, Mariana G; Alaniz, Laura D; Mazzolini, Guillermo

2014-01-01

During liver fibrogenesis the immune response and angiogenesis process are fine-tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt-1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis.

Sodium valproate, a histone deacetylase inhibitor, modulates the vascular endothelial growth inhibitor-mediated cell death in human osteosarcoma and vascular endothelial cells.

Science.gov (United States)

Yamanegi, Koji; Kawabe, Mutsuki; Futani, Hiroyuki; Nishiura, Hiroshi; Yamada, Naoko; Kato-Kogoe, Nahoko; Kishimoto, Hiromitsu; Yoshiya, Shinichi; Nakasho, Keiji

2015-05-01

The level of vascular endothelial growth inhibitor (VEGI) has been reported to be negatively associated with neovascularization in malignant tumors. The soluble form of VEGI is a potent anti-angiogenic factor due to its effects in inhibiting endothelial cell proliferation. This inhibition is mediated by death receptor 3 (DR3), which contains a death domain in its cytoplasmic tail capable of inducing apoptosis that can be subsequently blocked by decoy receptor 3 (DcR3). We investigated the effects of sodium valproate (VPA) and trichostatin A (TSA), histone deacetylase inhibitors, on the expression of VEGI and its related receptors in human osteosarcoma (OS) cell lines and human microvascular endothelial (HMVE) cells. Consequently, treatment with VPA and TSA increased the VEGI and DR3 expression levels without inducing DcR3 production in the OS cell lines. In contrast, the effect on the HMVE cells was limited, with no evidence of growth inhibition or an increase in the DR3 and DcR3 expression. However, VPA-induced soluble VEGI in the OS cell culture medium markedly inhibited the vascular tube formation of HMVE cells, while VEGI overexpression resulted in enhanced OS cell death. Taken together, the HDAC inhibitor has anti-angiogenesis and antitumor activities that mediate soluble VEGI/DR3-induced apoptosis via both autocrine and paracrine pathways. This study indicates that the HDAC inhibitor may be exploited as a therapeutic strategy modulating the soluble VEGI/DR3 pathway in osteosarcoma patients.

Gene therapy and angiogenesis in patients with coronary artery disease

DEFF Research Database (Denmark)

Kastrup, Jens

2010-01-01

Not all patients with severe coronary artery disease can be treated satisfactorily with current recommended medications and revascularization techniques. Various vascular growth factors have the potential to induce angiogenesis in ischemic tissue. Clinical trials have only evaluated the effect...... of VEGF and FGF in patients with coronary artery disease. The initial small and unblinded studies with either recombinant growth factor proteins or genes encoding growth factors were encouraging, demonstrating both clinical improvement and evidence of angiogenesis. However, subsequent larger double...

Gold and silver nanoparticles conjugated with heparin derivative possess anti-angiogenesis properties

Science.gov (United States)

Kemp, Melissa M.; Kumar, Ashavani; Mousa, Shaymaa; Dyskin, Evgeny; Yalcin, Murat; Ajayan, Pulickel; Linhardt, Robert J.; Mousa, Shaker A.

2009-11-01

Silver and gold nanoparticles display unique physical and biological properties that have been extensively studied for biological and medical applications. Typically, gold and silver nanoparticles are prepared by chemical reductants that utilize excess toxic reactants, which need to be removed for biological purposes. We utilized a clean method involving a single synthetic step to prepare metal nanoparticles for evaluating potential effects on angiogenesis modulation. These nanoparticles were prepared by reducing silver nitrate and gold chloride with diaminopyridinyl (DAP)-derivatized heparin (HP) polysaccharides. Both gold and silver nanoparticles reduced with DAPHP exhibited effective inhibition of basic fibroblast growth factor (FGF-2)-induced angiogenesis, with an enhanced anti-angiogenesis efficacy with the conjugation to DAPHP (Pcancer and inflammatory diseases.

Potential role of follicle-stimulating hormone (FSH) and transforming growth factor (TGFβ1) in the regulation of ovarian angiogenesis.

Science.gov (United States)

Kuo, Shih-Wei; Ke, Ferng-Chun; Chang, Geen-Dong; Lee, Ming-Ting; Hwang, Jiuan-Jiuan

2011-06-01

Angiogenesis occurs during ovarian follicle development and luteinization. Pituitary secreted FSH was reported to stimulate the expression of endothelial mitogen VEGF in granulosa cells. And, intraovarian cytokine transforming growth factor (TGF)β1 is known to facilitate FSH-induced differentiation of ovarian granulosa cells. This intrigues us to investigate the potential role of FSH and TGFβ1 regulation of granulosa cell function in relation to ovarian angiogenesis. Granulosa cells were isolated from gonadotropin-primed immature rats and treated once with FSH and/or TGFβ1 for 48 h, and the angiogenic potential of conditioned media (granulosa cell culture conditioned media; GCCM) was determined using an in vitro assay with aortic ring embedded in collagen gel and immunoblotting. FSH and TGFβ1 increased the secreted angiogenic activity in granulosa cells (FSH + TGFβ1 > FSH ≈ TGFβ1 >control) that was partly attributed to the increased secretion of pro-angiogenic factors VEGF and PDGF-B. This is further supported by the evidence that pre-treatment with inhibitor of VEGF receptor-2 (Ki8751) or PDGF receptor (AG1296) throughout or only during the first 2-day aortic ring culture period suppressed microvessel growth in GCCM-treated groups, and also inhibited the FSH + TGFβ1-GCCM-stimulated release of matrix remodeling-associated gelatinase activities. Interestingly, pre-treatment of AG1296 at late stage suppressed GCCM-induced microvessel growth and stability with demise of endothelial and mural cells. Together, we provide original findings that both FSH and TGFβ1 increased the secretion of VEGF and PDGF-B, and that in turn up-regulated the angiogenic activity in rat ovarian granulosa cells. This implicates that FSH and TGFβ1 play important roles in regulation of ovarian angiogenesis during follicle development. Copyright © 2010 Wiley-Liss, Inc.

Angiogenesis and Therapeutic Approaches to NF1 Tumors

National Research Council Canada - National Science Library

Muir, David F

2007-01-01

.... Invivo and in vitro models were used to firmly conclude that Nf1 haploinsufficiency in endothelial cells results inexaggerated proliferation and angiogenesis in response to key pro-angiogenic factors...

Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling

International Nuclear Information System (INIS)

Sun, Yunliang; Wu, Congshan; Ma, Jianxia; Yang, Yu; Man, Xiaohua; Wu, Hongyu; Li, Shude

2016-01-01

Deregulation of Toll-like receptor 4 (TLR4) is closely associated with the progression of various types of cancers, but its role in pancreatic carcinogenesis is unclear. This study aimed to investigate the role of TLR4 in the angiogenesis of pancreatic cancer and the underlying molecular mechanisms. The culture supernatant (conditioned medium) of PANC-1 cells after appropriate treatment was used for the treatment of HUVECs. The proliferation, migration and tube formation of HUVECs were assessed by MTT, Transwell and Matrigel, respectively. In pancreatic cancer tissues, TLR4, VEGF and CD31 were upregulated as determined by immunohistochemistry and the expression of TLR4 and VEGF was positively correlated with microvessel density as detected by CD31 staining. Activation of TLR4 signaling by LPS in PANC-1 cells resulted in increased VEGF and phosphorylation of AKT, which were abolished by TLR4 silencing with siRNA and PI3K/AKT signaling inhibitor LY294002. The conditioned medium from PANC-1 cells treated with LY294002 or transfected with TRL4 siRNA reduced the proliferation, migration and tube formation of HUVECs. In contrast, the conditioned medium from PANC-1 cells treated with LPS stimulated the proliferation, migration and tube formation of HUVECs, which was however significantly inhibited by pretreatment of PANC-1 cells with LY294002 or transfection with TRL4 siRNA. Our findings suggest TLR4 may promote angiogenesis in pancreatic cancer by activating the PI3K/AKT signaling pathway to induce VEGF expression.

Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling

Energy Technology Data Exchange (ETDEWEB)

Sun, Yunliang; Wu, Congshan [Department of Gastroenterology, Lianyungang Ganyu People’s Hospital, Ganyu, Jiangsu (China); Ma, Jianxia, E-mail: yz_mjx@163.com [Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai (China); Yang, Yu [Department of Gastroenterology, Huadong Hospital, Fudan University, Shanghai (China); Man, Xiaohua; Wu, Hongyu; Li, Shude [Department of Gastroenterology, Changhai Hospital, The Second Military Medical University, Shanghai (China)

2016-10-01

Deregulation of Toll-like receptor 4 (TLR4) is closely associated with the progression of various types of cancers, but its role in pancreatic carcinogenesis is unclear. This study aimed to investigate the role of TLR4 in the angiogenesis of pancreatic cancer and the underlying molecular mechanisms. The culture supernatant (conditioned medium) of PANC-1 cells after appropriate treatment was used for the treatment of HUVECs. The proliferation, migration and tube formation of HUVECs were assessed by MTT, Transwell and Matrigel, respectively. In pancreatic cancer tissues, TLR4, VEGF and CD31 were upregulated as determined by immunohistochemistry and the expression of TLR4 and VEGF was positively correlated with microvessel density as detected by CD31 staining. Activation of TLR4 signaling by LPS in PANC-1 cells resulted in increased VEGF and phosphorylation of AKT, which were abolished by TLR4 silencing with siRNA and PI3K/AKT signaling inhibitor LY294002. The conditioned medium from PANC-1 cells treated with LY294002 or transfected with TRL4 siRNA reduced the proliferation, migration and tube formation of HUVECs. In contrast, the conditioned medium from PANC-1 cells treated with LPS stimulated the proliferation, migration and tube formation of HUVECs, which was however significantly inhibited by pretreatment of PANC-1 cells with LY294002 or transfection with TRL4 siRNA. Our findings suggest TLR4 may promote angiogenesis in pancreatic cancer by activating the PI3K/AKT signaling pathway to induce VEGF expression.

Local injection of high-molecular hyaluronan promotes wound healing in old rats by increasing angiogenesis.

Science.gov (United States)

Huang, Luying; Wang, Yi; Liu, Hua; Huang, Jianhua

2018-02-02

Impaired angiogenesis contributes to delayed wound healing in aging. Hyaluronan (HA) has a close relationship with angiogenesis and wound healing. However, HA content decreases with age. In this study, we used high molecular weight HA (HMW-HA) (1650 kDa), and investigated its effects on wound healing in old rats by local injection. We found that HMW-HA significantly increases proliferation, migration and tube formation in endothelial cells, and protects endothelial cells against apoptosis. Local injection of HMW-HA promotes wound healing by increasing angiogenesis in old rats. HMW-HA increases the phosphorylation of Src, ERK and AKT, leading to increased angiogenesis, suggesting that local injection of HMW-HA promotes wound healing in elderly patients.

Desert hedgehog promotes ischemia-induced angiogenesis by ensuring peripheral nerve survival.

Science.gov (United States)

Renault, Marie-Ange; Chapouly, Candice; Yao, Qinyu; Larrieu-Lahargue, Frédéric; Vandierdonck, Soizic; Reynaud, Annabel; Petit, Myriam; Jaspard-Vinassa, Béatrice; Belloc, Isabelle; Traiffort, Elisabeth; Ruat, Martial; Duplàa, Cécile; Couffinhal, Thierry; Desgranges, Claude; Gadeau, Alain-Pierre

2013-03-01

Blood vessel growth and patterning have been shown to be regulated by nerve-derived signals. Desert hedgehog (Dhh), one of the Hedgehog family members, is expressed by Schwann cells of peripheral nerves. The purpose of this study was to investigate the contribution of Dhh to angiogenesis in the setting of ischemia. We induced hindlimb ischemia in wild-type and Dhh(-/-) mice. First, we found that limb perfusion is significantly impaired in the absence of Dhh. This effect is associated with a significant decrease in capillary and artery density in Dhh(-/-). By using mice in which the Hedgehog signaling pathway effector Smoothened was specifically invalidated in endothelial cells, we demonstrated that Dhh does not promote angiogenesis by a direct activation of endothelial cells. On the contrary, we found that Dhh promotes peripheral nerve survival in the ischemic muscle and, by doing so, maintains the pool of nerve-derived proangiogenic factors. Consistently, we found that denervation of the leg, immediately after the onset of ischemia, severely impairs ischemia-induced angiogenesis and decreases expression of vascular endothelial growth factor A, angiopoietin 1, and neurotrophin 3 in the ischemic muscle. This study demonstrates the crucial roles of nerves and factors regulating nerve physiology in the setting of ischemia-induced angiogenesis.

Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis

International Nuclear Information System (INIS)

Shibuya, Masabumi; Claesson-Welsh, Lena

2006-01-01

The VEGF/VPF (vascular endothelial growth factor/vascular permeability factor) ligands and receptors are crucial regulators of vasculogenesis, angiogenesis, lymphangiogenesis and vascular permeability in vertebrates. VEGF-A, the prototype VEGF ligand, binds and activates two tyrosine kinase receptors: VEGFR1 (Flt-1) and VEGFR2 (KDR/Flk-1). VEGFR1, which occurs in transmembrane and soluble forms, negatively regulates vasculogenesis and angiogenesis during early embryogenesis, but it also acts as a positive regulator of angiogenesis and inflammatory responses, playing a role in several human diseases such as rheumatoid arthritis and cancer. The soluble VEGFR1 is overexpressed in placenta in preeclampsia patients. VEGFR2 has critical functions in physiological and pathological angiogenesis through distinct signal transduction pathways regulating proliferation and migration of endothelial cells. VEGFR3, a receptor for the lymphatic growth factors VEGF-C and VEGF-D, but not for VEGF-A, regulates vascular and lymphatic endothelial cell function during embryogenesis. Loss-of-function variants of VEGFR3 have been identified in lymphedema. Formation of tumor lymphatics may be stimulated by tumor-produced VEGF-C, allowing increased spread of tumor metastases through the lymphatics. Mapping the signaling system of these important receptors may provide the knowledge necessary to suppress specific signaling pathways in major human diseases

A Mouse Model of the Cornea Pocket Assay for Angiogenesis Study

Science.gov (United States)

Tang, Zhongshu; Zhang, Fan; Li, Yang; Arjunan, Pachiappan; Kumar, Anil; Lee, Chunsik; Li, Xuri

2011-01-01

A normal cornea is clear of vascular tissues. However, blood vessels can be induced to grow and survive in the cornea when potent angiogenic factors are administered 1. This uniqueness has made the cornea pocket assay one of the most used models for angiogenesis studies. The cornea composes multiple layers of cells. It is therefore possible to embed a pellet containing the angiogenic factor of interest in the cornea to investigate its angiogenic effect 2,3. Here, we provide a step by step demonstration of how to (I) produce the angiogenic factor-containing pellet (II) embed the pellet into the cornea (III) analyze the angiogenesis induced by the angiogenic factor of interest. Since the basic fibroblast growth factor (bFGF) is known as one of the most potent angiogenic factors 4, it is used here to induce angiogenesis in the cornea. PMID:21876523

Angiogenesis is not impaired in connective tissue growth factor (CTGF) knock-out mice

NARCIS (Netherlands)

Kuiper, Esther J.; Roestenberg, Peggy; Ehlken, Christoph; Lambert, Vincent; van Treslong-de Groot, Henny Bloys; Lyons, Karen M.; Agostini, Hans-Jürgen T.; Rakic, Jean-Marie; Klaassen, Ingeborg; van Noorden, Cornelis J. F.; Goldschmeding, Roel; Schlingemann, Reinier O.

2007-01-01

Connective tissue growth factor (CTGF) is a member of the CCN family of growth factors. CTGF is important in scarring, wound healing, and fibrosis. It has also been implicated to play a role in angiogenesis, in addition to vascular endothelial growth factor (VEGF). In the eye, angiogenesis and

Fibromodulin Enhances Angiogenesis during Cutaneous Wound Healing

Directory of Open Access Journals (Sweden)

Zhong Zheng, PhD

2014-12-01

Conclusions: Altogether, we demonstrated that in addition to reducing scar formation, FMOD also promotes angiogenesis. As blood vessels organize and regulate wound healing, its potent angiogenic properties will further expand the clinical application of FMOD for cutaneous healing of poorly vascularized wounds.

The influence of platelet- derived products on angiogenesis and tissue repair: a concise update

Directory of Open Access Journals (Sweden)

Constanza E Martínez

2015-10-01

Full Text Available Platelet degranulation allows the release of a large amount of soluble mediators, is an essential step for wound healing initiation, and stimulates clotting and angiogenesis. The latter process is one of the most critical biological events observed during tissue repair,increasing the growth of blood vessels in the maturing wound. Angiogenesis requires the action of a variety of growth factors that act in an appropriate physiological ratio to assure functional blood vessel restoration. Platelets release main regulators of angiogenesis: Vascular Endothelial Growth Factors (VEGFs, basic fibroblast growth factor (FGF-2, and Platelet derived growth factors (PDGFs, among others. In order to stimulate tissue repair, platelet derived fractions have been used as an autologous source of growth factors and biomolecules, namely Platelet Rich Plasma (PRP, Platelet Poor Plasma (PPP and Platelet Rich Fibrin(PRF. The continuous release of these growth factors has been proposed to promote angiogenesis both in vitro and in vivo. Considering the existence of clinical trials currently evaluating the efficacy of autologous PRP, the present review analyses fundamental questions regarding the putative role of platelet derived fractions as regulators of angiogenesis and evaluates the possible clinical implications of these formulations.

Cytokines and Angiogenesis in the Corpus Luteum

Directory of Open Access Journals (Sweden)

António M. Galvão

2013-01-01

Full Text Available In adults, physiological angiogenesis is a rare event, with few exceptions as the vasculogenesis needed for tissue growth and function in female reproductive organs. Particularly in the corpus luteum (CL, regulation of angiogenic process seems to be tightly controlled by opposite actions resultant from the balance between pro- and antiangiogenic factors. It is the extremely rapid sequence of events that determines the dramatic changes on vascular and nonvascular structures, qualifying the CL as a great model for angiogenesis studies. Using the mare CL as a model, reports on locally produced cytokines, such as tumor necrosis factor α (TNF, interferon gamma (IFNG, or Fas ligand (FASL, pointed out their role on angiogenic activity modulation throughout the luteal phase. Thus, the main purpose of this review is to highlight the interaction between immune, endothelial, and luteal steroidogenic cells, regarding vascular dynamics/changes during establishment and regression of the equine CL.

VEGF blockade inhibits angiogenesis and reepithelialization of endometrium.

Science.gov (United States)

Fan, Xiujun; Krieg, Sacha; Kuo, Calvin J; Wiegand, Stanley J; Rabinovitch, Marlene; Druzin, Maurice L; Brenner, Robert M; Giudice, Linda C; Nayak, Nihar R

2008-10-01

Despite extensive literature on vascular endothelial growth factor (VEGF) expression and regulation by steroid hormones, the lack of clear understanding of the mechanisms of angiogenesis in the endometrium is a major limitation for use of antiangiogenic therapy targeting endometrial vessels. In the current work, we used the rhesus macaque as a primate model and the decidualized mouse uterus as a murine model to examine angiogenesis during endometrial breakdown and regeneration. We found that blockade of VEGF action with VEGF Trap, a potent VEGF blocker, completely inhibited neovascularization during endometrial regeneration in both models but had no marked effect on preexisting or newly formed vessels, suggesting that VEGF is essential for neoangiogenesis but not survival of mature vessels in this vascular bed. Blockade of VEGF also blocked reepithelialization in both the postmenstrual endometrium and the mouse uterus after decidual breakdown, evidence that VEGF has pleiotropic effects in the endometrium. In vitro studies with a scratch wound assay showed that the migration of luminal epithelial cells during repair involved signaling through VEGF receptor 2-neuropilin 1 (VEGFR2-NP1) receptors on endometrial stromal cells. The leading front of tissue growth during endometrial repair was strongly hypoxic, and this hypoxia was the local stimulus for VEGF expression and angiogenesis in this tissue. In summary, we provide novel experimental data indicating that VEGF is essential for endometrial neoangiogenesis during postmenstrual/postpartum repair.

Anti-angiogenesis effect of the novel anti-inflammatory and pro-resolving lipid mediators.

Science.gov (United States)

Jin, Yiping; Arita, Makoto; Zhang, Qiang; Saban, Daniel R; Chauhan, Sunil K; Chiang, Nan; Serhan, Charles N; Dana, Reza

2009-10-01

Resolvins and lipoxins are lipid mediators generated from essential polyunsaturated fatty acids that are the first dual anti-inflammatory and pro-resolving signals identified in the resolution phase of inflammation. Here the authors investigated the potential of aspirin-triggered lipoxin (LX) A4 analog (ATLa), resolving (Rv) D1, and RvE1, in regulating angiogenesis in a murine model. ATLa and RvE1 receptor expression was tested in different corneal cell populations by RT-PCR. Corneal neovascularization (CNV) was induced by suture or micropellet (IL-1 beta, VEGF-A) placement. Mice were then treated with ATLa, RvD1, RvE1, or vehicle, subconjunctivally at 48-hour intervals. Infiltration of neutrophils and macrophages was quantified after immunofluorescence staining. The mRNA expression levels of inflammatory cytokines, VEGFs, and VEGFRs were analyzed by real-time PCR. CNV was evaluated intravitally and morphometrically. The receptors for LXA4, ALX/Fpr-rs-2 and for RvE1, ChemR23 were each expressed by epithelium, stromal keratocytes, and infiltrated CD11b(+) cells in corneas. Compared to the vehicle-treated eye, ATLa-, RvD1-, and RvE1-treated eyes had reduced numbers of infiltrating neutrophils and macrophages and reduced mRNA expression levels of TNF-alpha, IL-1 alpha, IL-1 beta, VEGF-A, VEGF-C, and VEGFR2. Animals treated with these mediators had significantly suppressed suture-induced or IL-1 beta-induced hemangiogenesis (HA) but not lymphangiogenesis. Interestingly, only the application of ATLa significantly suppressed VEGF-A-induced HA. ATLa, RvE1, and RvD1 all reduce inflammatory corneal HA by early regulation of resolution mechanisms in innate immune responses. In addition, ATLa directly inhibits VEGF-A-mediated angiogenesis and is the most potent inhibitor of NV among this new genus of dual anti-inflammatory and pro-resolving lipid mediators.

Indirubin inhibits cell proliferation, migration, invasion and angiogenesis in tumor-derived endothelial cells

Directory of Open Access Journals (Sweden)

Li Z

2018-05-01

Full Text Available Zhuohong Li, Chaofu Zhu, Baiping An, Yu Chen, Xiuyun He, Lin Qian, Lan Lan, Shijie Li Department of Oncology, The Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China Purpose: Hepatocellular carcinoma is one of the most predominant malignancies with high fatality rate and its incidence is rising at an alarming rate because of its resistance to radio- and chemotherapy. Indirubin is the major active anti-tumor ingredient of a traditional Chinese herbal medicine. The present study aimed to analyze the effects of indirubin on cell proliferation, migration, invasion, and angiogenesis of tumor-derived endothelial cells (Td-EC. Methods: Td-EC were derived from human umbilical vein endothelial cells (HUVEC by treating HUVEC with the conditioned medium of human liver cancer cell line HepG2. Cell proliferation, migration, invasion, and angiogenesis were assessed by MTT, wound healing, in vitro cell invasion, and in vitro tube formation assay. Results: Td-EC were successfully obtained from HUVEC cultured with 50% culture supernatant from serum-starved HepG2 cells. Indirubin significantly inhibited Td-EC proliferation in a dose- and time-dependent manner. Indirubin also inhibited Td-EC migration, invasion, and angiogenesis. However, indirubin’s effects were weaker on HUVEC than Td-EC. Conclusion: Indirubin significantly inhibited Td-EC proliferation, migration, invasion, and angiogenesis. Keywords: indirubin, Td-EC, proliferation, migration, invasion, angiogenesis

Hypoxia-driven angiogenesis: role of tip cells and extracellular matrix scaffolding.

Science.gov (United States)

Germain, Stéphane; Monnot, Catherine; Muller, Laurent; Eichmann, Anne

2010-05-01

Angiogenesis is a highly coordinated tissue remodeling process leading to blood vessel formation. Hypoxia triggers angiogenesis via induction of expression of growth factors such as vascular endothelial growth factor (VEGF). VEGF instructs endothelial cells to form tip cells, which lead outgrowing capillary sprouts, whereas Notch signaling inhibits sprout formation. Basement membrane deposition and mechanical cues from the extracellular matrix (ECM) induced by hypoxia may participate to coordinated vessel sprouting in conjunction with the VEGF and Notch signaling pathways. Hypoxia regulates ECM composition, deposition, posttranslational modifications and rearrangement. In particular, hypoxia-driven vascular remodeling is dynamically regulated through modulation of ECM-modifying enzyme activities that eventually affect both matricellular proteins and growth factor availability. Better understanding of the complex interplay between endothelial cells and soluble growth factors and mechanical factors from the ECM will certainly have significant implications for understanding the regulation of developmental and pathological angiogenesis driven by hypoxia.

Lung cancer and angiogenesis imaging using synchrotron radiation

International Nuclear Information System (INIS)

Liu Xiaoxia; Zhao Jun; Xu, Lisa X; Sun Jianqi; Gu Xiang; Liu Ping; Xiao Tiqiao

2010-01-01

Early detection of lung cancer is the key to a cure, but a difficult task using conventional x-ray imaging. In the present study, synchrotron radiation in-line phase-contrast imaging was used to study lung cancer. Lewis lung cancer and 4T1 breast tumor metastasis in the lung were imaged, and the differences were clearly shown in comparison to normal lung tissue. The effect of the object-detector distance and the energy level on the phase-contrast difference was investigated and found to be in good agreement with the theory of in-line phase-contrast imaging. Moreover, 3D image reconstruction of lung tumor angiogenesis was obtained for the first time using a contrast agent, demonstrating the feasibility of micro-angiography with synchrotron radiation for imaging tumor angiogenesis deep inside the body.

Regulation of Angiogenesis by Aminoacyl-tRNA Synthetases

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Adam C. Mirando

2014-12-01

Full Text Available In addition to their canonical roles in translation the aminoacyl-tRNA synthetases (ARSs have developed secondary functions over the course of evolution. Many of these activities are associated with cellular survival and nutritional stress responses essential for homeostatic processes in higher eukaryotes. In particular, six ARSs and one associated factor have documented functions in angiogenesis. However, despite their connection to this process, the ARSs are mechanistically distinct and exhibit a range of positive or negative effects on aspects of endothelial cell migration, proliferation, and survival. This variability is achieved through the appearance of appended domains and interplay with inflammatory pathways not found in prokaryotic systems. Complete knowledge of the non-canonical functions of ARSs is necessary to understand the mechanisms underlying the physiological regulation of angiogenesis.

Their function on angiogenesis and cellular signalling

Indian Academy of Sciences (India)

Copper, although known as a micronutrient, has a pivotal role in modulating the cellular metabolism. Many studieshave reported the role of copper in angiogenesis. Copper chaperones are intracellular proteins that mediate coppertrafficking to various cell organelles. However, the role and function of copper chaperones in ...

Effect of the micronutrient iodine in thyroid carcinoma angiogenesis.

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Daniell, Kayla; Nucera, Carmelo

2016-12-20

Iodide is a micronutrient essential for thyroid hormone production. The uptake and metabolism of iodide by thyrocytes is crucial to proper thyroid function. Iodide ions are drawn into the thyroid follicular cell via the sodium-iodide symporter (NIS) in the cell membrane and become integrated into tyrosyl residues to ultimately form thyroid hormones. We sought to learn how an abnormal concentration of iodide within thyrocyte can have significant effects on the thyroid, specifically the surrounding vascular network. Insufficient levels of iodide can lead to increased expression or activity of several pathways, including vascular endothelial growth factor (VEGF). The VEGF protein fuel vessel growth (angiogenesis) and therefore enhances the nutrients available to surrounding cells. Alternatively, normal/surplus iodide levels can have inhibitory effects on angiogenesis. Varying levels of iodide in the thyroid can influence thyroid carcinoma cell proliferation and angiogenesis via regulation of the hypoxia inducible factor-1 (HIF-1) and VEGF-dependent pathway. We have reviewed a number of studies to investigate how the effect of iodide on angiogenic and oxidative stress regulation can affect the viability of thyroid carcinoma cells. The various studies outlined give key insights to the role of iodide in thyroid follicles function and vascular growth, generally highlighting that insufficient levels of iodide stimulate pathways resulting in vascular growth, and viceversa normal/surplus iodide levels inhibit such pathways. Intriguingly, TSH and iodine levels differentially regulate the expression levels of angiogenic factors. All cells, including carcinoma cells, increase uptake of blood nutrients, meaning the vascular profile is influential to tumor growth and progression. Importantly, variation in the iodine concentrations also influence BRAF V600E -mediated oncogenic activity and might deregulate tumor proliferation. Although the mechanisms are not well eluted, iodine

Recent advances in the discovery of small molecule c-Met Kinase inhibitors.

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Parikh, Palak K; Ghate, Manjunath D

2018-01-01

c-Met is a prototype member of a subfamily of heterodimeric receptor tyrosine kinases (RTKs) and is the receptor for hepatocyte growth factor (HGF). Binding of HGF to its receptor c-Met, initiates a wide range of cellular signalling, including those involved in proliferation, motility, migration and invasion. Importantly, dysregulated HGF/c-Met signalling is a driving factor for numerous malignancies and promotes tumour growth, invasion, dissemination and/or angiogenesis. Dysregulated HGF/c-Met signalling has also been associated with poor clinical outcomes and resistance acquisition to some approved targeted therapies. Thus, c-Met kinase has emerged as a promising target for cancer drug development. Different therapeutic approaches targeting the HGF/c-Met signalling pathway are under development for targeted cancer therapy, among which small molecule inhibitors of c-Met kinase constitute the largest effort within the pharmaceutical industry. The review is an effort to summarize recent advancements in medicinal chemistry development of small molecule c-Met kinase inhibitors as potential anti-cancer agents which would certainly help future researchers to bring further developments in the discovery of small molecule c-Met kinase inhibitors. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The orally available multikinase inhibitor regorafenib (BAY 73-4506) in multiple myeloma.

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Breitkreutz, Iris; Podar, Klaus; Figueroa-Vazquez, Vianihuini; Wilhelm, Scott; Hayden, Patrick J; Anderson, Kenneth C; Raab, Marc S

2018-05-01

A promising approach to the treatment of multiple myeloma (MM) involves agents that target not only the myeloma cells directly, but also the tumor microenvironment which promotes tumor cell growth, angiogenesis, and MM bone disease. Here we investigate the orally available multikinase inhibitor, regorafenib (BAY 73-4506), for its therapeutic efficacy in MM. Regorafenib is a potent inhibitor of angiogenic (VEGFR 1-3, PDGFR-b) as well as oncogenic (c-KIT, RET, FGFR, Raf) kinases. We show that regorafenib induces apoptosis in all MM cell lines at below clinically achievable concentrations. Regorafenib overcomes the growth advantage conferred by a stroma cell MM and an endothelial cell MM, co-culture systems, and abrogates growth factor-stimulated MEK, ERK, and AKT phosphorylation at nanomolar to micromolar concentrations. Moreover, it inhibits endothelial cell growth and tubule formation, abrogates both VEGF secretion and VEGF-induced MM cell migration, inhibits osteoclastogenesis, and shows synergistic cytotoxicity with dexamethasone, the immunomodulatory drug pomalidomide, and the p110δ inhibitor idelalisib. Most importantly, regorafenib significantly delays tumor growth in a xenograft mouse model of human MM. These results provide the rationale for further clinical evaluation of regorafenib, alone and in combination, in the treatment of MM.

DSGOST inhibits tumor growth by blocking VEGF/VEGFR2-activated angiogenesis.

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Choi, Hyeong Sim; Lee, Kangwook; Kim, Min Kyoung; Lee, Kang Min; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

2016-04-19

Tumor growth requires a process called angiogenesis, a new blood vessel formation from pre-existing vessels, as newly formed vessels provide tumor cells with oxygen and nutrition. Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang (DSGOST), one of traditional Chinese medicines, has been widely used in treatment of vessel diseases including Raynaud's syndrome in Northeast Asian countries including China, Japan and Korea. Therefore, we hypothesized that DSGOST might inhibit tumor growth by targeting newly formed vessels on the basis of its historical prescription. Here, we demonstrate that DSGOST inhibits tumor growth by inhibiting VEGF-induced angiogenesis. DSGOST inhibited VEGF-induced angiogenic abilities of endothelial cells in vitro and in vivo, which resulted from its inhibition of VEGF/VEGFR2 interaction. Furthermore, DSGOST attenuated pancreatic tumor growth in vivo by reducing angiogenic vessel numbers, while not affecting pancreatic tumor cell viability. Thus, our data conclude that DSGOST inhibits VEGF-induced tumor angiogenesis, suggesting a new indication for DSGOST in treatment of cancer.

Photoacoustic imaging of angiogenesis in subdermal islet transplant sites

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Shi, Wei; Pawlick, Rena; Bruni, Antonio; Rafiei, Yasmin; Pepper, Andrew R.; Gala-Lopez, Boris; Choi, Min; Malcolm, Andrew; Zemp, Roger J.; Shapiro, A. M. James

2016-03-01

Exogenous insulin administration is the mainstay treatment therapy for patients with Type-1 diabetes mellitus (T1DM). However, for select patients, clinical islet transplantation is an alternative therapeutic treatment. In this procedure, islets are transplanted into the hepatic portal vein, and despite improved success within the last decade, obstacles are still associated with this approach. It has been discovered that the subcutaneous space may be an effective alternative site for islet transplantation, and may provide advantages of easy access and potential for simple monitoring. The ability to monitor islet viability and the transplant microenvironment may be key to future success in islet transplantation. A subcutaneous device-less technique has been developed to facilitate angiogenesis in the islet transplant site, however, a method for monitoring the potential engraftment site have yet to be explored fully. Here we demonstrate the ability to track angiogenesis in mice with 1, 2, 3 and 4 weeks post-catheter implant on both sides of the abdomen using a FujiFilm VisualSonics Vevo-LAZR system. Quantitative analysis on vessel densities exhibited gradual vessel growth successfully induced by catheter implantation. Our study demonstrates the ability of employing photoacoustic and micro-ultrasound imaging to track angiogenesis around the catheter site prior to islet transplantation.

Wound healing effects of dipeptidyl peptidase-4 inhibitors: An emerging concept in management of diabetic foot ulcer-A review.

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Saboo, Apoorva; Rathnayake, Ayeshmanthe; Vangaveti, Venkat N; Malabu, Usman H

2016-01-01

Dipeptidyl peptidase-4 (DPP-4) inhibitors have a well-known effect on glycaemic control in patients with diabetes but little is known on their wound healing role in this group of population. This paper reviews the effects of DPP-4 inhibitors on wound healing of diabetic foot ulcers. Published data on effects and mechanism of DDP-4 inhibitors on wound healing were derived from Medline, PubMed and Google Scholar search of English language literature from 1994 to 2014 using the key words such as "DPP-4 inhibitors", "endothelial healing" "diabetes" and "chronic ulcers". DPP-4 inhibitors show a potential benefit in processes of wound healing in diabetic chronic foot ulcers. The enzyme inhibitors promote recruitment of endothelial progenitor cells and allow the final scaffolding of wounds. Furthermore DPP-4 inhibitors augment angiogenesis and have widespread effects on optimising the immune response to persistent hypoxia in chronic diabetes wounds. DPP-4 inhibitors show promise in the local wound healing of diabetic foot ulcers in addition to its already established glycaemic control. In the light of high rate of amputations due to non-healing ulcers with profound psychological and economical liability, more investigations on the usefulness of DPP-4 inhibitors in the high risk diabetes population are needed. Copyright © 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Roles of tissue plasminogen activator and its inhibitor in proliferative diabetic retinopathy

Institute of Scientific and Technical Information of China (English)

Shu-Ling; Wu; Dong-Mei; Zhan; Shu-Hong; Xi; Xiang-Lian; He

2014-01-01

AIM:To investigate the role of tissue plasminogen activator(t-PA) and plasminogen activator inhibitor(PAI)in proliferative diabetic retinopathy(PDR) and to discuss the correlations among t-PA, PAI and vascular endothelial growth factor(VEGF) expressions.METHODS:A total of 36 vitreous samples were collected from 36 patients with PDR(PDR group), and 17 vitreous samples from 17 patients with idiopathic macular hole were used as control. The concentrations of t-PA, PAI and VEGF in samples were determined by ELISA method. The correlations among t-PA, PAI and VEGF expressions were discussed.RESULTS:The concentrations of t-PA, PAI and VEGF in the PDR group were significantly higher than those in the control group(P <0.001). The t-PA and PAI expressions were highly correlated with the VEGF expression(P <0.001).CONCLUSION:In addition to VEGF, a variety of bioactive substances, such as t-PA and PAI, are involved in the pathogenesis involved in the angiogenesis of PDR.VEGF can activate t-PA expression, resulting in collagen tissue degradation and angiogenesis. VEGF may also activate the mechanism for endogenous anti-neovascularization.

Critical role of CDK11p58 in human breast cancer growth and angiogenesis

International Nuclear Information System (INIS)

Chi, Yayun; Huang, Sheng; Peng, Haojie; Liu, Mengying; Zhao, Jun; Shao, Zhiming; Wu, Jiong

2015-01-01

A capillary network is needed in cancer growth and metastasis. Induction of angiogenesis represents one of the major hallmarks of cancer. CDK11 p58 , a Ser/Thr kinase that belongs to the Cell Division Cycle 2-like 1 (CDC2L1) subfamily is associated with cell cycle progression, tumorigenesis, sister chromatid cohesion and apoptotic signaling. However, its role in breast cancer proliferation and angiogenesis remains unclear. Tumorigenicity assays and blood vessel assessment in athymic mice were used to assess the function of CDK11 p58 in tumor proliferation and angiogenesis. CCK-8 assay was used to detect breast cancer cell growth. Immunohistochemistry was used to detect the expression of vascular endothelial growth factor (VEGF), CD31 and CD34 in CDK11 positive patient breast cancer tissues. Dual-Luciferase array was used to analyze the function of CDK11 p58 in the regulation of VEGF promoter activity. Western blot was used to detect related protein expression levels. CDK11 p58 inhibited breast cancer growth and angiogenesis in breast cancer cells and in nude mice transplanted with tumors. Immunohistochemistry confirmed that CDK11 p58 was negatively associated with angiogenesis-related proteins such as VEGF, CD31 and CD34 in breast cancer patients. Real-time PCR and dual-luciferase assay showed CDK11 p58 inhibited the mRNA levels of VEGF and the promoter activity of VEGF. As CDK11 p58 is a Ser/Thr kinase, the kinase-dead mutant failed to inhibit VEGF mRNA and promoter activity. Western blot analysis showed the same pattern of related protein expression. The data suggested angiogenesis inhibition was dependent on CDK11 p58 kinase activity. This study indicates that CDK11 p58 inhibits the growth and angiogenesis of breast cancer dependent on its kinase activity. The online version of this article (doi:10.1186/s12885-015-1698-7) contains supplementary material, which is available to authorized users

Surgical revascularization induces angiogenesis in orthotopic bone allograft

NARCIS (Netherlands)

Willems, Wouter F.; Kremer, Thomas; Friedrich, Patricia; Bishop, Allen T.

2012-01-01

Remodeling of structural bone allografts relies on adequate revascularization, which can theoretically be induced by surgical revascularization. We developed a new orthotopic animal model to determine the technical feasibility of axial arteriovenous bundle implantation and resultant angiogenesis. We

Chalkley estimates of angiogenesis in early breast cancer--relevance to prognosis

DEFF Research Database (Denmark)

Offersen, Birgitte V; Sørensen, Flemming Brandt; Yilmaz, Mette

2002-01-01

The aim of this study was to investigate whether Chalkley estimates of angiogenesis add new knowledge regarding prediction of prognosis in 455 consecutive early breast carcinomas, both node-positive (52%) and node-negative (48%). Median follow-up was 101 months. Intense vascularization indicated......, high malignancy grade, negative oestrogen receptor, and increasing Chalkley counts (both tertiles and continuous) were independent markers of disease-specific death. Thus, in a univariate analysis it was found that high Chalkley estimates of angiogenesis indicated a poor prognosis, but high Chalkley...

The Use of Novel PET Tracers to Image Breast Cancer Biologic Processes Such as Proliferation, DNA Damage and Repair, and Angiogenesis.

Science.gov (United States)

Kenny, Laura

2016-02-01

The balance between proliferation and cell death is pivotal to breast tumor growth. Because of a combination of environmental and genetic factors leading to activation of oncogenes or inactivation of tumor suppressor genes, these processes become deregulated in cancer. PET imaging of proliferation, angiogenesis, and DNA damage and repair offers the opportunity to monitor therapeutic efficacy to detect changes in tumor biology that may precede physical size reduction and simultaneously allows the study of intratumoral and intertumoral heterogeneity.This review examines recent developments in breast cancer imaging using novel probes. The probes discussed here are not licensed for routine use and are at various stages of development ranging from preclinical development (e.g., the DNA repair marker γH2AX) to clinical validation in larger studies (such as the proliferation probe 3'-deoxy-3'-(18)F-fluorothymidine [(18)F-FLT]). In breast cancer, most studies have focused on proliferation imaging mainly based on (18)F-labeled thymidine analogs. Initial studies have been promising; however, the results of larger validation studies are necessary before being incorporated into routine clinical use. Although there are distinct advantages in using process-specific probes, properties such as metabolism need careful consideration, because high background uptake in the liver due to glucuronidation in the case of (18)F-FLT may limit utility for imaging of liver metastases.Targeting angiogenesis has had some success in tumors such as renal cell carcinoma; however, angiogenesis inhibitors have not been particularly successful in the clinical treatment of breast cancer. This could be potentially attributed to patient selection due to the lack of validated predictive and responsive biomarkers; the quest for a successful noninvasive biomarker for angiogenesis could solve this challenge. Finally, we look at cell death including apoptosis and DNA damage and repair probes, the most well

Cyclooxygenase-2 Pathway Correlates with VEGF Expression in Head and Neck Cancer. Implications for Tumor Angiogenesis and Metastasis

Directory of Open Access Journals (Sweden)

Oreste Gallo

2001-01-01

Full Text Available We evaluated the role of COX-2 pathway in 35 head and neck cancers (HNCs by analyzing COX-2 expression and prostaglandin E2 (PGE2 production in relation to tumor angiogenesis and lymph node metastasis. COX-2 activity was also correlated to vascular endothelial growth factor (VEGF mRNA and protein expression. COX-2 mRNA and protein expression was higher in tumor samples than in normal mucosa. PGE2 levels were higher in the tumor front zone in comparison with tumor core and normal mucosa (P<0001. Specimens from patients with lymph node metastasis exhibited higher COX-2 protein expression (P=.0074, PGEZ levels (P=.0011 and microvessel density (P<.0001 than specimens from patients without metastasis. A significant correlation between COX-2 and tumor vascularization (rs=0.450, P=.007 as well as between COX-2 and microvessel density with VEGF expression in tumor tissues was found (rs=0.450, P=.007; rs=0.620, P=.0001, respectively. The induction of COX-2 mRNA and PGE2 synthesis by EGF and Escherichia coli lipopolysaccharide (LPS in A-431 and SCC-9 cell lines, resulted in an increase in VEGF mRNA and protein production. Indomethacin and celecoxib reversed the EGF- and LPS-dependent COX-2, VEGF, and PGE2 increases. This study suggests a central role of COX-2 pathway in HNC angiogenesis by modulating VEGF production and indicates that COX-2 inhibitors may be useful in HNC treatment.

Cediranib, a pan-VEGFR inhibitor, and olaparib, a PARP inhibitor, in combination therapy for high grade serous ovarian cancer.

Science.gov (United States)

Ivy, S Percy; Liu, Joyce F; Lee, Jung-Min; Matulonis, Ursula A; Kohn, Elise C

2016-01-01

An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC. Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts. Advances in the treatment of HGSOC that improve progression-free and overall survival have proven elusive despite examination of molecularly targeted therapy. HGSOC patients with deleterious germline or somatic mutations in BRCA1 or BRCA2 (BRCAm) are most responsive to PARP inhibitors (PARPi). PARPi combined with angiogenesis inhibition improved anti-cancer response and duration in both BRCAm and BRCA wild type HGSOC patients, compared to olaparib single agent treatment, demonstrating therapeutic chemical and contextual synthetic lethality.

The Proton-Sensing G-Protein Coupled Receptor GPR4 Promotes Angiogenesis in Head and Neck Cancer.

Directory of Open Access Journals (Sweden)

Zhibin Jing

Full Text Available Squamous cell carcinoma of the head and neck (SCCHN is an aggressive disease with poor survival and is the sixth most common cancer worldwide. Gastroesophageal reflux is a common event in SCCHN patients. GPR4 is a proton-sensing G-protein coupled receptor, which can be activated by acidosis. The objective of this study was to explore the role of GPR4 in acid exposure and tumor angiogenesis in SCCHN. In this study, we confirmed that overexpressing GPR4 in SCCHN cells could increase the expression and secretion of IL6, IL8 and VEGFA at pH 5.9. This effect could be inhibited by SB203580 (a p38 inhibitor. Western blot analysis indicated that phosphorylation of p38 increased in GPR4 infected cells at pH 5.9, which could be inhibited by SB203580. In tube formation assay, HMEC-1 cells were incubated with conditioned medium (CM, pH 5.9, 6.5, 7.4 derived from control and GPR4 infected SCCHN cells. Tube length was significantly increased in HMEC-1 cells incubated with CM from GPR4 infected cells compared with control cells at pH5.9, which indicated the pro-angiogenic effect of GPR4 in acidic pH. The neutralizing antibodies of IL6, IL8 and VEGFA could inhibit tube formation of HMEC-1 cells. In vivo, the effect of GPR4 on angiogenesis was investigated with the chick chorioallantoic membrane (CAM model. Control and GPR4 infected SCCHN cells were seeded onto the upper CAM surface (n = 5 in each group and 5 μL DMEM/F12 (pH 5.9, 6.5, 7.4 was added to the surface of the cell every 24 h. Four days later, the upper CAM were harvested and the ratio of the vascular area to the CAM area was quantified using Image-Pro Plus 6.0 software. GPR4 infected cells could recruit more vascular than control cells at pH5.9. In conclusion, we suggested that GPR4 induces angiogenesis via GPR4-induced p38-mediated IL6, IL8 and VEGFA secretion at acidic extracellular pH in SCCHN.

Evaluation of radiotracers for the detection of atherosclerotic vulnerable plaque and myocardial angiogenesis

International Nuclear Information System (INIS)

Dimastromatteo, Julien

2010-01-01

Cardiovascular diseases are the leading cause of mortality worldwide. Coronary events are mainly caused by coronary plaque rupture or erosion. However, at present, there is no noninvasive tool available for the detection of vulnerable plaques. The first part of thesis is about evaluation of new radiotracers for the detection of atherosclerotic vulnerable plaques. 99m Tc-B2702p, 20 derivatives, 99m Tc-VP and 99m Tc-VINP28 were evaluated in an experimental model of atherosclerosis (ApoE-/- mice with left carotid artery ligation). 99m Tc- B2702p1 is a potentially useful radiotracer for the in vivo molecular imaging of VCAM-1 expression in atherosclerotic plaques. Myocardial angiogenesis is an important post infarction phenomenon. Angiogenic therapy improves experimentally cardiac parameters. However, clinical trials using the same therapy are more controversial. At present, clinical imaging tools don't allow us to assess angiogenesis therapy. The second part of thesis is about validation of 99m Tc-RAFT-RGD in the detection of myocardial angiogenesis. 99m Tc-RAFT-RGD allow us to perform noninvasive molecular imaging of myocardial angiogenesis in an experimental model. (author)

Acetylbritannilactone Modulates Vascular Endothelial Growth Factor Signaling and Regulates Angiogenesis in Endothelial Cells.

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Jingshan Zhao

Full Text Available The present study was conducted to determine the effects of 1-O-acetylbritannilactone (ABL, a compound extracted from Inula britannica L., on vascular endothelial growth factor (VEGF signaling and angiogenesis in endothelial cells (ECs. We showed that ABL promotes VEGF-induced cell proliferation, growth, migration, and tube formation in cultured human ECs. Furthermore, the modulatory effect of ABL on VEGF-induced Akt, MAPK p42/44, and p38 phosphorylation, as well as on upstream VEGFR-2 phosphorylation, were associated with VEGF-dependent Matrigel angiogenesis in vivo. In addition, animals treated with ABL (26 mg/kg/day recovered blood flow significantly earlier than control animals, suggesting that ABL affects ischemia-mediated angiogenesis and arteriogenesis in vivo. Finally, we demonstrated that ABL strongly reduced the levels of VEGFR-2 on the cell surface, enhanced VEGFR-2 endocytosis, which consistent with inhibited VE-cadherin, a negative regulator of VEGF signaling associated with VEGFR-2 complex formation, but did not alter VE-cadherin or VEGFR-2 expression in ECs. Our results suggest that ABL may serve as a novel therapeutic intervention for various cardiovascular diseases, including chronic ischemia, by regulating VEGF signaling and modulating angiogenesis.

Endoglin inhibition leads to intussusceptive angiogenesis via activation of factors related to COUP-TFII signaling pathway.

Directory of Open Access Journals (Sweden)

Ruslan Hlushchuk

Full Text Available Angiogenesis is a highly coordinated, extremely complex process orchestrated by multiple signaling molecules and blood flow conditions. While sprouting mode of angiogenesis is very well investigated, the molecular mechanisms underlying intussusception, the second mode of angiogenesis, remain largely unclear. In the current study two molecules involved in vascular growth and differentiation, namely endoglin (ENG/CD105 and chicken ovalbumin upstream promoter transcription factor II (COUP-TFII were examined to unravel their specific roles in angiogenesis. Down- respectively up-regulation of both molecules tightly correlates with intussusceptive microvascular growth. Upon ENG inhibition in chicken embryo model, formation of irregular capillary meshwork accompanied by increased expression of COUP-TFII could be observed. This dynamic expression pattern of ENG and COUP-TFII during vascular development and remodeling correlated with formation of pillars and progression of intussusceptive angiogenesis. Similar findings could be observed in mammalian model of acute rat Thy1.1 glomerulonephritis, which was induced by intravenous injection of anti-Thy1 antibody and has shown upregulation of COUP-TFII in initial phase of intussusception, while ENG expression was not disturbed compared to the controls but decreased over the time of pillar formation. In this study, we have shown that ENG inhibition and at the same time up-regulation of COUP-TFII expression promotes intussusceptive angiogenesis.

Comparative Evaluation of TRAIL, FGF-2 and VEGF-A-Induced Angiogenesis In Vitro and In Vivo.

Science.gov (United States)

Cartland, Siân P; Genner, Scott W; Zahoor, Amna; Kavurma, Mary M

2016-12-02

Tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL) has been implicated in angiogenesis; the growth of new blood vessels from an existing vessel bed. Our aim was to compare pro-angiogenic responses of TRAIL, vascular endothelial growth-factor-A (VEGF-A) and fibroblast growth-factor-2 (FGF-2) either separately (10 ng/mL) or in combination, followed by the assessment of proliferation, migration and tubule formation using human microvascular endothelial-1 (HMEC-1) cells in vitro. Angiogenesis was also measured in vivo using the Matrigel plug assay. TRAIL and FGF-2 significantly augmented HMEC-1 cell proliferation and migration, with combination treatment having an enhanced effect on cell migration only. In contrast, VEGF-A did not stimulate HMEC-1 migration at 10 ng/mL. Tubule formation was induced by all three factors, with TRAIL more effective compared to VEGF-A, but not FGF-2. TRAIL at 400 ng/mL, but not VEGF-A, promoted CD31-positive staining into the Matrigel plug. However, FGF-2 was superior, stimulating cell infiltration and angiogenesis better than TRAIL and VEGF-A in vivo. These findings demonstrate that each growth factor is more effective at different processes of angiogenesis in vitro and in vivo. Understanding how these molecules stimulate different processes relating to angiogenesis may help identify new strategies and treatments aimed at inhibiting or promoting dysregulated angiogenesis in people.

Triptolide Suppresses Alkali Burn-Induced Corneal Angiogenesis Along with a Downregulation of VEGFA and VEGFC Expression.

Science.gov (United States)

Wang, Geng; Li, Na; Lv, Xiaohong; Ahmed, Naila; Li, Xinlei; Liu, Huidong; Ma, Jing; Zhang, Yafang

2017-07-01

Triptolide (TPL) is an active compound extracted from a Chinese herbal medicine tripterygium wilfordii Hook. f. (Celastraceae), which has been used as an anti-inflammatory drug for years. It also inhibits the growth and proliferation of different types of cancer cells. The inhibitory effect of TPL on angiogenesis after chemical-induced corneal inflammation was studied in vivo. The effects of TPL on the proliferation, apoptosis, migration, and tube formation of rat aortic endothelial cells (RAECs) were studied in vitro. Cell proliferation and apoptosis were measured by MTT assay and flow cytometry, respectively. Migration was analyzed using the scratch wound healing assay and transwell assay. Tube formation assay was used to examine angiogenesis. Real-time PCR and Western blot were used to determine the expression of vascular endothelial growth factor A (VEGFA) and VEGFC. To study the in vivo effects of TPL, the mouse model of alkali burn-induced corneal angiogenesis was used. The angiogenesis was analyzed by determining the density of the newly generated blood vessels in corneas. We found that TPL induced apoptosis and inhibited the proliferation of RAECs in a dose-dependent manner. TPL inhibited migration and tube formation of RAECs and decreased the expression of VEGFA and VEGFC in vitro. Furthermore, TPL suppressed alkali burn-induced corneal angiogenesis and inhibited the expression of VEGFA and VEGFC in corneas in vivo. In conclusion, topical TPL as a pharmacological agent has the ability to reduce angiogenesis in cornea and may have clinical indications for the treatment of corneal angiogenesis diseases which have to be further explored. Anat Rec, 300:1348-1355, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Essential contribution of tumor-derived perlecan to epidermal tumor growth and angiogenesis

DEFF Research Database (Denmark)

Jiang, Xinnong; Multhaupt, Hinke; Chan, En

2004-01-01

As a major heparan sulfate proteoglycan (PG) in basement membranes, perlecan has been linked to tumor invasion, metastasis, and angiogenesis. Here we produced epidermal tumors in immunocompromised rats by injection of mouse RT101 tumor cells. Tumor sections stained with species-specific perlecan...... factor. In vivo, antisense perlecan-transfected cells generated no tumors, whereas untransfected and vector-transfected cells formed tumors with obvious neovascularization, suggesting that tumor perlecan rather than host perlecan controls tumor growth and angiogenesis....

VEGF selectively induces Down syndrome critical region 1 gene expression in endothelial cells: a mechanism for feedback regulation of angiogenesis?

International Nuclear Information System (INIS)

Yao, Y.-G; Duh, Elia J.

2004-01-01

The Down syndrome critical region 1 (DSCR1) gene (also known as MCIP1, Adapt78) encodes a regulatory protein that binds to calcineurin catalytic A subunit and acts as a regulator of the calcineurin-mediated signaling pathway. We show in this study that DSCR1 is greatly induced in endothelial cells in response to VEGF, TNF-α, and A23187 treatment, and that this up-regulation is inhibited by inhibitors of the calcineurin-NFAT (nuclear factor of activated T cells) signaling pathway as well as by PKC inhibition and a Ca 2+ chelator. We hypothesized that the up-regulation of DSCR1 gene expression in endothelial cells could act as an endogenous feedback inhibitor for angiogenesis by regulating the calcineurin-NFAT signaling pathway. Our transient transfection analyses confirm that the overexpression of DSCR1 abrogates the up-regulation of reporter gene expression driven by both the cyclooxygenase 2 and DSCR1 promoters in response to stimulators. Our results indicate that DSCR1 up-regulation may represent a potential molecular mechanism underlying the regulation of angiogenic genes activated by the calcineurin-NFAT signaling pathway in endothelial cells

The Multiple Roles of EG-VEGF/PROK1 in Normal and Pathological Placental Angiogenesis

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Nadia Alfaidy

2014-01-01

Full Text Available Placentation is associated with several steps of vascular adaptations throughout pregnancy. These vascular changes occur both on the maternal and fetal sides, consisting of maternal uterine spiral arteries remodeling and placental vasculogenesis and angiogenesis, respectively. Placental angiogenesis is a pivotal process for efficient fetomaternal exchanges and placental development. This process is finely controlled throughout pregnancy, and it involves ubiquitous and pregnancy-specific angiogenic factors. In the last decade, endocrine gland derived vascular endothelial growth factor (EG-VEGF, also called prokineticin 1 (PROK1, has emerged as specific placental angiogenic factor that controls many aspects of normal and pathological placental angiogenesis such as recurrent pregnancy loss (RPL, gestational trophoblastic diseases (GTD, fetal growth restriction (FGR, and preeclampsia (PE. This review recapitulates EG-VEGF mediated-angiogenesis within the placenta and at the fetomaternal interface and proposes that its deregulation might contribute to the pathogenesis of several placental diseases including FGR and PE. More importantly this paper argues for EG-VEGF clinical relevance as a potential biomarker of the onset of pregnancy pathologies and discusses its potential usefulness for future therapeutic directions.

The multiple roles of EG-VEGF/PROK1 in normal and pathological placental angiogenesis.

Science.gov (United States)

Alfaidy, Nadia; Hoffmann, Pascale; Boufettal, Houssine; Samouh, Naima; Aboussaouira, Touria; Benharouga, Mohamed; Feige, Jean-Jacques; Brouillet, Sophie

2014-01-01

Placentation is associated with several steps of vascular adaptations throughout pregnancy. These vascular changes occur both on the maternal and fetal sides, consisting of maternal uterine spiral arteries remodeling and placental vasculogenesis and angiogenesis, respectively. Placental angiogenesis is a pivotal process for efficient fetomaternal exchanges and placental development. This process is finely controlled throughout pregnancy, and it involves ubiquitous and pregnancy-specific angiogenic factors. In the last decade, endocrine gland derived vascular endothelial growth factor (EG-VEGF), also called prokineticin 1 (PROK1), has emerged as specific placental angiogenic factor that controls many aspects of normal and pathological placental angiogenesis such as recurrent pregnancy loss (RPL), gestational trophoblastic diseases (GTD), fetal growth restriction (FGR), and preeclampsia (PE). This review recapitulates EG-VEGF mediated-angiogenesis within the placenta and at the fetomaternal interface and proposes that its deregulation might contribute to the pathogenesis of several placental diseases including FGR and PE. More importantly this paper argues for EG-VEGF clinical relevance as a potential biomarker of the onset of pregnancy pathologies and discusses its potential usefulness for future therapeutic directions.

Marine Compound Catunaregin Inhibits Angiogenesis through the Modulation of Phosphorylation of Akt and eNOS in vivo and in vitro

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Jun-Xiu Liu

2014-05-01

Full Text Available Angiogenesis is the formation of blood vessels from pre-existing vasculature. Excessive or uncontrolled angiogenesis is a major contributor to many pathological conditions whereas inhibition of aberrant angiogenesis is beneficial to patients with pathological angiogenesis. Catunaregin is a core of novel marine compound isolated from mangrove associate. The potential anti-angiogenesis of catunaregin was investigated in human umbilical vein endothelial cells (HUVECs and zebrafish. HUVECs were treated with different concentrations of catunaregin in the presence or absence of VEGF. The angiogenic phenotypes including cell invasion cell migration and tube formation were evaluated following catunaregin treatment in HUVECs. The possible involvement of AKT, eNOS and ERK1/2 in catunaregin-induced anti-angiogenesis was explored using Western blotting. The anti-angiogenesis of catunaregin was further tested in the zebrafish embryo neovascularization and caudal fin regeneration assays. We found that catunaregin dose-dependently inhibited angiogenesis in both HUVECs and zebrafish embryo neovascularization and zebrafish caudal fin regeneration assays. In addition, catunaregin significantly decreased the phosphorylation of Akt and eNOS, but not the phosphorylation of ERK1/2. The present work demonstrates that catunaregin exerts the anti-angiogenic activity at least in part through the regulation of the Akt and eNOS signaling pathways.

Angiogenesis in Chronic Obstructive Pulmonary Disease

OpenAIRE

Góralczyk, Barbara; Drela, Ewelina; Góralczyk, Krzysztof; Szczypiorska, Anna; Rość, Danuta

2012-01-01

Angiogenesis is a very important process that occurs in both physiological and pathological states. The new blood vessels formation is characteristic for cancers, ischemic diseases and inflammatory diseases. The process is controlled by factors that stimulate and inhibit neovascularization. The next stages of the neovascularization are known as well as the role of the extracellular matrix, cells and cytokines/factors growth modulating this process. The cells of the endothelium and proangiogen...

Wars2 is a determinant of angiogenesis

Czech Academy of Sciences Publication Activity Database

Wang, M.; Sips, P.; Khin, E.; Rotival, M.; Sun, X.; Ahmed, R.; Widjaja, A. A.; Schafer, S.; Yusoff, P.; Choksi, P. K.; Ko, N. S. J.; Singh, M. K.; Epstein, D.; Guan, Y.; Houštěk, Josef; Mráček, Tomáš; Nůsková, Hana; Mikell, B.; Tan, J.; Pesce, F.; Kolář, František; Bottolo, L.; Mancini, M.; Hubner, N.; Pravenec, Michal; Petretto, E.; MacRae, C.; Cook, S. A.

2016-01-01

Roč. 7, Jul (2016), s. 12061 ISSN 2041-1723 R&D Projects: GA MŠk(CZ) LL1204; GA ČR(CZ) GB14-36804G; GA MZd(CZ) NT12370 Institutional support: RVO:67985823 Keywords : Wars2 mutant gene * angiogenesis * coronary flow * spontaneously hypertensive rat Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 12.124, year: 2016

Umbilical Cord-Derived Mesenchymal Stem Cells Relieve Hindlimb Ischemia through Enhancing Angiogenesis in Tree Shrews

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Cunping Yin

2016-01-01

Full Text Available Hindlimb ischemia is still a clinical problem with high morbidity and mortality. Patients suffer from consequent rest pain, ulcers, cool limbs, and even amputation. Angiogenesis is a promising target for the treatment of ischemic limbs, providing extra blood for the ischemic region. In the present study, we investigated the role of umbilical cord-derived mesenchymal stem cells (UC-MSCs in regulating angiogenesis and relieving hindlimb ischemia. UC-MSCs were isolated from the umbilical cord of tree shrews. Angiography results showed that UC-MSCs injection significantly promoted angiogenesis in tree shrews. Moreover, the ankle brachial index, transcutaneous oxygen pressure, blood perfusion, and capillary/muscle fiber ratio were all markedly increased by the application of UC-MSCs. In addition, the conditioned culture of human umbilical vein endothelial cells using medium collected from UC-MSCs showed higher expression of angiogenic markers and improved migration ability. In short, the isolated UC-MSCs notably contributed to restoring blood supply and alleviating the symptoms of limb ischemia through enhancing angiogenesis.

Enzastaurin (LY317615), a Protein Kinase C Beta Selective Inhibitor, Enhances Antiangiogenic Effect of Radiation

International Nuclear Information System (INIS)

Willey, Christopher D.; Xiao Dakai; Tu Tianxiang; Kim, Kwang Woon; Moretti, Luigi; Niermann, Kenneth J.; Tawtawy, Mohammed N.; Quarles, Chad C. Ph.D.; Lu Bo

2010-01-01

Purpose: Angiogenesis has generated interest in oncology because of its important role in cancer growth and progression, particularly when combined with cytotoxic therapies, such as radiotherapy. Among the numerous pathways influencing vascular growth and stability, inhibition of protein kinase B(Akt) or protein kinase C(PKC) can influence tumor blood vessels within tumor microvasculature. Therefore, we wanted to determine whether PKC inhibition could sensitize lung tumors to radiation. Methods and Materials: The combination of the selective PKCβ inhibitor Enzastaurin (ENZ, LY317615) and ionizing radiation were used in cell culture and a mouse model of lung cancer. Lung cancer cell lines and human umbilical vascular endothelial cells (HUVEC) were examined using immunoblotting, cytotoxic assays including cell proliferation and clonogenic assays, and Matrigel endothelial tubule formation. In vivo, H460 lung cancer xenografts were examined for tumor vasculature and proliferation using immunohistochemistry. Results: ENZ effectively radiosensitizes HUVEC within in vitro models. Furthermore, concurrent ENZ treatment of lung cancer xenografts enhanced radiation-induced destruction of tumor vasculature and proliferation by IHC. However, tumor growth delay was not enhanced with combination treatment compared with either treatment alone. Analysis of downstream effectors revealed that HUVEC and the lung cancer cell lines differed in their response to ENZ and radiation such that only HUVEC demonstrate phosphorylated S6 suppression, which is downstream of mTOR. When ENZ was combined with the mTOR inhibitor, rapamycin, in H460 lung cancer cells, radiosensitization was observed. Conclusion: PKC appears to be crucial for angiogenesis, and its inhibition by ENZ has potential to enhance radiotherapy in vivo.

Comparative Evaluation of TRAIL, FGF-2 and VEGF-A-Induced Angiogenesis In Vitro and In Vivo

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Siân P. Cartland

2016-12-01

Full Text Available Tumor necrosis-factor-related apoptosis-inducing ligand (TRAIL has been implicated in angiogenesis; the growth of new blood vessels from an existing vessel bed. Our aim was to compare pro-angiogenic responses of TRAIL, vascular endothelial growth-factor-A (VEGF-A and fibroblast growth-factor-2 (FGF-2 either separately (10 ng/mL or in combination, followed by the assessment of proliferation, migration and tubule formation using human microvascular endothelial-1 (HMEC-1 cells in vitro. Angiogenesis was also measured in vivo using the Matrigel plug assay. TRAIL and FGF-2 significantly augmented HMEC-1 cell proliferation and migration, with combination treatment having an enhanced effect on cell migration only. In contrast, VEGF-A did not stimulate HMEC-1 migration at 10 ng/mL. Tubule formation was induced by all three factors, with TRAIL more effective compared to VEGF-A, but not FGF-2. TRAIL at 400 ng/mL, but not VEGF-A, promoted CD31-positive staining into the Matrigel plug. However, FGF-2 was superior, stimulating cell infiltration and angiogenesis better than TRAIL and VEGF-A in vivo. These findings demonstrate that each growth factor is more effective at different processes of angiogenesis in vitro and in vivo. Understanding how these molecules stimulate different processes relating to angiogenesis may help identify new strategies and treatments aimed at inhibiting or promoting dysregulated angiogenesis in people.

Angiogenesis PET Tracer Uptake (68Ga-NODAGA-E[(cRGDyK)]₂) in Induced Myocardial Infarction in Minipigs

DEFF Research Database (Denmark)

Rasmussen, Thomas; Follin, Bjarke; Kastrup, Jens

2016-01-01

Angiogenesis is part of the healing process following an ischemic injury and is vital for the post-ischemic repair of the myocardium. Therefore, it is of particular interest to be able to noninvasively monitor angiogenesis. This might, not only permit risk stratification of patients following...... myocardial infarction, but could also facilitate development and improvement of new therapies directed towards stimulation of the angiogenic response. During angiogenesis endothelial cells must adhere to one another to form new microvessels. αvβ₃ integrin has been found to be highly expressed in activated...... endothelial cells and has been identified as a critical modulator of angiogenesis. (68)Ga-NODAGA-E[c(RGDyK)]₂ (RGD) has recently been developed by us as an angiogenesis positron-emission-tomography (PET) ligand targeted towards αvβ₃ integrin. In the present study, we induced myocardial infarction in Göttingen...

Upregulation of Syndecan-1 in the bone marrow microenvironment in multiple myeloma is associated with angiogenesis

DEFF Research Database (Denmark)

Andersen, Niels F; Kristensen, Ida B; Preiss, Birgitte S

2014-01-01

: In this study, we examined the association between bone marrow angiogenesis estimated as micro-vessel density (MVD) and gene expression of SDC1, HGF, VEGF and IL6 in whole bone marrow biopsies from healthy volunteers (n = 10), patients with monoclonal gammopathy of undetermined significance (MGUS) (n = 35...... plasma cell percentage and SDC1 gene expression was detected in patients with MM (P angiogenesis and gene...... expression of HGF, VEGF and IL6 was seen. CONCLUSION: Our study indicates that SDC1 expressed by the bone marrow microenvironment is involved in angiogenesis in MM....

Visualising and quantifying angiogenesis in metastatic colorectal cancer

DEFF Research Database (Denmark)

Hansen, Torben Frøstrup; Nielsen, Boye Schnack; Jakobsen, Anders

2013-01-01

Angiogenesis plays an important role in tumour growth and dissemination. We have recently shown that blood vessel density, determined by image analysis based on microRNA-126 (miRNA-126) in situ hybridization (ISH) in the primary tumours of metastatic colorectal cancers (mCRC), is predictive...

Infiltrating Mast Cells Correlate with Angiogenesis in Bone Metastases from Gastric Cancer Patients

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Michele Ammendola

2015-02-01

Full Text Available While gastric cancer is a well established angiogenesis driven tumor, no data has been published regarding angiogenesis stimulated by mast cells (MCs positive for tryptase in bone metastases from gastric cancer patients (BMGCP. It is well established that MCs play a role in immune responses and more recently it was demonstrated that MCs have been involved in tumor angiogenesis. We analyzed infiltrating MCs and neovascularization in BMGCP diagnosed by histology. A series of 15 stage T3-4N2-3M1 (by AJCC for Gastric Cancer Staging 7th Edition BMGCP from bone biopsies were selected. Tumour tissue samples were evaluated by mean of immunohistochemistry and image analysis methods in terms of MCs density positive to tryptase (MCDPT, MCs area positive to tryptase (MCAPT, microvascular density (MVD and endothelial area (EA. A significant correlation between MCDPT, MCAPT, MVD and EA groups to each other was found by Pearson and t-test analysis (r ranged from 0.68 to 0.82; p-value ranged from 0.00 to 0.02. Our very preliminary data suggest that infiltrating MCs positive for tryptase may play a role in BMGCP angiogenesis, and could be further evaluated as a novel target of anti-angiogenic therapy.

MicroRNA-9 Couples Brain Neurogenesis and Angiogenesis

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Romain Madelaine

2017-08-01

Full Text Available In the developing brain, neurons expressing VEGF-A and blood vessels grow in close apposition, but many of the molecular pathways regulating neuronal VEGF-A and neurovascular system development remain to be deciphered. Here, we show that miR-9 links neurogenesis and angiogenesis through the formation of neurons expressing VEGF-A. We found that miR-9 directly targets the transcription factors TLX and ONECUTs to regulate VEGF-A expression. miR-9 inhibition leads to increased TLX and ONECUT expression, resulting in VEGF-A overexpression. This untimely increase of neuronal VEGF-A signal leads to the thickening of blood vessels at the expense of the normal formation of the neurovascular network in the brain and retina. Thus, this conserved transcriptional cascade is critical for proper brain development in vertebrates. Because of this dual role on neural stem cell proliferation and angiogenesis, miR-9 and its downstream targets are promising factors for cellular regenerative therapy following stroke and for brain tumor treatment.

Hypoxia, hypoxia-inducible transcription factor, and macrophages in human atherosclerotic plaques are correlated with intraplaque angiogenesis

NARCIS (Netherlands)

Sluimer, Judith C.; Gasc, Jean-Marie; van Wanroij, Job L.; Kisters, Natasja; Groeneweg, Mathijs; Sollewijn Gelpke, Maarten D.; Cleutjens, Jack P.; van den Akker, Luc H.; Corvol, Pierre; Wouters, Bradly G.; Daemen, Mat J.; Bijnens, Ann-Pascale J.

2008-01-01

We sought to examine the presence of hypoxia in human carotid atherosclerosis and its association with hypoxia-inducible transcription factor (HIF) and intraplaque angiogenesis. Atherosclerotic plaques develop intraplaque angiogenesis, which is a typical feature of hypoxic tissue and expression of

Endothelial progenitor cells physiology and metabolic plasticity in brain angiogenesis and blood-brain barrier modeling

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Natalia Malinovskaya

2016-12-01

Full Text Available Currently, there is a considerable interest to the assessment of blood-brain barrier (BBB development as a part of cerebral angiogenesis developmental program. Embryonic and adult angiogenesis in the brain is governed by the coordinated activity of endothelial progenitor cells, brain microvascular endothelial cells, and non-endothelial cells contributing to the establishment of the BBB (pericytes, astrocytes, neurons. Metabolic and functional plasticity of endothelial progenitor cells controls their timely recruitment, precise homing to the brain microvessels, and efficient support of brain angiogenesis. Deciphering endothelial progenitor cells physiology would provide novel engineering approaches to establish adequate microfluidically-supported BBB models and brain microphysiological systems for translational studies.

Angiogenesis in urinary bladder carcinoma as defined by ...

African Journals Online (AJOL)

Background: Among the patients with bladder cancer, a group is still at risk of disease recurrence, progression, and death from their cancer after curative treatment. Angiogenesis is a crucial pathogenic mechanism for this type of urothelial carcinoma and is a potential therapeutic target. Objectives: To quantify tumor ...

Bee products prevent VEGF-induced angiogenesis in human umbilical vein endothelial cells

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Mishima Satoshi

2009-11-01

Full Text Available Abstract Background Vascular endothelial growth factor (VEGF is a key regulator of pathogenic angiogenesis in diseases such as cancer and diabetic retinopathy. Bee products [royal jelly (RJ, bee pollen, and Chinese red propolis] from the honeybee, Apis mellifera, have been used as traditional health foods for centuries. The aim of this study was to investigate the anti-angiogenic effects of bee products using human umbilical vein endothelial cells (HUVECs. Methods In an in vitro tube formation assay, HUVECs and fibroblast cells were incubated for 14 days with VEGF and various concentrations of bee products [RJ, ethanol extract of bee pollen, ethanol extract of Chinese red propolis and its constituent, caffeic acid phenethyl ester (CAPE]. To clarify the mechanism of in vitro angiogenesis, HUVEC proliferation and migration were induced by VEGF with or without various concentrations of RJ, bee pollen, Chinese red propolis, and CAPE. Results RJ, bee pollen, Chinese red propolis, and CAPE significantly suppressed VEGF-induced in vitro tube formation in the descending order: CAPE > Chinese red propolis >> bee pollen > RJ. RJ and Chinese red propolis suppressed both VEGF-induced HUVEC proliferation and migration. In contrast, bee pollen and CAPE suppressed only the proliferation. Conclusion Among the bee products, Chinese red propolis and CAPE in particular showed strong suppressive effects against VEGF-induced angiogenesis. These findings indicate that Chinese red propolis and CAPE may have potential as preventive and therapeutic agents against angiogenesis-related human diseases.

Angiogenesis concept in odontogenic keratocyst: A comparative study

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Donia Sadri

2017-01-01

Full Text Available Context: Recent reports have indicated that angiogenesis possibly affects the biologic behavior of the lesions. Aim: Given the different clinical behaviors of odontogenic keratocyst (OKC, the present study was undertaken to evaluate the concept of angiogenesis in pathogenesis and clinical behavior of OKC. Setting and Design: This experimental study was carried out on 22 and 24 samples of OKCs and dentigerous cysts (DCs, respectively. Methods: Immunohistochemical staining was approached using CD34 and vascular endothelial growth factor (VEGF antibodies. The expression of VEGF was first reported by determining the counts of stained cells, including epithelial cells, fibroblasts, and endothelial cells, followed by the percentage of stained cells in each sample based on a 0–2 scoring system. The counts of CD34+ cells were reported in each group in the form of means ± standard deviations. In addition, the patterns of blood vessels in the samples prepared from the walls of both cysts were evaluated. Statistical Analysis Used: Mann–Whitney U-test, Chi-squared test, and t-test were used for analysis of data, and statistical significance was defined at p < 0.05. Results: The expression percentage and scores of VEGF and the mean expression rate of CD34 were significantly higher in OKCs than DCs (p = 0.045, 0.000, and < 0.001. No significant difference was detected in the vascular patterns of these lesions (p = 0.58. Finally, there was a strong correlation between the expressions of the two markers in the samples (Correlation coefficient = 0.766. Conclusion: The present results indicate the angiogenesis may play an important role in the pathogenesis and the unique clinical behavior of OKC.

Angiogenesis in Pituitary Adenomas: Human Studies and New Mutant Mouse Models

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Carolina Cristina

2014-01-01

Full Text Available The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives.

Angiogenesis in pituitary adenomas: human studies and new mutant mouse models.

Science.gov (United States)

Cristina, Carolina; Luque, Guillermina María; Demarchi, Gianina; Lopez Vicchi, Felicitas; Zubeldia-Brenner, Lautaro; Perez Millan, Maria Ines; Perrone, Sofia; Ornstein, Ana Maria; Lacau-Mengido, Isabel M; Berner, Silvia Inés; Becu-Villalobos, Damasia

2014-01-01

The role of angiogenesis in pituitary tumor development has been questioned, as pituitary tumors have been usually found to be less vascularized than the normal pituitary tissue. Nevertheless, a significantly higher degree of vasculature has been shown in invasive or macropituitary prolactinomas when compared to noninvasive and microprolactinomas. Many growth factors and their receptors are involved in pituitary tumor development. For example, VEGF, FGF-2, FGFR1, and PTTG, which give a particular vascular phenotype, are modified in human and experimental pituitary adenomas of different histotypes. In particular, vascular endothelial growth factor, VEGF, the central mediator of angiogenesis in endocrine glands, was encountered in experimental and human pituitary tumors at different levels of expression and, in particular, was higher in dopamine agonist resistant prolactinomas. Furthermore, several anti-VEGF techniques lowered tumor burden in human and experimental pituitary adenomas. Therefore, even though the role of angiogenesis in pituitary adenomas is contentious, VEGF, making permeable pituitary endothelia, might contribute to adequate temporal vascular supply and mechanisms other than endothelial cell proliferation. The study of angiogenic factor expression in aggressive prolactinomas with resistance to dopamine agonists will yield important data in the search of therapeutical alternatives.

CXCR4(+) dendritic cells promote angiogenesis during embryo implantation in mice.

Science.gov (United States)

Barrientos, Gabriela; Tirado-González, Irene; Freitag, Nancy; Kobelt, Peter; Moschansky, Petra; Klapp, Burghard F; Thijssen, Victor L J L; Blois, Sandra M

2013-04-01

Early pregnancy is characterized by decidual adaption to the developing embryo involving angiogenesis and vascular growth. Failure of decidual vascular expansion is linked to diseases of pregnancy. Dendritic cells (DC) have been associated with vascular growth during early gestation, though it is unknown whether their capacity to modulate angiogenesis is ubiquitous to all DC subsets. Here, we show that DC normally found associated with the decidual vasculature co-express the C-X-C chemokine receptor type 4 (CXCR4). In addition, we demonstrate that impaired homing of CXCR4(+)DC during early gestation provoked a disorganized decidual vasculature with impaired spiral artery remodeling later in gestation. In contrast, adoptive transfer experiments provided evidence that CXCR4(+)DC are able to rescue early pregnancy by normalizing decidual vascular growth and delivery of pro-angiogenic factors, which results in adequate remodeling of the spiral arteries during placental development. Taken together, our results indicate an important role of CXCR4(+)DC in the regulation of decidual angiogenesis and highlight the importance of the CXCL12/CXCR4 pathway during this process, suggesting that this may represent a key pathway to evaluate during pregnancy pathologies associated with impaired vascular expansion.

Protein kinase D1 signaling in angiogenic gene expression and VEGF-mediated angiogenesis

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Bin eRen MD, Phd, FAHA

2016-05-01

Full Text Available Protein kinase D 1 (PKD-1 is a signaling kinase important in fundamental cell functions including migration, proliferation and differentiation. PKD-1 is also a key regulator of gene expression and angiogenesis that is essential for cardiovascular development and tumor progression. Further understanding molecular aspects of PKD-1 signaling in the regulation of angiogenesis may have translational implications in obesity, cardiovascular disease and cancer. The author will summarize and provide the insights into molecular mechanisms by which PKD-1 regulates transcriptional expression of angiogenic genes, focusing on the transcriptional regulation of CD36 by PKD-1-FoxO1 signaling axis along with the potential implications of this axis in arterial differentiation and morphogenesis. He will also discuss a new concept of dynamic balance between proangiogenic and antiangiogenic signaling in determining angiogenic switch, and stress how PKD-1 signaling regulates VEGF signaling-mediated angiogenesis.

CCL5 promotes vascular endothelial growth factor expression and induces angiogenesis by down-regulating miR-199a in human chondrosarcoma cells.

Science.gov (United States)

Liu, Guan-Ting; Huang, Yuan-Li; Tzeng, Huey-En; Tsai, Chun-Hao; Wang, Shih-Wei; Tang, Chih-Hsin

2015-02-28

Chondrosarcoma is a primary malignant bone cancer, with a potent capacity to invade locally and cause distant metastasis. Angiogenesis is a critical step in tumor growth and metastasis. Chemokine CCL5 (previously called RANTES) has been shown to facilitate tumor progression and metastasis. However, the relationship of CCL5 with vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study, CCL5 increased VEGF expression and also promoted chondrosarcoma medium-mediated angiogenesis in vitro as well as angiogenesis effects in the chick chorioallantoic membrane and Matrigel plug nude mice model in vivo. MicroRNA analysis was performed in CCL5-treated chondrosarcoma cells versus control cells to investigate the mechanism of CCL5-mediated promotion of chondrosarcoma angiogenesis. Among the miRNAs regulated by CCL5, miR-199a was the most downregulated miRNA after CCL5 treatment. In addition, co-transfection with miR-199a mimic reversed the CCL5-mediated VEGF expression and angiogenesis in vitro and in vivo. Moreover, overexpression of CCL5 increased tumor-associated angiogenesis and tumor growth by downregulating miR-199a in the xenograft tumor angiogenesis model. Taken together, these results demonstrated that CCL5 promotes VEGF-dependent angiogenesis in human chondrosarcoma cells by downregulating miR-199a. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Inositol Polyphosphate Multikinase Inhibits Angiogenesis via Inositol Pentakisphosphate-Induced HIF-1α Degradation.

Science.gov (United States)

Fu, Chenglai; Tyagi, Richa; Chin, Alfred C; Rojas, Tomas; Li, Ruo-Jing; Guha, Prasun; Bernstein, Isaac A; Rao, Feng; Xu, Risheng; Cha, Jiyoung Y; Xu, Jing; Snowman, Adele M; Semenza, Gregg L; Snyder, Solomon H

2018-02-02

Inositol polyphosphate multikinase (IPMK) and its major product inositol pentakisphosphate (IP5) regulate a variety of cellular functions, but their role in vascular biology remains unexplored. We have investigated the role of IPMK in regulating angiogenesis. Deletion of IPMK in fibroblasts induces angiogenesis in both in vitro and in vivo models. IPMK deletion elicits a substantial increase of VEGF (vascular endothelial growth factor), which mediates the regulation of angiogenesis by IPMK. The regulation of VEGF by IPMK requires its catalytic activity. IPMK is predominantly nuclear and regulates gene transcription. However, IPMK does not apparently serve as a transcription factor for VEGF. HIF (hypoxia-inducible factor)-1α is a major determinant of angiogenesis and induces VEGF transcription. IPMK deletion elicits a major enrichment of HIF-1α protein and thus VEGF. HIF-1α is constitutively ubiquitinated by pVHL (von Hippel-Lindau protein) followed by proteasomal degradation under normal conditions. However, HIF-1α is not recognized and ubiquitinated by pVHL in IPMK KO (knockout) cells. IP5 reinstates the interaction of HIF-1α and pVHL. HIF-1α prolyl hydroxylation, which is prerequisite for pVHL recognition, is interrupted in IPMK-deleted cells. IP5 promotes HIF-1α prolyl hydroxylation and thus pVHL-dependent degradation of HIF-1α. Deletion of IPMK in mouse brain increases HIF-1α/VEGF levels and vascularization. The increased VEGF in IPMK KO disrupts blood-brain barrier and enhances brain blood vessel permeability. IPMK, via its product IP5, negatively regulates angiogenesis by inhibiting VEGF expression. IP5 acts by enhancing HIF-1α hydroxylation and thus pVHL-dependent degradation of HIF-1α. © 2017 American Heart Association, Inc.

Halting angiogenesis by non-viral somatic gene therapy alleviates psoriasis and murine psoriasiform skin lesions

DEFF Research Database (Denmark)

Zibert, John Robert; Wallbrecht, Katrin; Schön, Margarete

2011-01-01

Dysregulated angiogenesis is a hallmark of chronic inflammatory diseases, including psoriasis, a common skin disorder that affects approximately 2% of the population. Studying both human psoriasis in 2 complementary xenotransplantation models and psoriasis-like skin lesions in transgenic mice......-15) by in vivo electroporation reduced cutaneous angiogenesis and vascularization in all 3 models. As demonstrated using red fluorescent protein-coupled RDD, the treatment resulted in muscular expression of the gene product and its deposition within the cutaneous hyperangiogenic connective tissue....... High-resolution ultrasound revealed reduced cutaneous blood flow in vivo after electroporation with RDD but not with control plasmids. In addition, angiogenesis- and inflammation-related molecular markers, keratinocyte proliferation, epidermal thickness, and clinical disease scores were downregulated...

Discovery and Development of ATP-Competitive mTOR Inhibitors Using Computational Approaches.

Science.gov (United States)

Luo, Yao; Wang, Ling

2017-11-16

The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation, metabolism, and angiogenesis. This protein is an attractive target for new anticancer drug development. Significant progress has been made in hit discovery, lead optimization, drug candidate development and determination of the three-dimensional (3D) structure of mTOR. Computational methods have been applied to accelerate the discovery and development of mTOR inhibitors helping to model the structure of mTOR, screen compound databases, uncover structure-activity relationship (SAR) and optimize the hits, mine the privileged fragments and design focused libraries. Besides, computational approaches were also applied to study protein-ligand interactions mechanisms and in natural product-driven drug discovery. Herein, we survey the most recent progress on the application of computational approaches to advance the discovery and development of compounds targeting mTOR. Future directions in the discovery of new mTOR inhibitors using computational methods are also discussed. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Combinatorial Pharmacophore-Based 3D-QSAR Analysis and Virtual Screening of FGFR1 Inhibitors

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Nannan Zhou

2015-06-01

Full Text Available The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR signaling pathway plays crucial roles in cell proliferation, angiogenesis, migration, and survival. Aberration in FGFRs correlates with several malignancies and disorders. FGFRs have proved to be attractive targets for therapeutic intervention in cancer, and it is of high interest to find FGFR inhibitors with novel scaffolds. In this study, a combinatorial three-dimensional quantitative structure-activity relationship (3D-QSAR model was developed based on previously reported FGFR1 inhibitors with diverse structural skeletons. This model was evaluated for its prediction performance on a diverse test set containing 232 FGFR inhibitors, and it yielded a SD value of 0.75 pIC50 units from measured inhibition affinities and a Pearson’s correlation coefficient R2 of 0.53. This result suggests that the combinatorial 3D-QSAR model could be used to search for new FGFR1 hit structures and predict their potential activity. To further evaluate the performance of the model, a decoy set validation was used to measure the efficiency of the model by calculating EF (enrichment factor. Based on the combinatorial pharmacophore model, a virtual screening against SPECS database was performed. Nineteen novel active compounds were successfully identified, which provide new chemical starting points for further structural optimization of FGFR1 inhibitors.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries

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Han Bucong

2012-11-01

Full Text Available Abstract Background Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. Results We evaluated support vector machines (SVM as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33% of 13.56M PubChem, 1,496 (0.89% of 168 K MDDR, and 719 (7.73% of 9,305 MDDR compounds similar to the known inhibitors. Conclusions SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates.

Development and experimental test of support vector machines virtual screening method for searching Src inhibitors from large compound libraries.

Science.gov (United States)

Han, Bucong; Ma, Xiaohua; Zhao, Ruiying; Zhang, Jingxian; Wei, Xiaona; Liu, Xianghui; Liu, Xin; Zhang, Cunlong; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2012-11-23

Src plays various roles in tumour progression, invasion, metastasis, angiogenesis and survival. It is one of the multiple targets of multi-target kinase inhibitors in clinical uses and trials for the treatment of leukemia and other cancers. These successes and appearances of drug resistance in some patients have raised significant interest and efforts in discovering new Src inhibitors. Various in-silico methods have been used in some of these efforts. It is desirable to explore additional in-silico methods, particularly those capable of searching large compound libraries at high yields and reduced false-hit rates. We evaluated support vector machines (SVM) as virtual screening tools for searching Src inhibitors from large compound libraries. SVM trained and tested by 1,703 inhibitors and 63,318 putative non-inhibitors correctly identified 93.53%~ 95.01% inhibitors and 99.81%~ 99.90% non-inhibitors in 5-fold cross validation studies. SVM trained by 1,703 inhibitors reported before 2011 and 63,318 putative non-inhibitors correctly identified 70.45% of the 44 inhibitors reported since 2011, and predicted as inhibitors 44,843 (0.33%) of 13.56M PubChem, 1,496 (0.89%) of 168 K MDDR, and 719 (7.73%) of 9,305 MDDR compounds similar to the known inhibitors. SVM showed comparable yield and reduced false hit rates in searching large compound libraries compared to the similarity-based and other machine-learning VS methods developed from the same set of training compounds and molecular descriptors. We tested three virtual hits of the same novel scaffold from in-house chemical libraries not reported as Src inhibitor, one of which showed moderate activity. SVM may be potentially explored for searching Src inhibitors from large compound libraries at low false-hit rates.

On the mathematical modeling of wound healing angiogenesis in skin as a reaction-transport process.

Science.gov (United States)

Flegg, Jennifer A; Menon, Shakti N; Maini, Philip K; McElwain, D L Sean

2015-01-01

Over the last 30 years, numerous research groups have attempted to provide mathematical descriptions of the skin wound healing process. The development of theoretical models of the interlinked processes that underlie the healing mechanism has yielded considerable insight into aspects of this critical phenomenon that remain difficult to investigate empirically. In particular, the mathematical modeling of angiogenesis, i.e., capillary sprout growth, has offered new paradigms for the understanding of this highly complex and crucial step in the healing pathway. With the recent advances in imaging and cell tracking, the time is now ripe for an appraisal of the utility and importance of mathematical modeling in wound healing angiogenesis research. The purpose of this review is to pedagogically elucidate the conceptual principles that have underpinned the development of mathematical descriptions of wound healing angiogenesis, specifically those that have utilized a continuum reaction-transport framework, and highlight the contribution that such models have made toward the advancement of research in this field. We aim to draw attention to the common assumptions made when developing models of this nature, thereby bringing into focus the advantages and limitations of this approach. A deeper integration of mathematical modeling techniques into the practice of wound healing angiogenesis research promises new perspectives for advancing our knowledge in this area. To this end we detail several open problems related to the understanding of wound healing angiogenesis, and outline how these issues could be addressed through closer cross-disciplinary collaboration.

The effects of CD147 on the cell proliferation, apoptosis, invasion, and angiogenesis in glioma.

Science.gov (United States)

Yin, Haoyuan; Shao, Ying; Chen, Xuan

2017-01-01

To analyze the effects of extracellular matrix metalloproteinase inducer (CD147) on glioma proliferation, apoptosis, invasion, and angiogenesis. Tissue samples were obtained from 101 glioma cases while normal brain tissues were obtained from 30 brain injury cases. Immunohistochemical assay was performed to detect the expressions of CD147, CD34, and VEGF in tissue samples. QRT-PCR was performed to detect the relative expression of CD147 mRNA in human glioma cell lines. CD147 siRNA was transfected into glioma cell line U251. Cell proliferation, apoptosis, invasion, and angiogenesis were tested by MTT, flow cytometry, Transwell assay, and vasculogenic mimicry assay, respectively. Expressions of relative proteins were analyzed with western blot. CD147 was positively expressed with the percentage of 0, 37.5, 44.8, 67.9, and 85.7 % in normal tissues and glioma tissues with WHO grades I-IV, respectively, and the scores of MVDand VEGF were associated with the expression of CD147. CD147 was significantly upregulated in the human glioma cell lines (P CD147 suppressed cell proliferation, blocked cell cycle, induced apoptosis, inhibited cell invasion and angiogenesis in glioma cells in vitro. The expression of CD147 was significantly associated with WHO tumor grade and angiogenesis; silencing of CD147 contributed to inhibition of glioma proliferation, invasion, and angiogenesis. Our study provided firm evidence that CD 147 is a potential glioma target for anti-angiogenic therapies.

YKL-40-Induced Inhibition of miR-590-3p Promotes Interleukin-18 Expression and Angiogenesis of Endothelial Progenitor Cells

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Te-Mao Li

2017-04-01

Full Text Available YKL-40, also known as human cartilage glycoprotein-39 or chitinase-3-like-1, is a pro-inflammatory protein that is highly expressed in rheumatoid arthritis (RA patients. Angiogenesis is a critical step in the pathogenesis of RA, promoting the infiltration of inflammatory cells into joints and providing oxygen and nutrients to RA pannus. In this study, we examined the effects of YKL-40 in the production of the pro-inflammatory cytokine interleukin-18 (IL-18, and the stimulation of angiogenesis and accumulation of osteoblasts. We observed that YKL-40 induces IL-18 production in osteoblasts and thereby stimulates angiogenesis of endothelial progenitor cells (EPCs. We found that this process occurs through the suppression of miR-590-3p via the focal adhesion kinase (FAK/PI3K/Akt signaling pathway. YKL-40 inhibition reduced angiogenesis in in vivo models of angiogenesis: the chick embryo chorioallantoic membrane (CAM and Matrigel plug models. We report that YKL-40 stimulates IL-18 expression in osteoblasts and facilitates EPC angiogenesis.

WISP-3 inhibition of miR-452 promotes VEGF-A expression in chondrosarcoma cells and induces endothelial progenitor cells angiogenesis.

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Lin, Chih-Yang; Tzeng, Huey-En; Li, Te-Mao; Chen, Hsien-Te; Lee, Yi; Yang, Yi-Chen; Wang, Shih-Wei; Yang, Wei-Hung; Tang, Chih-Hsin

2017-06-13

Chondrosarcoma is the second most prevalent general primary tumor of bone following osteosarcoma. Chondrosarcoma development may be linked to angiogenesis, which is principally elicited by vascular endothelial growth factor-A (VEGF-A). VEGF-A level has been recognized as a prognostic marker in angiogenesis. WNT1-inducible signaling pathway protein-3 (WISP)-3/CCN6 belongs to the CCN family and is involved in regulating several cellular functions, including cell proliferation, differentiation, and migration. Nevertheless, the effect of WISP-3 on VEGF-A production and angiogenesis in human chondrosarcoma remains largely unknown. This current study shows that WISP-3 promoted VEGF-A production and induced angiogenesis of human endothelial progenitor cells. Moreover, WISP-3-enhanced VEGF-A expression and angiogenesis involved the c-Src and p38 signaling pathways, while miR-452 expression was negatively affected by WISP-3 via the c-Src and p38 pathways. Our results illustrate the clinical significance of WISP-3, VEGF-A and miR-452 in human chondrosarcoma patients. WISP-3 may illustrate a novel therapeutic target in the metastasis and angiogenesis of chondrosarcoma.

Radiographic progression is associated with resolution of systemic inflammation in patients with axial spondylarthritis treated with tumor necrosis factor α inhibitors

DEFF Research Database (Denmark)

Pedersen, Susanne Juhl; Sørensen, Inge Juul; Lambert, Robert G W

2011-01-01

To investigate the relationship of circulating biomarkers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and YKL-40), angiogenesis (vascular endothelial growth factor), cartilage turnover (C-terminal crosslinking telopeptide of type II collagen [CTX-II], total aggrecan, matrix...... metalloproteinase 3 [MMP-3], and cartilage oligomeric matrix protein [COMP]), and bone turnover (CTX-I and osteocalcin) to inflammation on magnetic resonance imaging (MRI) and radiographic progression in patients with axial spondylarthritis (SpA) beginning tumor necrosis factor α (TNFα) inhibitor therapy....

Digital Microscopy Assessment of Angiogenesis in Different Breast Cancer Compartments

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Anca Haisan

2013-01-01

Full Text Available Background/Aim. Tumour angiogenesis defined by microvessel density (MVD is generally accepted as a prognostic factor in breast cancer. However, due to variability of measurement systems and cutoffs, it is questionable to date whether it contributes to predictive outline. Our study aims to grade vascular heterogeneity by comparing clear-cut compartments: tumour associated stroma (TAS, tumour parenchyma, and tumour invasive front. Material and Methods. Computerized vessel area measurement was performed using a tissue cytometry system (TissueFAXS on slides originated from 50 patients with breast cancer. Vessels were marked using immunohistochemistry with CD34. Regions of interest were manually defined for each tumour compartment. Results. Tumour invasive front vascular endothelia area was 2.15 times higher than that in tumour parenchyma and 4.61 times higher than that in TAS (P<0.002. Worth to mention that the lymph node negative subgroup of patients show a slight but constant increase of vessel index in all examined compartments of breast tumour. Conclusion. Whole slide digital examination and region of interest (ROI analysis are a valuable tool in scoring angiogenesis markers and disclosing their prognostic capacity. Our study reveals compartments’ variability of vessel density inside the tumour and highlights the propensity of invasive front to associate an active process of angiogenesis with potential implications in adjuvant therapy.

Vascular endothelial growth factors and angiogenesis in eye disease

NARCIS (Netherlands)

Witmer, A. N.; Vrensen, G. F. J. M.; van Noorden, C. J. F.; Schlingemann, R. O.

2003-01-01

The vascular endothelial growth factor (VEGF) family of growth factors controls pathological angiogenesis and increased vascular permeability in important eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). The purpose of this review is to develop new insights

Antitumor activity of the multikinase inhibitor regorafenib in patient-derived xenograft models of gastric cancer.

Science.gov (United States)

Huynh, Hung; Ong, Richard; Zopf, Dieter

2015-10-29

Unresectable gastric cancer is associated with poor outcomes, with few treatment options available after failure of cytotoxic chemotherapy. Clinical trials of targeted therapies have generally shown no survival benefit in gastric cancer, with the exceptions of the antibodies ramucirumab (anti-VEGFR2) and trastuzumab (anti-HER2/neu). Given the efficacy of the multikinase inhibitor regorafenib in other gastrointestinal tumors, we investigated its potential in gastric cancer. The antitumor activity of oral regorafenib was assessed in eight murine patient-derived gastric cancer xenograft models. Dose-response experiments assessed the efficacy and tolerability of oral regorafenib 5, 10, and 15 mg/kg/day in two models, with 10 mg/kg/day selected for further investigation in all eight models. Tumor weight and volume was monitored during treatment; tumor cell proliferation, angiogenesis, apoptosis, and intracellular signaling were assessed using immunohistochemistry and Western blotting of total tumor lysates at the end of treatment. Regorafenib showed dose-dependent inhibition of tumor growth and was well tolerated, with no significant decreases in bodyweight or evident toxicity. Regorafenib 10 mg/kg/day significantly inhibited tumor growth in all eight models (72 to 96 %; all p Regorafenib reduced tumor angiogenesis 3- to 11-fold versus controls in all models (all p Regorafenib was effective in patient-derived models of gastric cancer of different histological subtypes, with inhibition of tumor growth, angiogenesis, and tumor-cell proliferation observed in almost all models. These findings are consistent with the observed activity of regorafenib in preclinical models of other gastrointestinal tumors, and support further clinical investigation in gastric cancer.

Adjuvant Anti-Angiogenesis Drugs Are No Benefit in Kidney Cancer

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Results from a recent clinical trial show that post-surgical therapy with two anti-angiogenesis drugs does not improve progression-free survival for patients with kidney cancer and may cause serious side effects.

THE ROLE OF AUTOPHAGY AND ANGIOGENESIS IN COLORECTAL CANCER

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K. V. Rachkovsky

2017-01-01

Full Text Available The purpose of the study was a review of available data on the role of autophagy and angiogenesis in the development, progression and prognosis of colorectal cancer. Material and methods. Databases searched were Medline, Cochrane Library and Elibrary. Of 340 studies, 48 were used to write a systematic review. Results. To date, there is a variety of prognostic markers used in the study of pathogenesis, diagnosis and treatment of colorectal cancer. The review describes the molecular mechanisms of the participation of various proteins of autophagy and angiogenesis in the pathogenesis and progression of colorectal cancer, and the potential importance of their use in clinical practice is presented. Conclusion. Many of the existing markers can be used not only in assessing the prognosis, but also sensitivity to chemotherapy. However, the contradictory results of studies with respect to certain proteins require further study, validation, and subsequent introduction into practice. 

Angiogenesis and Endometriosis

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Ana Luiza L. Rocha

2013-01-01

Full Text Available A comprehensive review was performed to survey the role of angiogenesis in the pathogenesis of endometriosis. This is a multifactorial disease in which the development and maintenance of endometriotic implants depend on their invasive capacity and angiogenic potential. The peritoneal fluid of patients with endometriosis is a complex suspension carrying inflammatory cytokines, growth factors, steroid hormones, proangiogenic factors, macrophages, and endometrial and red blood cells. These cells and their signaling products concur to promote the spreading of new blood vessels at the endometriotic lesions and surroundings, which contributes to the endometriotic implant survival. Experimental studies of several antiangiogenic agents demonstrated the regression of endometriotic lesions by reducing their blood supply. Further studies are necessary before these novel agents can be introduced into clinical practice, in particular the establishment of the safety of anti-angiogenic medications in women who are seeking to become pregnant.

Angiogenesis PET Tracer Uptake (68Ga-NODAGA-E[(cRGDyK]2 in Induced Myocardial Infarction in Minipigs

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Thomas Rasmussen

2016-06-01

Full Text Available Angiogenesis is part of the healing process following an ischemic injury and is vital for the post-ischemic repair of the myocardium. Therefore, it is of particular interest to be able to noninvasively monitor angiogenesis. This might, not only permit risk stratification of patients following myocardial infarction, but could also facilitate development and improvement of new therapies directed towards stimulation of the angiogenic response. During angiogenesis endothelial cells must adhere to one another to form new microvessels. αvβ3 integrin has been found to be highly expressed in activated endothelial cells and has been identified as a critical modulator of angiogenesis. 68Ga-NODAGA-E[c(RGDyK]2 (RGD has recently been developed by us as an angiogenesis positron-emission-tomography (PET ligand targeted towards αvβ3 integrin. In the present study, we induced myocardial infarction in Göttingen minipigs. Successful infarction was documented by 82Rubidium-dipyridamole stress PET and computed tomography. RGD uptake was demonstrated in the infarcted myocardium one week and one month after induction of infarction by RGD-PET. In conclusion, we demonstrated angiogenesis by noninvasive imaging using RGD-PET in minipigs hearts, which resemble human hearts. The perspectives are very intriguing and might permit the evaluation of new treatment strategies targeted towards increasing the angiogenetic response, e.g., stem-cell treatment.

Biochemical study on some tumour angiogenesis factors and inhibitors in breast cancer

International Nuclear Information System (INIS)

Mohamed, N.M.E

2007-01-01

This pilot study was undertaken to investigate the significance of some tumour angiogenic factors (e.g. MMP, ADAM-12 and VEGF) and tumour angiogenic inhibitors (endostatin and TIMP-1) in the aetiology of breast cancer and their responsiveness to cancer treatment as well . We also sought to assess the significance of these angiogenic and antiangiogenic factors in the prognosis and diagnosis of breast cancer. The cases were allocated into five groups: Normal control group (Gr.l), fibroadenoma (Gr.l l), breast cancer (invasive duct carcinoma type grade l l) (Gr.lll) , breast cancer + chemo hormonal therapy (Gr.IV), and breast cancer + chemo hormonal and radiotherapy (Gr.V).Results obtained from this study reported absence of matrix metalloproteinase-9 (MMP-9)activity in the urine and serum of normal subjects and fibroadenoma patients and its significant depression in the urine and serum of breast cancer patients treated with chemo hormonal therapy alone or followed by radiotherapy, compared to breast cancer group as reference. A significantly mild elevation in urinary MMP-2 activity and a non significant change in its activity in the serum of fibroadenoma patients, compared to the dramatic rise in the urine and serum of breast cancer patients were observed

Angiogenesis is induced by airway smooth muscle strain.

Science.gov (United States)

Hasaneen, Nadia A; Zucker, Stanley; Lin, Richard Z; Vaday, Gayle G; Panettieri, Reynold A; Foda, Hussein D

2007-10-01

Angiogenesis is an important feature of airway remodeling in both chronic asthma and chronic obstructive pulmonary disease (COPD). Airways in those conditions are exposed to excessive mechanical strain during periods of acute exacerbations. We recently reported that mechanical strain of human airway smooth muscle (HASM) led to an increase in their proliferation and migration. Sustained growth in airway smooth muscle in vivo requires an increase in the nutritional supply to these muscles, hence angiogenesis. In this study, we examined the hypothesis that cyclic mechanical strain of HASM produces factors promoting angiogenic events in the surrounding vascular endothelial cells. Our results show: 1) a significant increase in human lung microvascular endothelial cell (HMVEC-L) proliferation, migration, and tube formation following incubation in conditioned media (CM) from HASM cells exposed to mechanical strain; 2) mechanical strain of HASM cells induced VEGF expression and release; 3) VEGF neutralizing antibodies inhibited the proliferation, migration, and tube formations of HMVEC-L induced by the strained airway smooth muscle CM; 4) mechanical strain of HASM induced a significant increase in hypoxia-inducible factor-1alpha (HIF-1alpha) mRNA and protein, a transcription factor required for VEGF gene transcription; and 5) mechanical strain of HASM induced HIF-1alpha/VEGF through dual phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and ERK pathways. In conclusion, exposing HASM cells to mechanical strain induces signal transduction pathway through PI3K/Akt/mTOR and ERK pathways that lead to an increase in HIF-1alpha, a transcription factor required for VEGF expression. VEGF release by mechanical strain of HASM may contribute to the angiogenesis seen with repeated exacerbation of asthma and COPD.

Osteogenesis and angiogenesis: The potential for engineering bone

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JM Kanczler

2008-05-01

Full Text Available The repair of large bone defects remains a major clinical orthopaedic challenge. Bone is a highly vascularised tissue reliant on the close spatial and temporal connection between blood vessels and bone cells to maintain skeletal integrity. Angiogenesis thus plays a pivotal role in skeletal development and bone fracture repair. Current procedures to repair bone defects and to provide structural and mechanical support include the use of grafts (autologous, allogeneic or implants (polymeric or metallic. These approaches face significant limitations due to insufficient supply, potential disease transmission, rejection, cost and the inability to integrate with the surrounding host tissue.The engineering of bone tissue offers new therapeutic strategies to aid musculoskeletal healing. Various scaffold constructs have been employed in the development of tissue-engineered bone; however, an active blood vessel network is an essential pre-requisite for these to survive and integrate with existing host tissue. Combination therapies of stem cells and polymeric growth factor release scaffolds tailored to promote angiogenesis and osteogenesis are under evaluation and development actively to stimulate bone regeneration. An understanding of the cellular and molecular interactions of blood vessels and bone cells will enhance and aid the successful development of future vascularised bone scaffold constructs, enabling survival and integration of bioengineered bone with the host tissue. The role of angiogenic and osteogenic factors in the adaptive response and interaction of osteoblasts and endothelial cells during the multi step process of bone development and repair will be highlighted in this review, with consideration of how some of these key mechanisms can be combined with new developments in tissue engineering to enable repair and growth of skeletal fractures. Elucidation of the processes of angiogenesis, osteogenesis and tissue engineering strategies offer

VEGF-mediated angiogenesis stimulates neural stem cell proliferation and differentiation in the premature brain

International Nuclear Information System (INIS)

Sun, Jinqiao; Sha, Bin; Zhou, Wenhao; Yang, Yi

2010-01-01

This study investigated the effects of angiogenesis on the proliferation and differentiation of neural stem cells in the premature brain. We observed the changes in neurogenesis that followed the stimulation and inhibition of angiogenesis by altering vascular endothelial growth factor (VEGF) expression in a 3-day-old rat model. VEGF expression was overexpressed by adenovirus transfection and down-regulated by siRNA interference. Using immunofluorescence assays, Western blot analysis, and real-time PCR methods, we observed angiogenesis and the proliferation and differentiation of neural stem cells. Immunofluorescence assays showed that the number of vWF-positive areas peaked at day 7, and they were highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at every time point. The number of neural stem cells, neurons, astrocytes, and oligodendrocytes in the subventricular zone gradually increased over time in the VEGF up-regulation group. Among the three groups, the number of these cells was highest in the VEGF up-regulation group and lowest in the VEGF down-regulation group at the same time point. Western blot analysis and real-time PCR confirmed these results. These data suggest that angiogenesis may stimulate the proliferation of neural stem cells and differentiation into neurons, astrocytes, and oligodendrocytes in the premature brain.

The role of angiogenesis in damage and recovery from ischemic stroke.

Science.gov (United States)

Arenillas, Juan F; Sobrino, Tomás; Castillo, José; Dávalos, Antoni

2007-06-01

Ischemic stroke is burdened with a high morbidity and mortality in our society. However, there are few effective and largely available therapies for this devastating disease. In additon to advancing acute reperfusion therapies, there is a need to develop treatments aimed to promote repair and regeneration of brain tissue damaged by ischemia (neurorecovery). Therapeutic angiogenesis and vasculogenesis represent novel approaches of regenerative medicine that may help in the cure of patients with acute ischemic stroke. Translation of our knowledge about these processes from the bench to bedside is still underway. Although angiogenesis (the sprouting of new blood vessels from pre-existing vascular structures) is likely to contribute to neurorepair, the finality of the angiogenic response in acute ischemic stroke has not been fully elucidated. The first therapeutic approach to angiogenesis after ischemic stroke would be the modulation of the endogenous angiogenic response. In this setting, early instauration of physical activity, statins, and peroxisome proliferator-activated receptor-gamma agonists may enhance angiogenesis and neuroregeneration. Gene therapy with vascular growth factors has been successfully tested in patients affected by chronic myocardial and peripheral ischemia. Regarding brain ischemia, experiments in animal models have shown that the effect of these growth factors is critically affected by the dosage, route of delivery, and time of administration in relation to stroke onset. In addition, the optimal angiogenic substance is unknown. Finally, vectors for gene transfer should be further optimized. Therapeutic vasculogenesis consists of the administration of exogenous endothelial progenitor cells in order to enhance brain repair processes. Endothelial progenitor cells may be recruited in response to cerebral ischemia and participate in reparative vasculogenesis after acute ischemic stroke. Further research is needed to clarify their role and

Oxidative stress in tumor microenvironment——Its role in angiogenesis

Institute of Scientific and Technical Information of China (English)

Armando ROJAS; Raúl SILVA; Héctor FIGUEROA; Miguel A MORALES

2008-01-01

The tumor angiogenesis process is believed to be dependent on an "angiogenic switch" formed by a cascade of biologic events as a consequence of the "cross-talk" between tumor cells and several components of local microenvironment including endothelial cells, macrophages, mast cells and stromal components. Oxidative stress represents an important stimulus that widely contributes to this angiogenic switch, which is particularly relevant in lungs,where oxidative stress is originated from different sources including the incomplete reduction of oxygen during respiration,exposure to hypoxia/reoxygenation, stimulated resident or chemoattracted immune ceils to lung tissues, as well as by a variety of chemicals compounds. In the present review we highlight the role of oxidative stress in tumor angiogenesis as a key signal linked to other relevant actors in this complex process.

Promotion of adipogenesis by an EP2 receptor agonist via stimulation of angiogenesis in pulmonary emphysema.

Science.gov (United States)

Tsuji, Takao; Yamaguchi, Kazuhiro; Kikuchi, Ryota; Itoh, Masayuki; Nakamura, Hiroyuki; Nagai, Atsushi; Aoshiba, Kazutetsu

2014-08-01

Body weight loss is a common manifestation in patients with chronic obstructive pulmonary disease (COPD), particularly those with severe emphysema. Adipose angiogenesis is a key mediator of adipogenesis and use of pro-angiogenic agents may serve as a therapeutic option for lean COPD patients. Since angiogenesis is stimulated by PGE2, we examined whether ONO-AE1-259, a selective E-prostanoid (EP) 2 receptor agonist, might promote adipose angiogenesis and adipogenesis in a murine model of elastase-induced pulmonary emphysema (EIE mice). Mice were intratracheally instilled with elastase or saline, followed after 4 weeks by intraperitoneal administration of ONO-AE1-259 for 4 weeks. The subcutaneous adipose tissue (SAT) weight decreased in the EIE mice, whereas in the EIE mice treated with ONO-AE1-259, the SAT weight was largely restored, which was associated with significant increases in SAT adipogenesis, angiogenesis, and VEGF protein production. In contrast, ONO-AE1-259 administration induced no alteration in the weight of the visceral adipose tissue. These results suggest that in EIE mice, ONO-AE1-259 stimulated adipose angiogenesis possibly via VEGF production, and thence, adipogenesis. Our data pave the way for the development of therapeutic interventions for weight loss in emphysema patients, e.g., use of pro-angiogenic agents targeting the adipose tissue vascular component. Copyright © 2014 Elsevier Inc. All rights reserved.

Thyroidal angiogenesis in zebrafish (Danio rerio) exposed to high ...

African Journals Online (AJOL)

STORAGESEVER

2009-04-20

Apr 20, 2009 ... As a well known environmental contaminant, perchlorate inhibits thyroidal iodide uptake and reduces thyroid hormone levels. In zebrafish (Danio rerio) exposed to high concentrations of sodium perchlorate (200, 350 and 500 mg/L) for 10 days, remarkable angiogenesis was identified, not only.

[The role of endothelial cells and endothelial precursor cells in angiogenesis].

Science.gov (United States)

Poreba, Małgorzata; Usnarska-Zubkiewicz, Lidia; Kuliczkowski, Kazimierz

2006-01-01

Endothelium plays a key role in maintenance of vascular homeostasis in human organism. According to new data endothelial cells and hematopoietic cells have a common precursor in prenatal life--a hemangioblast, which explains the fact of sharing the same determinants on the surface of both type of cells. Circulating endothelial precursors were identified in adults and this suggests that hemangioblasts may be present not only during embriogenesis. In some clinical situations the increased numbers of endothelial cells and endothelial precursors were noted, and especially in patients with neoplastic diseases, which is probably the result of increased angiogenesis. Endothelial precursors are thought to be the promice for therapeutic purposes in future--to increase local angiogenesis.

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

DEFF Research Database (Denmark)

Fork, Christian; Gu, Lunda; Hitzel, Juliane

2015-01-01

OBJECTIVE: Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. APPROACH AND RESULTS...... of JARID1B in the vascular system, Jarid1b knockout mice were studied. As global knockout results in increased mortality and developmental defects, tamoxifen-inducible and endothelial-specific knockout mice were generated. Acute knockout of Jarid1b attenuated retinal angiogenesis and endothelial sprout...

Apurinic/apyrimidinic endonuclease 1 regulates angiogenesis in a transforming growth factor β-dependent manner in human osteosarcoma.

Science.gov (United States)

Jiang, Xuan; Shan, Jinlu; Dai, Nan; Zhong, Zhaoyang; Qing, Yi; Yang, Yuxing; Zhang, Shiheng; Li, Chongyi; Sui, Jiangdong; Ren, Tao; Li, Mengxia; Wang, Dong

2015-10-01

Angiogenesis plays an important role in tumor growth and metastasis and has been reported to be inversely correlated with overall survival of osteosarcoma patients. It has been shown that apurinic/apyrimidinic endonuclease 1 (APE1), a dually functional protein possessing both base excision repair and redox activities, is involved in tumor angiogenesis, although these mechanisms are not fully understood. Our previous study showed that the expression of transforming growth factor β (TGFβ) was significantly reduced in APE1-deficient osteosarcoma cells. Transforming growth factor β promotes cancer metastasis through various mechanisms including immunosuppression, angiogenesis, and invasion. In the current study, we initially revealed that APE1, TGFβ, and microvessel density (MVD) have pairwise correlation in osteosarcoma tissue samples, whereas TGFβ, tumor size, and MVD were inversely related to the prognosis of the cohort. We found that knocking down APE1 in osteosarcoma cells resulted in TGFβ downregulation. In addition, APE1-siRNA led to suppression of angiogenesis in vitro based on HUVECs in Transwell and Matrigel tube formation assays. Reduced secretory protein level of TGFβ of culture medium also resulted in decreased phosphorylation of Smad3 of HUVECs. In a mouse xenograft model, siRNA-mediated silencing of APE1 downregulated TGFβ expression, tumor size, and MVD. Collectively, the current evidence indicates that APE1 regulates angiogenesis in osteosarcoma by controlling the TGFβ pathway, suggesting a novel target for anti-angiogenesis therapy in human osteosarcoma. © 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.

MicroRNA-939 governs vascular integrity and angiogenesis through targeting γ-catenin in endothelial cells

International Nuclear Information System (INIS)

Hou, Shiqiang; Fang, Ming; Zhu, Qian; Liu, Ying; Liu, Liang; Li, Xinming

2017-01-01

Coronary collateral circulation (CCC) functions as a natural bypass in the event of coronary obstruction, which markedly improves prognosis in patients with coronary artery disease (CAD). MicroRNAs (miRNAs) have been implicated in multiple physiological and pathological processes, including angiogenesis involved in CCC growth. The roles that miRNA-939 (miR-939) plays in angiogenesis remain largely unknown. We conducted this study to explore the expression of miR-939 in CAD patients and its role in angiogenesis. For the first time, our results indicated that the expression of circulating miR-939 was down-regulated in patients with sufficient CCC compared with patients with poor CCC. Overexpression of miR-939 in primary human umbilical vein endothelial cells (HUVECs) significantly inhibited the proliferation, adhesion and tube formation, but promoted the migration of cells. In contrast, miR-939 knockdown exerted reverse effects. We further identified that γ-catenin was a novel target of miR-939 by translational repression, which could rescue the effects of miR-939 in HUVECs. In summary, this study revealed that the expression of circulating miR-939 was down-regulated in CAD patients with sufficient CCC. MiR-939 abolished vascular integrity and repressed angiogenesis through directly targeting γ-catenin. It provided a potential biomarker and a therapeutic target for CAD. - Highlights: • Circulating miR-939 is decreased in sufficient coronary collateral circulation. • MiR-939 abolishes vascular integrity in endothelial cells. • MiR-939 represses angiogenesis. • γ-catenin is a novel target of miR-939.

Thyroidal angiogenesis in zebrafish ( Danio rerio ) exposed to high ...

African Journals Online (AJOL)

As a well known environmental contaminant, perchlorate inhibits thyroidal iodide uptake and reduces thyroid hormone levels. In zebrafish (Danio rerio) exposed to high concentrations of sodium perchlorate (200, 350 and 500 mg/L) for 10 days, remarkable angiogenesis was identified, not only histopathologically but also ...

Negative regulation of NOD1 mediated angiogenesis by PPARγ-regulated miR-125a

International Nuclear Information System (INIS)

Kang, Hyesoo; Park, Youngsook; Lee, Aram; Seo, Hyemin; Kim, Min Jung; Choi, Jihea; Jo, Ha-neul; Jeong, Ha-neul; Cho, Jin Gu; Chang, Woochul; Lee, Myeong-Sok; Jeon, Raok; Kim, Jongmin

2017-01-01

Infection with pathogens activates the endothelial cell and its sustained activation may result in impaired endothelial function. Endothelial dysfunction contributes to the pathologic angiogenesis that is characteristic of infection-induced inflammatory pathway activation. Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a protein receptor which recognizes bacterial molecules and stimulates an immune reaction in various cells; however, the underlying molecular mechanisms in the regulation of inflammation-triggered angiogenesis are not fully understood. Here we report that peroxisome proliferator-activated receptor gamma (PPARγ)-mediated miR-125a serves as an important regulator of NOD1 agonist-mediated angiogenesis in endothelial cells by directly targeting NOD1. Treatment of human umbilical vein endothelial cells with natural PPARγ ligand, 15-Deoxy-Delta12,14-prostaglandin J2, led to inhibition of NOD1 expression; contrarily, protein levels of NOD1 were significantly increased by PPARγ knockdown. We report that PPARγ regulation of NOD1 expression is a novel microRNA-mediated regulation in endothelial cells. MiR-125a expression was markedly decreased in human umbilical vein endothelial cells subjected to PPARγ knockdown while 15-Deoxy-Delta12,14-prostaglandin J2 treatment increased the level of miR-125a. In addition, NOD1 is closely regulated by miR-125a, which directly targets the 3′ untranslated region of NOD1. Moreover, both overexpression of miR-125a and PPARγ activation led to inhibition of NOD1 agonist-induced tube formation in endothelial cells. Finally, NOD1 agonist increased the formation of cranial and subintestinal vessel plexus in zebrafish, and this effect was abrogated by concurrent PPARγ activation. Overall, these findings identify a PPARγ-miR-125a-NOD1 signaling axis in endothelial cells that is critical in the regulation of inflammation-mediated angiogenesis. - Highlights: • Expression of NOD1 is regulated by

Gamabufotalin, a major derivative of bufadienolide, inhibits VEGF-induced angiogenesis by suppressing VEGFR-2 signaling pathway.

Science.gov (United States)

Tang, Ning; Shi, Lei; Yu, Zhenlong; Dong, Peipei; Wang, Chao; Huo, Xiaokui; Zhang, Baojing; Huang, Shanshan; Deng, Sa; Liu, Kexin; Ma, Tonghui; Wang, Xiaobo; Wu, Lijun; Ma, Xiao-Chi

2016-01-19

Gamabufotalin (CS-6), a main active compound isolated from Chinese medicine Chansu, has been shown to strongly inhibit cancer cell growth and inflammatory response. However, its effects on angiogenesis have not been known yet. Here, we sought to determine the biological effects of CS-6 on signaling mechanisms during angiogenesis. Our present results fully demonstrate that CS-6 could significantly inhibit VEGF triggered HUVECs proliferation, migration, invasion and tubulogenesis in vitro and blocked vascularization in Matrigel plugs impregnated in C57/BL6 mice as well as reduced vessel density in human lung tumor xenograft implanted in nude mice. Computer simulations revealed that CS-6 interacted with the ATP-binding sites of VEGFR-2 using molecular docking. Furthermore, western blot analysis indicated that CS-6 inhibited VEGF-induced phosphorylation of VEGFR-2 kinase and suppressed the activity of VEGFR-2-mediated signaling cascades. Therefore, our studies demonstrated that CS-6 inhibited angiogenesis by inhibiting the activation of VEGFR-2 signaling pathways and CS-6 could be a potential candidate in angiogenesis-related disease therapy.

Uncaria rhynchophylla induces angiogenesis in vitro and in vivo.

Science.gov (United States)

Choi, Do-Young; Huh, Jeong-Eun; Lee, Jae-Dong; Cho, Eun-Mi; Baek, Yong-Hyeon; Yang, Ha-Ru; Cho, Yoon-Je; Kim, Kang-Il; Kim, Deog-Yoon; Park, Dong-Suk

2005-12-01

Angiogenesis consists of the proliferation, migration, and differentiation of endothelial cells, and angiogenic factors and matrix protein interactions modulate this process. The aim of this study was to determine the angiogenic properties of Uncaria rhynchophylla. Uncaria rhynchophylla significantly enhanced human umbilical vein endothelial cells (HUVECs) proliferation in a dose-dependent manner. Neutralization of vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) by monoclonal antibody suppressed the Uncaria rhynchophylla stimulatory effect on proliferation. In addition, Uncaria rhynchophylla significantly increased chemotactic-migration on gelatin and tubular structures on Matrigel of HUVECs in a dose-dependent manner. Interestingly, Uncaria rhynchophylla dose-dependently increased VEGF, and bFGF gene expression and protein secretion of HUVEC. The angiogenic activity of Uncaria rhynchophylla was confirmed using an in vivo Matrigel angiogenesis model, showing promotion of blood vessel formation. These results suggest that Uncaria rhynchophylla could potentially used to accelerate vascular wound healing or to promote the growth of collateral blood vessel in ischemic tissues.

BAG3 controls angiogenesis through regulation of ERK phosphorylation.

Science.gov (United States)

Falco, A; Festa, M; Basile, A; Rosati, A; Pascale, M; Florenzano, F; Nori, S L; Nicolin, V; Di Benedetto, M; Vecchione, M L; Arra, C; Barbieri, A; De Laurenzi, V; Turco, M C

2012-12-13

BAG3 is a co-chaperone of the heat shock protein (Hsp) 70, is expressed in many cell types upon cell stress, however, its expression is constitutive in many tumours. We and others have previously shown that in neoplastic cells BAG3 exerts an anti-apoptotic function thus favoring tumour progression. As a consequence we have proposed BAG3 as a target of antineoplastic therapies. Here we identify a novel role for BAG3 in regulation of neo-angiogenesis and show that its downregulation results in reduced angiogenesis therefore expanding the role of BAG3 as a therapeutical target. In brief we show that BAG3 is expressed in endothelial cells and is essential for the interaction between ERK and its phosphatase DUSP6, as a consequence its removal results in reduced binding of DUSP6 to ERK and sustained ERK phosphorylation that in turn determines increased levels of p21 and p15 and cell-cycle arrest in the G1 phase.

Tyrosine kinase inhibitor BIBF1120 ameliorates inflammation, angiogenesis and fibrosis in CCl4-induced liver fibrogenesis mouse model

NARCIS (Netherlands)

Öztürk Akcora, Büsra; Storm, Gerrit; Prakash, Jai; Bansal, Ruchi

2017-01-01

Hepatic fibrosis, a progressive chronic disease mainly caused by hepatitis viral infections, alcohol abuse or metabolic syndrome leading to liver dysfunction and is the growing cause of mortality worldwide. Tyrosine kinase inhibitor BIBF1120 (Nintedanib) has been evaluated in clinical trials for

Angiogenesis in gliomas.

Directory of Open Access Journals (Sweden)

Elzbieta Czykier

2008-02-01

Full Text Available Brain gliomas are characterized by invasive growth and neovascularisation potential. Angiogenesis plays a major role in the progression of gliomas and its determination has a great prognostic value. The aim of the study was to assess the vascularisation of chosen brain gliomas and to estimate how it is correlated with tumour histological type, malignancy grade, location and size, and with age and sex of patients. Tumour vascularisation analysis was based on the determination of microvascular proliferation (MVP and microvessel density (MVD. Microvascular proliferation was measured with immunohistochemical methods using mouse monoclonal antibodies to detect cell proliferation antigens. The following antibodies were used Ki-67 and PCNA (DAKO. Identification of vessels was performed by CD31 antibody and anti-human von Willebrand factor (DAKO. The highest microvascular proliferation and microvascular density were observed in multiform glioblastomas and the lowest in oligodendrogliomas. Significant correlation was observed between the vascularisation and malignancy grade.

Apparent diffusion coefficient correlation with oesophageal tumour stroma and angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Aoyagi, Tomoyoshi; Shuto, Kiyohiko; Okazumi, Shinichi; Hayano, Kohichi; Satoh, Asami; Saitoh, Hiroshige; Shimada, Hideaki; Nabeya, Yoshihiro; Matsubara, Hisahiro [Chiba University, Department of Frontier Surgery, Graduate School of Medicine, Chiba (Japan); Kazama, Toshiki [Chiba University, Department of Radiology, Graduate School of Medicine, Chiba (Japan)

2012-06-15

Because diffusion-weighted imaging (DWI) can predict the prognosis of patients with oesophageal squamous cell carcinoma (ESCC), we hypothesised that apparent diffusion coefficient (ADC) values might be correlated with the collagen content and tumour angiogenesis. The purpose of this study was to determine the correlation between ADC values of ESCC before treatment and oesophageal tumour stroma and angiogenesis. Seventeen patients with ESCC were enrolled. The ADC values were calculated from the DWI score. Seventeen patients who had undergone oesophagectomy were analysed for tumour stroma, vascular endothelial growth factor (VEGF) and CD34. Tissue collagen was stained with azocarmine and aniline blue to quantitatively analyse the extracellular matrix in cancer stroma. Tissues were stained with VEGF and CD34 to analyse the angiogenesis. The ADC values decreased with stromal collagen growth. We found a negative correlation between the tumour ADC and the amount of stromal collagen (r = -0.729, P = 0.001), i.e. the ADC values decreased with growth of VEGF. We also found a negative correlation between the ADC of the tumours and the amount of VEGF (r = 0.538, P = 0.026). Our results indicated that the ADC value may be a novel prognostic factor and contribute to the treatment of oesophageal cancer. circle Magnetic resonance apparent diffusion coefficient values inversely indicate tumour stromal collagen circle There is also negative correlation between ADCs and vascular endothelial growth factor circle ADC values may contribute to the treatment of oesophageal cancer. (orig.)

Apparent diffusion coefficient correlation with oesophageal tumour stroma and angiogenesis

International Nuclear Information System (INIS)

Aoyagi, Tomoyoshi; Shuto, Kiyohiko; Okazumi, Shinichi; Hayano, Kohichi; Satoh, Asami; Saitoh, Hiroshige; Shimada, Hideaki; Nabeya, Yoshihiro; Matsubara, Hisahiro; Kazama, Toshiki

2012-01-01

Because diffusion-weighted imaging (DWI) can predict the prognosis of patients with oesophageal squamous cell carcinoma (ESCC), we hypothesised that apparent diffusion coefficient (ADC) values might be correlated with the collagen content and tumour angiogenesis. The purpose of this study was to determine the correlation between ADC values of ESCC before treatment and oesophageal tumour stroma and angiogenesis. Seventeen patients with ESCC were enrolled. The ADC values were calculated from the DWI score. Seventeen patients who had undergone oesophagectomy were analysed for tumour stroma, vascular endothelial growth factor (VEGF) and CD34. Tissue collagen was stained with azocarmine and aniline blue to quantitatively analyse the extracellular matrix in cancer stroma. Tissues were stained with VEGF and CD34 to analyse the angiogenesis. The ADC values decreased with stromal collagen growth. We found a negative correlation between the tumour ADC and the amount of stromal collagen (r = -0.729, P = 0.001), i.e. the ADC values decreased with growth of VEGF. We also found a negative correlation between the ADC of the tumours and the amount of VEGF (r = 0.538, P = 0.026). Our results indicated that the ADC value may be a novel prognostic factor and contribute to the treatment of oesophageal cancer. circle Magnetic resonance apparent diffusion coefficient values inversely indicate tumour stromal collagen circle There is also negative correlation between ADCs and vascular endothelial growth factor circle ADC values may contribute to the treatment of oesophageal cancer. (orig.)

Amphiregulin enhances VEGF-A production in human chondrosarcoma cells and promotes angiogenesis by inhibiting miR-206 via FAK/c-Src/PKCδ pathway.

Science.gov (United States)

Wang, Chao-Qun; Huang, Yu-Wen; Wang, Shih-Wei; Huang, Yuan-Li; Tsai, Chun-Hao; Zhao, Yong-Ming; Huang, Bi-Fei; Xu, Guo-Hong; Fong, Yi-Chin; Tang, Chih-Hsin

2017-01-28

Chondrosarcoma is the second most common primary malignancy of bone after myeloma and osteosarcoma. Chondrosarcoma development may be linked to angiogenesis, which is principally elicited by vascular endothelial growth factor-A (VEGF-A). The expression of VEGF-A has been recognized as a prognostic marker in angiogenesis. Amphiregulin (AR), an epidermal growth factor receptor ligand, promotes tumor proliferation, metastasis and angiogenesis. However, the role of AR in VEGF-A expression and angiogenesis in human chondrosarcoma remains largely unknown. This current study shows that AR promoted VEGF-A production and induced angiogenesis of human endothelial progenitor cells. Moreover, AR-enhanced VEGF-A expression and angiogenesis involved the FAK, c-Src and PKCδ signaling pathways, while miR-206 expression was negatively mediated by AR via the FAK, c-Src and PKCδ pathways. Our results illustrate the clinical significance between AR, VEGF-A and miR-206, as well as tumor stage, in human chondrosarcoma. AR may represent a novel therapeutic target in the metastasis and angiogenesis of chondrosarcoma. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Agent-based model of angiogenesis simulates capillary sprout initiation in multicellular networks.

Science.gov (United States)

Walpole, J; Chappell, J C; Cluceru, J G; Mac Gabhann, F; Bautch, V L; Peirce, S M

2015-09-01

Many biological processes are controlled by both deterministic and stochastic influences. However, efforts to model these systems often rely on either purely stochastic or purely rule-based methods. To better understand the balance between stochasticity and determinism in biological processes a computational approach that incorporates both influences may afford additional insight into underlying biological mechanisms that give rise to emergent system properties. We apply a combined approach to the simulation and study of angiogenesis, the growth of new blood vessels from existing networks. This complex multicellular process begins with selection of an initiating endothelial cell, or tip cell, which sprouts from the parent vessels in response to stimulation by exogenous cues. We have constructed an agent-based model of sprouting angiogenesis to evaluate endothelial cell sprout initiation frequency and location, and we have experimentally validated it using high-resolution time-lapse confocal microscopy. ABM simulations were then compared to a Monte Carlo model, revealing that purely stochastic simulations could not generate sprout locations as accurately as the rule-informed agent-based model. These findings support the use of rule-based approaches for modeling the complex mechanisms underlying sprouting angiogenesis over purely stochastic methods.

Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis.

Science.gov (United States)

Weidemann, Anja K; Crawshaw, Ania A; Byrne, Emily; Young, Helen S

2013-09-26

Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF)-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation) and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased cardiovascular risk.

The MAPK-dependent regulation of the Jagged/Notch gene expression by VEGF, bFGF or PPAR gamma mediated angiogenesis in HUVEC

DEFF Research Database (Denmark)

Kiec-Wilk, B; Grzybowska-Galuszka, J; Polus, A

2010-01-01

The Jagged-Notch signalling, plays a crucial role in cell differentiation. Angiogenesis, is regulated by VEGF, bFGF as well as by the free fatty acid metabolites , which are regulators of transcription factors such as peroxisome proliferation activating receptors (PPARs). The study analyzed...... the signalling pathways involved in the regulation of Jagged-1/Notch-4 expression in endothelial cells (HUVECs) in response to VEGF, bFGF and PPAR-gamma exogenous activator - ciglitazone. HUVECs were incubated with investigated substances for 24 hours, with or without the presence of the MAP-kinases inhibitors...... were used. Jagged-1 and Notch-4 gene expression was determined using quantitative Real-Time PCR. The Jagged-1/Notch-4 protein expression was compared by flow cytometry, when the phosphorylation-dependent activation of kinases was estimated by Western-blot method. The opposite effect of VEGF, b...

 The role of metalloproteinases in modification of extracellular matrix in invasive tumor growth, metastasis and angiogenesis

Directory of Open Access Journals (Sweden)

Krzysztof Fink

2012-09-01

Full Text Available Extracellular matrix metalloproteinases (MMPs are a family of endopeptydases which recquire a zinc ion at their active site, for proteolityc activity. There are six members of the MMP family: matrilysins, collagenases, stromelysins, gelatinases, membrane MMPs and other MMPs. Activity of MMPs is regulated at the level of gene transcription, mRNA stability, zymogene proteolitic activation, inhibition of an active enzyme and MMP degradation. Tissue inhibitors of metalloproteinases (TIMPs are main intracellular inhibitors of MMPs. Host cells can be stimulated by tumor cells to produce MMPs by secreted interleukins, interferons, growth factors and an extracellular matrix metalloproteinase inducer (EMMPRIN. MMPs are produced by tumor cells, fibroblasts, macrophages, mast cells, polimorphonuclear neutrophiles (PMNs and endothelial cells (ECs. MMPs affect many stages of tumor development, facilitating its growth through promoting tumor cells proliferation, invasion and migration, new blood vessels formation and blocking tumor cells apoptosis. MMPs can promote tumor development in several ways. ECM degradation results in release of peptide growth factors. Growth factors linked with cell surface or binding proteins can also be liberated by MMPs. MMPs can indirectly regulate integrin signalling or cleave E-cadherins, facilitating cell migration. MMPs support metastasis inducing an epithelial to mesenchymal transition (EMT. MMP also support transendothelial migration. MMPs support angiogenesis by releasing pro-angiogenic factors and degrading ECM to support ECs migration. Cell surface growth factor receptors are also cleaved by MMPs, which results in inhibition of tumor development, so is release of anti-angiogenic factors from ECM. 

Aging impairs transcriptional regulation of vascular endothelial growth factor in human microvascular endothelial cells: implications for angiogenesis and cell survival.

Science.gov (United States)

Ahluwalia, A; Jones, M K; Szabo, S; Tarnawski, A S

2014-04-01

In some tissues, aging impairs angiogenesis and reduces expression of vascular endothelial growth factor A (VEGF), a fundamental regulator of angiogenesis. We previously examined angiogenesis in aging and young gastric mucosa in vivo and in vitro and showed that an imbalance between expressions of VEGF (pro-angiogenic factor) and endostatin (anti-angiogenic protein) results in an aging-related impairment of angiogenesis in rats. However, the human relevance of these findings, and whether these mechanisms apply to endothelial cells derived from other tissues, is not clear. Since P-STAT3 and P-CREB are transcription factors that, in association with HIF-1α, can activate VEGF gene expression in some cells (e.g., liver cancer cells, vascular smooth muscle cells), we examined the expression of these two proteins in human dermal microvascular endothelial cells (HMVECs) derived from aging and neonatal individuals. We examined and quantified in vitro angiogenesis, expression of VEGF, P-STAT3, P-CREB and importin-α in HMVECs isolated from neonates (neonatal) and a 66 year old subject (aging). We also examined the effects of treatment with exogenous VEGF and endostatin on in vitro angiogenesis in these cells. Endothelial cells isolated from aging individuals had impaired angiogenesis (vs. neonatal endothelial cells) and reduced expression of VEGF mRNA and protein. Aged HMVECs also had reduced importin-α expression, and reduced expression and nuclear translocation of P-STAT3 and P-CREB. Reduced VEGF gene expression in aged HMVECs strongly correlated with the decreased levels of P-STAT3, P-CREB and importin-α in these cells. Our study clearly demonstrates that endothelial cells from aging individuals have impaired angiogenesis and reduced expression of VEGF likely due to impaired nuclear transport of P-STAT3 and P-CREB transcription factors in these cells.

Structural exploration for the refinement of anticancer matrix metalloproteinase-2 inhibitor designing approaches through robust validated multi-QSARs

Science.gov (United States)

Adhikari, Nilanjan; Amin, Sk. Abdul; Saha, Achintya; Jha, Tarun

2018-03-01

Matrix metalloproteinase-2 (MMP-2) is a promising pharmacological target for designing potential anticancer drugs. MMP-2 plays critical functions in apoptosis by cleaving the DNA repair enzyme namely poly (ADP-ribose) polymerase (PARP). Moreover, MMP-2 expression triggers the vascular endothelial growth factor (VEGF) having a positive influence on tumor size, invasion, and angiogenesis. Therefore, it is an urgent need to develop potential MMP-2 inhibitors without any toxicity but better pharmacokinetic property. In this article, robust validated multi-quantitative structure-activity relationship (QSAR) modeling approaches were attempted on a dataset of 222 MMP-2 inhibitors to explore the important structural and pharmacophoric requirements for higher MMP-2 inhibition. Different validated regression and classification-based QSARs, pharmacophore mapping and 3D-QSAR techniques were performed. These results were challenged and subjected to further validation to explain 24 in house MMP-2 inhibitors to judge the reliability of these models further. All these models were individually validated internally as well as externally and were supported and validated by each other. These results were further justified by molecular docking analysis. Modeling techniques adopted here not only helps to explore the necessary structural and pharmacophoric requirements but also for the overall validation and refinement techniques for designing potential MMP-2 inhibitors.

Protein Structure in Context: The Molecular Landscape of Angiogenesis

Science.gov (United States)

Span, Elise A.; Goodsell, David S.; Ramchandran, Ramani; Franzen, Margaret A.; Herman, Tim; Sem, Daniel S.

2013-01-01

A team of students, educators, and researchers has developed new materials to teach cell signaling within its cellular context. Two nontraditional modalities are employed: physical models, to explore the atomic details of several of the proteins in the angiogenesis signaling cascade, and illustrations of the proteins in their cellular environment,…

Modulation of thioacetamide-induced hepatic inflammations, angiogenesis and fibrosis by andrographolide in mice.

Science.gov (United States)

Lee, Tzung-Yan; Chang, Hen-Hong; Wen, Chorng-Kai; Huang, Tse-Hung; Chang, Ya-Shu

2014-12-02

Liver fibrosis is a complex disease in which several pathological processes, such as inflammation and angiogenesis, are closely integrated. We hypothesised that treatment with the pharmacological agent, andrographolide (AP), which has multiple mechanisms of action, will provide a greater understanding of the role of AP during the multiple pathological processes that occur in advanced liver disease. Liver fibrogenesis was induced in mice using thioacetamide (TAA), which was administrated for 6 weeks. Andrographolide (5, 20 or 100mg/kg) was then given once daily following TAA injection. Liver collagen was examined using hydroxyproline and α-SMA, while the inflammatory response was quantified by Western blot and RT-PCR assays. Liver angiogenesis, neutrophil infiltration and hypoxia were assessed using CD11b+, vWF and HIF-1α immunostaining. Mice with liver injuries that were treated with andrographolide showed improved inflammatory response and diminished angiogenesis and hepatic fibrosis. Andrographolide treatment inhibited liver neutrophil infiltration, while a decreased in TNF-α and COX-2 signalling indicated macrophage activation. Andrographolide decreased overall liver hypoxia, as shown by the downregulation of hypoxia-inducible cascade genes, such as VEGF. Andrographolide treatment resulted in a significant decrease in hepatic fibrogenesis, α-SMA abundance, and TGF-βR1 expression. The present results suggest that multi-targeted therapies directed against angiogenesis, inflammation, and fibrosis should be considered for the treatment of advanced liver injury. They further suggest that andrographolide treatment may be a novel therapeutic agent for the treatment of liver disease. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Decreased angiogenesis and arthritic disease in rabbits treated with an αvβ3 antagonist

Science.gov (United States)

Storgard, Chris M.; Stupack, Dwayne G.; Jonczyk, Alfred; Goodman, Simon L.; Fox, Robert I.; Cheresh, David A.

1999-01-01

Rheumatoid arthritis (RA) is an inflammatory disease associated with intense angiogenesis and vascular expression of integrin αvβ3. Intra-articular administration of a cyclic peptide antagonist of integrin αvβ3 to rabbits with antigen-induced arthritis early in disease resulted in inhibition of synovial angiogenesis and reduced synovial cell infiltrate, pannus formation, and cartilage erosions. These effects were not associated with lymphopenia or impairment of leukocyte function. Furthermore, when administered in chronic, preexisting disease, the αvβ3 antagonist effectively diminished arthritis severity and was associated with a quantitative increase in apoptosis of the angiogenic blood vessels. Therefore, angiogenesis appears to be a central factor in the initiation and persistence of arthritic disease, and antagonists of integrin αvβ3 may represent a novel therapeutic strategy for RA. PMID:9884333

Vascular pericyte density and angiogenesis associated with adenocarcinoma of the prostate.

Science.gov (United States)

Killingsworth, Murray C; Wu, Xiaojuan

2011-01-01

Angiogenesis facilitates metabolism, proliferation and metastasis of adenocarcinoma cells in the prostate, as without the development of new vasculature tumor growth cannot be sustained. However, angiogenesis is variable with the well-known phenomenon of vascular 'hotspots' seen associated with viable tumor cell mass. With the recent recognition of pericytes as molecular regulators of angiogenesis, we have examined the interaction of these cells in actively growing new vessels. Pericyte interactions with developing new vessels were examined using transmission electron microscopy. Pericyte distribution was mapped from α-SMA+ immunostained histological sections and quantified using image analysis. Data was obtained from peripheral and more central regions of 27 cases with Gleason scores of 4-9. Pericyte numbers were increased around developing new vessel sprouts at sites of luminal maturation. Numbers were reduced around the actively growing tips of migrating endothelial cells and functional new vessels. Tumor regions internal to a 500-μm peripheral band showed higher microvessel pericyte density than the peripheral region. Pericytes were found to be key cellular components of developing new vessels in adenocarcinoma of the prostate. Their numbers increased at sites of luminal maturation with these cells displaying an activated phenotype different to quiescent pericytes. Increased pericyte density was found internal to the peripheral region, suggesting more mature vessels lie more centrally. Copyright © 2011 S. Karger AG, Basel.

Vascular endothelial growth factor inhibitors: investigational therapies for the treatment of psoriasis

Directory of Open Access Journals (Sweden)

Weidemann AK

2013-09-01

Full Text Available Anja K Weidemann,1 Ania A Crawshaw,2 Emily Byrne,3 Helen S Young1 1The Dermatology Centre, Salford Royal NHS Foundation Trust, The University of Manchester, Manchester, UK; 2Royal Sussex County Hospital, Brighton, UK; 3University Hospital of South Manchester, Manchester, UK Abstract: Psoriasis is a common inflammatory autoimmune condition in which environmental factors and genetic predisposition contribute to the development of disease in susceptible individuals. Angiogenesis is known to be a key pathogenic feature of psoriasis. Local and systemic elevation of vascular endothelial growth factor (VEGF-A has been demonstrated in the skin and plasma of patients with psoriasis and is known to correlate with improvement following some traditional psoriasis treatments. A number of VEGF inhibitors are licensed for the treatment of malignancies and eye disease and isolated case reports suggest that some individuals with psoriasis may improve when exposed to these agents. The small number of cases and lack of unified reporting measures makes it difficult to draw generalizations and underline the heterogeneity of psoriasis as a disease entity. Though not yet licensed for the treatment of psoriasis in humans, experimental data supports the potential of VEGF inhibitors to influence relevant aspects of human cell biology (such as endothelial cell differentiation and to improve animal models of skin disease. Given the multi-factorial nature of psoriasis it is unlikely that VEGF inhibitors will be effective in all patients, however they have the potential to be a valuable addition to the therapeutic arsenal in selected cases. Current VEGF inhibitors in clinical use are associated with a number of potentially serious side effects including hypertension, left ventricular dysfunction, and gastrointestinal perforation. Such risks require careful consideration in psoriasis populations particularly in light of growing concerns linking psoriasis to increased

Inhibition of VEGF-dependent angiogenesis by the anti-CD82 monoclonal antibody 4F9 through regulation of lipid raft microdomains

International Nuclear Information System (INIS)

Nomura, Sayaka; Iwata, Satoshi; Hatano, Ryo; Komiya, Eriko; Dang, Nam H.; Iwao, Noriaki; Ohnuma, Kei; Morimoto, Chikao

2016-01-01

CD82 (also known as KAI1) belongs to the tetraspanin superfamily of type III transmembrane proteins, and is involved in regulating cell adhesion, migration and proliferation. In contrast to these well-established roles of CD82 in tumor biology, its function in endothelial cell (EC) activity and tumor angiogenesis is yet to be determined. In this study, we show that suppression of CD82 negatively regulates vascular endothelial growth factor (VEGF)-induced angiogenesis. Moreover, we demonstrate that the anti-CD82 mAb 4F9 effectively inhibits phosphorylation of VEGF receptor 2 (VEGFR2), which is the principal mediator of the VEGF-induced angiogenic signaling process in tumor angiogenesis, by regulating the organization of the lipid raft microdomain signaling platform in human EC. Our present work therefore suggests that CD82 on EC is a potential target for anti-angiogenic therapy in VEGFR2-dependent tumor angiogenesis. -- Highlights: •Knockdown of CD82 decreases EC migration, proliferation and angiogenesis. •Anti-CD82 mAb 4F9 inhibits EC migration, proliferation and angiogenesis. •4F9 inhibits VEGFR2 phosphorylation via control of CD82 distribution in lipid rafts.

Inhibition of VEGF-dependent angiogenesis by the anti-CD82 monoclonal antibody 4F9 through regulation of lipid raft microdomains

Energy Technology Data Exchange (ETDEWEB)

Nomura, Sayaka; Iwata, Satoshi; Hatano, Ryo [Division of Clinical Immunology, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Komiya, Eriko [Department of Therapy Development and Innovation for Immune Disorders and Cancers, Graduate School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421 (Japan); Dang, Nam H. [Division of Hematology/Oncology, University of Florida, 1600 SW Archer Road- Box 100278, Room MSB M410A, Gainesville, FL, 32610 (United States); Iwao, Noriaki [Department of Hematology, School of Medicine, Juntendo University, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421 (Japan); Ohnuma, Kei, E-mail: kohnuma@juntendo.ac.jp [Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Morimoto, Chikao [Division of Clinical Immunology, Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan); Department of Rheumatology and Allergy, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639 (Japan)

2016-05-20

CD82 (also known as KAI1) belongs to the tetraspanin superfamily of type III transmembrane proteins, and is involved in regulating cell adhesion, migration and proliferation. In contrast to these well-established roles of CD82 in tumor biology, its function in endothelial cell (EC) activity and tumor angiogenesis is yet to be determined. In this study, we show that suppression of CD82 negatively regulates vascular endothelial growth factor (VEGF)-induced angiogenesis. Moreover, we demonstrate that the anti-CD82 mAb 4F9 effectively inhibits phosphorylation of VEGF receptor 2 (VEGFR2), which is the principal mediator of the VEGF-induced angiogenic signaling process in tumor angiogenesis, by regulating the organization of the lipid raft microdomain signaling platform in human EC. Our present work therefore suggests that CD82 on EC is a potential target for anti-angiogenic therapy in VEGFR2-dependent tumor angiogenesis. -- Highlights: •Knockdown of CD82 decreases EC migration, proliferation and angiogenesis. •Anti-CD82 mAb 4F9 inhibits EC migration, proliferation and angiogenesis. •4F9 inhibits VEGFR2 phosphorylation via control of CD82 distribution in lipid rafts.

Angiogenesis in calcium phosphate scaffolds by inorganic copper ion release

NARCIS (Netherlands)

Barralet, Jake E.; Gbureck, Uwe; Habibovic, Pamela; Vorndran, Elke; Gerard, Catherine; Doillon, Charles J.

2009-01-01

Angiogenesis in a tissue-engineered device may be induced by incorporating growth factors (e.g., vascular endothelial growth factor [VEGF]), genetically modified cells, and/or vascular cells. It represents an important process during the formation and repair of tissue and is essential for

Ionizing radiation modulates the exposure of the HUIV26 cryptic epitope within collagen type IV during angiogenesis

International Nuclear Information System (INIS)

Brooks, Peter C.; Roth, Jennifer M.; Lymberis, Stella C.; DeWyngaert, Keith; Broek, Daniel; Formenti, Silvia C.

2002-01-01

Purpose: The majority of the research on the biologic effects of ionizing radiation has focused on the impact of radiation on cells in terms of gene expression, DNA damage, and cytotoxicity. In comparison, little information is available concerning the direct effects of radiation on the extracellular microenvironment, specifically the extracellular matrix and its main component, collagen. We have developed a series of monoclonal antibodies that bind to cryptic epitopes of collagen Type IV that are differentially exposed during matrix remodeling and are key mediators of angiogenesis. We have hypothesized that ionizing radiation might affect the process of angiogenesis through a direct effect on the extracellular matrix and specifically on collagen Type IV. Methods and Materials: Angiogenesis was induced in a chick chorioallantoic membrane (CAM) model; 24 h later, a single-dose treatment with ionizing radiation (0.5, 5, and 20 cGy) was administered. Angiogenesis was assessed, and the exposure of two cryptic regulatory epitopes within collagen Type IV (HUI77 and HUIV26) was studied in vitro by solid-phase ELISA and in vivo by immunofluorescence staining. Results: A dose-dependent reduction of angiogenesis with maximum inhibition (85%-90%) occurring at 20 cGy was demonstrated in the CAM model. Exposure of the cryptic HUIV26 site, an angiogenesis control element, was inhibited both in vitro and in vivo by the same radiation dose, whereas little if any change was observed for the HUI77 cryptic epitope. Conclusions: A dose-dependent alteration of the functional exposure of the HUIV26 cryptic epitope is induced by radiation in vitro and in the CAM model in vivo. This radiation-induced change in protein structure and function may contribute to the inhibitory effects of ionizing radiation on new blood vessel growth and warrants further studies in other models

STAT3-regulated exosomal miR-21 promotes angiogenesis and is involved in neoplastic processes of transformed human bronchial epithelial cells.

Science.gov (United States)

Liu, Yi; Luo, Fei; Wang, Bairu; Li, Huiqiao; Xu, Yuan; Liu, Xinlu; Shi, Le; Lu, Xiaolin; Xu, Wenchao; Lu, Lu; Qin, Yu; Xiang, Quanyong; Liu, Qizhan

2016-01-01

Although microRNA (miRNA) enclosed in exosomes can mediate intercellular communication, the roles of exosomal miRNA and angiogenesis in lung cancer remain unclear. We investigated functions of STAT3-regulated exosomal miR-21 derived from cigarette smoke extract (CSE)-transformed human bronchial epithelial (HBE) cells in the angiogenesis of CSE-induced carcinogenesis. miR-21 levels in serum were higher in smokers than those in non-smokers. The medium from transformed HBE cells promoted miR-21 levels in normal HBE cells and angiogenesis of human umbilical vein endothelial cells (HUVEC). Transformed cells transferred miR-21 into normal HBE cells via exosomes. Knockdown of STAT3 reduced miR-21 levels in exosomes derived from transformed HBE cells, which blocked the angiogenesis. Exosomes derived from transformed HBE cells elevated levels of vascular endothelial growth factor (VEGF) in HBE cells and thereby promoted angiogenesis in HUVEC cells. Inhibition of exosomal miR-21, however, decreased VEGF levels in recipient cells, which blocked exosome-induced angiogenesis. Thus, miR-21 in exosomes leads to STAT3 activation, which increases VEGF levels in recipient cells, a process involved in angiogenesis and malignant transformation of HBE cells. These results, demonstrating the function of exosomal miR-21 from transformed HBE cells, provide a new perspective for intervention strategies to prevent carcinogenesis of lung cancer. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Therapies based on inhibitors of the epidermal growth factor receptor: enclosing the future

International Nuclear Information System (INIS)

Diaz, Arlhee; Lage, Agustin

2007-01-01

The Epidermal Growth Factor Receptor (EGFR) is considered an important target for rational drug design due to its key role in numerous tumors. Potential contribution of EGFR-related signaling pathways to promote tumorigenic processes, including cell proliferation, angiogenesis, and resistance to apoptosis has been well established. Two classes of anti-EGFR agents in late-stage clinical testing include monoclonal antibodies against extracellular EGFR domain (Cetuximab, Nimotuzumab) and small molecules tyrosine kinase inhibitors, which inhibit the receptor enzyme activity (Gefitinib, Erlotinib). A considerable body of evidence has emerged since its introduction in the treatment of cancer patients. However, important questions such as reliable surrogate markers to predict response to the treatment, or optimal sequence and combination of these agents with conventional therapies remain to be addressed. Identify and validate predictive factors to select patients likely to respond to EGFR inhibitors, such as mutations that confer resistance versus those associated with sensitivity is required. A better understanding of molecular mechanisms associated with antitumor activity will useful to predict the interaction of these agents with other therapies in order to avoid antagonisms or overlapping effects resulting in no adding effects. Finally, the benefits derived from EGFR inhibitors as first-line therapy in selected populations, and the optimal doses and ways to delivery to the tumor site resulting in optimal target modulation should be established by the ongoing investigation. (Author)

Extracellular anti-angiogenic proteins augment an endosomal protein trafficking pathway to reach mitochondria and execute apoptosis in HUVECs.

Science.gov (United States)

Chen, Mo; Qiu, Tao; Wu, Jiajie; Yang, Yang; Wright, Graham D; Wu, Min; Ge, Ruowen

2018-03-09

Classic endocytosis destinations include the recycling endosome returning to the plasma membrane or the late endosome (LE) merging with lysosomes for cargo degradation. However, the anti-angiogenic proteins angiostatin and isthmin, are endocytosed and trafficked to mitochondria (Mito) to execute apoptosis of endothelial cells. How these extracellular proteins reach mitochondria remains a mystery. Through confocal and super-resolution fluorescent microscopy, we demonstrate that angiostatin and isthmin are trafficked to mitochondria through the interaction between LE and Mito. Using purified organelles, the LE-Mito interaction is confirmed through in vitro lipid-fusion assay, as well as single vesicle total internal reflection fluorescent microscopy. LE-Mito interaction enables the transfer of not only lipids but also proteins from LE to Mito. Angiostatin and isthmin augment this endosomal protein trafficking pathway and make use of it to reach mitochondria to execute apoptosis. Cell fractionation and biochemical analysis identified that the cytosolic scaffold protein Na+/H+ exchanger regulatory factor 1 (NHERF1) associated with LE and the t-SNARE protein synaptosome-associated protein 25 kDa (SNAP25) associated with Mito form an interaction complex to facilitate LE-Mito interaction. Proximity ligation assay coupled with fluorescent microscopy showed that both NHERF1 and SNAP25 are located at the contacting face between LE and Mito. RNAi knockdown of either NHERF1 or SNAP25 suppressed not only the mitochondrial trafficking of angiostatin and isthmin but also their anti-angiogenic and pro-apoptotic functions. Hence, this study reveals a previously unrealized endosomal protein trafficking pathway from LE to Mito that allows extracellular proteins to reach mitochondria and execute apoptosis.

Albendazole inhibits endothelial cell migration, tube formation, vasopermeability, VEGF receptor-2 expression and suppresses retinal neovascularization in ROP model of angiogenesis

Energy Technology Data Exchange (ETDEWEB)

Pourgholami, Mohammad H., E-mail: mh.pourgholami@unsw.edu.au [University of New South Wales, Department of Surgery, St George Hospital (SESIAHS), Sydney (Australia); Khachigian, Levon M.; Fahmy, Roger G. [Centre for Vascular Research, The University of New South Wales, Department of Haematology, The Prince of Wales Hospital, Sydney (Australia); Badar, Samina; Wang, Lisa; Chu, Stephanie Wai Ling; Morris, David Lawson [University of New South Wales, Department of Surgery, St George Hospital (SESIAHS), Sydney (Australia)

2010-07-09

The angiogenic process begins with the cell proliferation and migration into the primary vascular network, and leads to vascularization of previously avascular tissues and organs as well to growth and remodeling of the initially homogeneous capillary plexus to form a new microcirculation. Additionally, an increase in microvascular permeability is a crucial step in angiogenesis. Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. We have previously reported that albendazole suppresses VEGF levels and inhibits malignant ascites formation, suggesting a possible effect on angiogenesis. This study was therefore designed to investigate the antiangiogenic effect of albendazole in non-cancerous models of angiogenesis. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with albendazole led to inhibition of tube formation, migration, permeability and down-regulation of the VEGF type 2 receptor (VEGFR-2). In vivo albendazole profoundly inhibited hyperoxia-induced retinal angiogenesis in mice. These results provide new insights into the antiangiogenic effects of albendazole.

Albendazole inhibits endothelial cell migration, tube formation, vasopermeability, VEGF receptor-2 expression and suppresses retinal neovascularization in ROP model of angiogenesis

International Nuclear Information System (INIS)

Pourgholami, Mohammad H.; Khachigian, Levon M.; Fahmy, Roger G.; Badar, Samina; Wang, Lisa; Chu, Stephanie Wai Ling; Morris, David Lawson

2010-01-01

The angiogenic process begins with the cell proliferation and migration into the primary vascular network, and leads to vascularization of previously avascular tissues and organs as well to growth and remodeling of the initially homogeneous capillary plexus to form a new microcirculation. Additionally, an increase in microvascular permeability is a crucial step in angiogenesis. Vascular endothelial growth factor (VEGF) plays a central role in angiogenesis. We have previously reported that albendazole suppresses VEGF levels and inhibits malignant ascites formation, suggesting a possible effect on angiogenesis. This study was therefore designed to investigate the antiangiogenic effect of albendazole in non-cancerous models of angiogenesis. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with albendazole led to inhibition of tube formation, migration, permeability and down-regulation of the VEGF type 2 receptor (VEGFR-2). In vivo albendazole profoundly inhibited hyperoxia-induced retinal angiogenesis in mice. These results provide new insights into the antiangiogenic effects of albendazole.

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells

OpenAIRE

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-01-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of newdrug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation o...

Enhancement of cell-based therapeutic angiogenesis using a novel type of injectable scaffolds of hydroxyapatite-polymer nanocomposite microspheres.

Directory of Open Access Journals (Sweden)

Yohei Mima

Full Text Available BACKGROUND: Clinical trials demonstrate the effectiveness of cell-based therapeutic angiogenesis in patients with severe ischemic diseases; however, their success remains limited. Maintaining transplanted cells in place are expected to augment the cell-based therapeutic angiogenesis. We have reported that nano-hydroxyapatite (HAp coating on medical devices shows marked cell adhesiveness. Using this nanotechnology, HAp-coated poly(l-lactic acid (PLLA microspheres, named nano-scaffold (NS, were generated as a non-biological, biodegradable and injectable cell scaffold. We investigate the effectiveness of NS on cell-based therapeutic angiogenesis. METHODS AND RESULTS: Bone marrow mononuclear cells (BMNC and NS or control PLLA microspheres (LA were intramuscularly co-implanted into mice ischemic hindlimbs. When BMNC derived from enhanced green fluorescent protein (EGFP-transgenic mice were injected into ischemic muscle, the muscle GFP level in NS+BMNC group was approximate fivefold higher than that in BMNC or LA+BMNC groups seven days after operation. Kaplan-Meier analysis demonstrated that NS+BMNC markedly prevented hindlimb necrosis (P<0.05 vs. BMNC or LA+BMNC. NS+BMNC revealed much higher induction of angiogenesis in ischemic tissues and collateral blood flow confirmed by three-dimensional computed tomography angiography than those of BMNC or LA+BMNC groups. NS-enhanced therapeutic angiogenesis and arteriogenesis showed good correlations with increased intramuscular levels of vascular endothelial growth factor and fibroblast growth factor-2. NS co-implantation also prevented apoptotic cell death of transplanted cells, resulting in prolonged cell retention. CONCLUSION: A novel and feasible injectable cell scaffold potentiates cell-based therapeutic angiogenesis, which could be extremely useful for the treatment of severe ischemic disorders.

Lectin-like oxidized LDL receptor-1 is an enhancer of tumor angiogenesis in human prostate cancer cells.

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Iván González-Chavarría

Full Text Available Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1 has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells.

Differential expression of IL-6/IL-6R and MAO-A regulates invasion/angiogenesis in breast cancer.

Science.gov (United States)

Bharti, Rashmi; Dey, Goutam; Das, Anjan Kumar; Mandal, Mahitosh

2018-04-26

Monoamine oxidases (MAO) are mitochondrial enzymes functioning in oxidative metabolism of monoamines. The action of MAO-A has been typically described in neuro-pharmacological domains. Here, we have established a co-relation between IL-6/IL-6R and MAO-A and their regulation in hypoxia induced invasion/angiogenesis. We employed various in-vitro and in-vivo techniques and clinical samples. We studied a co-relation among MAO-A and IL-6/IL-6R and tumour angiogenesis/invasion in hypoxic environment in breast cancer model. Activation of IL-6/IL-6R and its downstream was found in hypoxic cancer cells. This elevation of IL-6/IL-6R caused sustained inhibition of MAO-A in hypoxic environment. Inhibition of IL-6R signalling or IL-6R siRNA increased MAO-A activity and inhibited tumour angiogenesis and invasion significantly in different models. Further, elevation of MAO-A with 5-azacytidine (5-Aza) modulated IL-6 mediated angiogenesis and invasive signatures including VEGF, MMPs and EMT in hypoxic breast cancer. High grade invasive ductal carcinoma (IDC) clinical specimen displayed elevated level of IL-6R and depleted MAO-A expression. Expression of VEGF and HIF-1α was unregulated and loss of E-Cadherin was observed in high grade IDC tissue specimen. Suppression of MAO-A by IL-6/IL-6R activation promotes tumour angiogenesis and invasion in hypoxic breast cancer environment.

Alpha-, gamma- and delta-tocopherols reduce inflammatory angiogenesis in human microvascular endothelial cells.

Science.gov (United States)

Wells, Shannon R; Jennings, Merilyn H; Rome, Courtney; Hadjivassiliou, Vicky; Papas, Konstantinos A; Alexander, Jonathon S

2010-07-01

Vitamin E, a micronutrient (comprising alpha-, beta-, gamma- and delta-tocopherols, alpha-, beta-, gamma- and delta-tocotrienols), has documented antioxidant and non-antioxidant effects, some of which inhibit inflammation and angiogenesis. We compared the abilities of alpha-, gamma- and delta-tocopherols to regulate human blood cytotoxicity (BEC) and lymphatic endothelial cytotoxicity (LEC), proliferation, invasiveness, permeability, capillary formation and suppression of TNF-alpha-induced VCAM-1 as in vitro models of inflammatory angiogenesis. alpha-, gamma- and delta-tocopherols were not toxic to either cell type up to 40 microM. In BEC, confluent cell density was decreased by all concentrations of delta- and gamma-tocopherol (10-40 microM) but not by alpha-tocopherol. LEC showed no change in cell density in response to tocopherols. delta-Tocopherol (40 microM), but not other isomers, decreased BEC invasiveness. In LEC, all doses of gamma-tocopherol, as well as the highest dose of alpha-tocopherol (40 microM), decreased cell invasiveness. delta-Tocopherol had no effect on LEC invasiveness at any molarity. delta-Tocopherol dose dependently increased cell permeability at 48 h in BEC and LEC; alpha- and gamma-tocopherols showed slight effects. Capillary tube formation was decreased by high dose (40 microM) concentrations of alpha-, gamma- and delta-tocopherol, but showed no effects with smaller doses (10-20 microM) in BEC. gamma-Tocopherol (10-20 microM) and alpha-tocopherol (10 microM), but not delta-tocopherol, increased LEC capillary tube formation. Lastly, in BEC, alpha-, gamma- and delta-tocopherol each dose-dependently reduced TNF-alpha-induced expression of VCAM-1. In LEC, there was no significant change to TNF-alpha-induced VCAM-1 expression with any concentration of alpha-, gamma- or delta-tocopherol. These data demonstrate that physiological levels (0-40 microM) of alpha-, gamma- and delta-tocopherols are nontoxic and dietary tocopherols, especially delta

Radioiodinated VEGF to image tumor angiogenesis in a LS180 tumor xenograft model

International Nuclear Information System (INIS)

Yoshimoto, Mitsuyoshi; Kinuya, Seigo; Kawashima, Atsuhiro; Nishii, Ryuichi; Yokoyama, Kunihiko; Kawai, Keiichi

2006-01-01

Introduction: Angiogenesis is essential for tumor growth or metastasis. A method involving noninvasive detection of angiogenic activity in vivo would provide diagnostic information regarding antiangiogenic therapy targeting vascular endothelial cells as well as important insight into the role of vascular endothelial growth factor (VEGF) and its receptor (flt-1 and KDR) system in tumor biology. We evaluated radioiodinated VEGF 121 , which displays high binding affinity for KDR, and VEGF 165 , which possesses high binding affinity for flt-1 and low affinity for KDR, as angiogenesis imaging agents using the LS180 tumor xenograft model. Methods: VEGF 121 and VEGF 165 were labeled with 125 I by the chloramine-T method. Biodistribution was observed in an LS180 human colon cancer xenograft model. Additionally, autoradiographic imaging and immunohistochemical staining of tumors were performed with 125 I-VEGF 121 . Results: 125 I-VEGF 121 and 125 I-VEGF 165 exhibited strong, continuous uptake by tumors and the uterus, an organ characterized by angiogenesis. 125 I-VEGF 121 uptake in tumors was twofold higher than that of 125 I-VEGF 165 (9.12±98 and 4.79±1.08 %ID/g at 2 h, respectively). 125 I-VEGF 121 displayed higher tumor to nontumor (T/N) ratios in most normal organs in comparison with 125 I-VEGF 165 . 125 I-VEGF 121 accumulation in tumors decreased with increasing tumor volume. Autoradiographic and immunohistochemical analyses confirmed that the difference in 125 I-VEGF 121 tumor accumulation correlated with degree of tumor vascularity. Conclusion: Radioiodinated VEGF 121 is a promising tracer for noninvasive delineation of angiogenesis in vivo

Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1α and Notch1 in head neck squamous cell carcinoma.

Directory of Open Access Journals (Sweden)

Wei-Ming Wang

Full Text Available Angiogenesis, a marker of cancer development, affects response to radiotherapy sensibility. This preclinical study aims to understand the receptor tyrosine kinase-mediated angiogenesis in head neck squamous cell carcinoma (HNSCC. The receptor tyrosine kinase activity in a transgenic mouse model of HNSCC was assessed. The anti-tumorigenetic and anti-angiogenetic effects of cetuximab-induced epidermal growth factor receptor (EGFR inhibition were investigated in xenograft and transgenic mouse models of HNSCC. The signaling transduction of Notch1 and hypoxia-inducible factor-1α (HIF-1α was also analyzed. EGFR was overexpressed and activated in the Tgfbr1/Pten deletion (2cKO mouse model of HNSCC. Cetuximab significantly delayed tumor onset by reducing tumor angiogenesis. This drug exerted similar effects on heterotopic xenograft tumors. In the human HNSCC tissue array, increased EGFR expression correlated with increased HIF-1α and micro vessel density. Cetuximab inhibited tumor-induced angiogenesis in vitro and in vivo by significantly downregulating HIF-1α and Notch1. EGFR is involved in the tumor angiogenesis of HNSCC via the HIF-1α and Notch1 pathways. Therefore, targeting EGFR by suppressing hypoxia- and Notch-induced angiogenesis may benefit HNSCC therapy.

Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer

OpenAIRE

Wang, Xinjing; Zhu, Qinyi; Lin, Yingying; Wu, Li; Wu, Xiaoli; Wang, Kai; He, Qizhi; Xu, Congjian; Wan, Xiaoping; Wang, Xipeng

2017-01-01

Background: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14+Tie2+, TEMs) as key contributors to angiogenesis and metastasis of EOC. Methods: Tissue slides were evaluated by immunofluore...

Diclofenac, a selective COX-2 inhibitor, inhibits DMH-induced colon tumorigenesis through suppression of MCP-1, MIP-1α and VEGF.

Science.gov (United States)

Kaur, Jasmeet; Sanyal, S N

2011-09-01

Angiogenesis is a physiological process involving growth of new blood vessels from pre-existing ones; however, it also plays a critical role in tumor progression. It favors the transition from hyperplasia to neoplasia, that is, from a state of cellular multiplication to uncontrolled proliferation. Therefore targeting angiogenesis will be profitable as a mechanism to inhibit tumor's lifeline. Further, it is important to understand the cross-communication between vascular endothelial growth factor (VEGF)-master switch in angiogenesis and other molecules in the neoplastic and pro-inflammatory milieu. We studied the role of two important chemokines [monocyte chemoattractant protein (MCP)-1 and macrophage inflammatory protein (MIP)-lα] alongwith VEGF and matrix metalloproteinases (MMPs) in non-steroidal anti-inflammatory drugs (NSAIDs)-induced chemopreventive effect in experimental colon cancer in rat. 1,2-Dimethylhydrazine (DMH, 30 mg/kg body weight, subcutaneously (s.c.) once-a-week) for 18 wk was used as pro-carcinogen and diclofenac (8 mg/kg body weight, orally daily) as the preferential cyclooxygenase-2 (COX-2) inhibitor. Expression of COX-2 and VEGF was found to be significantly elevated in the DMH-treated group as compared to the control, which was lowered notably by Diclofenac co-administration with DMH. Gelatin zymography showed prominent MMP-9 activity in the DMH-treated rats, while the activity was nearly absent in all the other groups. Expression of MCP-1 was found to be markedly increased whereas MIP-1α expression was found to be decreased in colonic mucosa from DMH-treated rats, which was reversed in the DMH + Diclofenac group. Our results indicate potential role of chemokines alongwith VEGF in angiogenesis in DMH-induced cancer and its chemoprevention with diclofenac. Copyright ©2011 Wiley-Liss, Inc.

TLX controls angiogenesis through interaction with the von Hippel-Lindau protein.

Science.gov (United States)

Zeng, Zhao-Jun; Johansson, Erik; Hayashi, Amiko; Chavali, Pavithra L; Akrap, Nina; Yoshida, Takeshi; Kohno, Kimitoshi; Izumi, Hiroto; Funa, Keiko

2012-06-15

TLX is known as the orphan nuclear receptor indispensable for maintaining neural stem cells in adult neurogenesis. We report here that neuroblastoma cell lines express high levels of TLX, which further increase in hypoxia to enhance the angiogenic capacity of these cells. The proangiogenetic activity of TLX appears to be induced by its direct binding to the von Hippel-Lindau protein (pVHL), which stabilizes TLX. In turn, TLX competes with hydroxylated hypoxia-inducible factor (HIF-α) for binding to pVHL, which contributes to the stabilization of HIF-2α in neuroblastoma during normoxia. Upon hypoxia, TLX increases in the nucleus where it binds in close proximity of the HIF-response element on the VEGF-promoter chromatin, and, together with HIF-2α, recruits RNA polymerase II to induce VEGF expression. Conversely, depletion of TLX by shRNA decreases the expression of HIF-2α and VEGF as well as the growth-promoting and colony-forming capacity of the neuroblastoma cell lines IMR-32 and SH-SY5Y. On the contrary, silencing HIF-2α will slightly increase TLX, suggesting that TLX acts to maintain a hypoxic environment when HIF-2α is decreasing. Our results demonstrate TLX to play a key role in controlling angiogenesis by regulating HIF-2α. TLX and pVHL might counterbalance each other in important fate decisions such as self-renewal and differentiation, as well as angiogenesis and anti-angiogenesis.

TLX controls angiogenesis through interaction with the von Hippel-Lindau protein

Directory of Open Access Journals (Sweden)

Zhao-jun Zeng

2012-04-01

TLX is known as the orphan nuclear receptor indispensable for maintaining neural stem cells in adult neurogenesis. We report here that neuroblastoma cell lines express high levels of TLX, which further increase in hypoxia to enhance the angiogenic capacity of these cells. The proangiogenetic activity of TLX appears to be induced by its direct binding to the von Hippel-Lindau protein (pVHL, which stabilizes TLX. In turn, TLX competes with hydroxylated hypoxia-inducible factor (HIF-α for binding to pVHL, which contributes to the stabilization of HIF-2α in neuroblastoma during normoxia. Upon hypoxia, TLX increases in the nucleus where it binds in close proximity of the HIF-response element on the VEGF-promoter chromatin, and, together with HIF-2α, recruits RNA polymerase II to induce VEGF expression. Conversely, depletion of TLX by shRNA decreases the expression of HIF-2α and VEGF as well as the growth-promoting and colony-forming capacity of the neuroblastoma cell lines IMR-32 and SH-SY5Y. On the contrary, silencing HIF-2α will slightly increase TLX, suggesting that TLX acts to maintain a hypoxic environment when HIF-2α is decreasing. Our results demonstrate TLX to play a key role in controlling angiogenesis by regulating HIF-2α. TLX and pVHL might counterbalance each other in important fate decisions such as self-renewal and differentiation, as well as angiogenesis and anti-angiogenesis.

Methyl jasmonate abolishes the migration, invasion and angiogenesis of gastric cancer cells through down-regulation of matrix metalloproteinase 14

International Nuclear Information System (INIS)

Zheng, Liduan; Li, Dan; Xiang, Xuan; Tong, Ling; Qi, Meng; Pu, Jiarui; Huang, Kai; Tong, Qiangsong

2013-01-01

Recent evidence indicates that methyl jasmonate (MJ), a plant stress hormone, exhibits anti-cancer activity on human cancer cells. The aim of this study is to determine whether sub-cytotoxic MJ can abolish the migration, invasion and angiogenesis gastric cancer cells. Human gastric cancer cell lines SGC-7901 and MKN-45 were treated with diverse concentrations of MJ. Cell viability, proliferation, migration, invasion and angiogenesis capabilities of cancer cells were measured by MTT colorimetry, EdU incorporation, scratch assay, matrigel invasion assay, and tube formation assay. Gene expression was detected by western blot and real-time quantitative RT-PCR. Binding of transcription factor on gene promoter was detected by chromatin immunoprecipitation. Sub-cytotoxic (0.05 to 0.2 mM) MJ attenuated the migration, invasion and angiogenesis, but not the cell viability or proliferation, of gastric cancer cells in a time- and dose-dependent manner, with down-regulation of matrix metalloproteinase 14 (MMP-14) and its downstream gene vascular endothelial growth factor. Restoration of MMP-14 expression rescued the SGC-7901 and MKN-45 cells from sub-cytotoxic MJ-inhibited migration, invasion and angiogenesis. In addition, sub-cytotoxic MJ decreased the specificity protein 1 (Sp1) expression and binding on MMP-14 promoter, while restoration of Sp1 expression rescued the cancer cells from sub-cytotoxic MJ-mediated defects in MMP-14 expression, migration, invasion and angiogenesis. Sub-cytotoxic MJ attenuates the MMP-14 expression via decreasing the Sp1 expression and binding on MMP-14 promoter, thus inhibiting the migration, invasion and angiogenesis of gastric cancer cells

Regulation of angiogenesis in human skeletal muscle with specific focus on pro- angiogenic and angiostatic factors

DEFF Research Database (Denmark)

Høier, Birgitte

It is well established that acute exercise promotes an angiogenic response and that a period of exercise training results in capillary growth. Skeletal muscle angiogenesis is a complex process that requires a coordinated interplay of multiple factors and compounds to ensure proper vascular function....... The angiogenic process is initiated through changes in mechanical and/or metabolic factors during exercise and when exercise is repeated these stimuli may result in capillary growth if needed. The present PhD thesis is based on six studies in which the regulation of angiogenesis in skeletal muscle...... was studied in peripheral arterial disease. Vascular endothelial growth factor (VEGF) is the most important factor in exercise-induced angiogenesis and is located primarily in muscle cells but also in endothelial cells, pericytes, and in the extracellular matrix. VEGF protein secretion to the interstitium...

Sprouting angiogenesis in human midterm uterus and fallopian tube is guided by endothelial tip cells.

Science.gov (United States)

Rusu, M C; Motoc, A G M; Pop, F; Folescu, R

2013-01-01

Five samples of human midterm fetal uterus and fallopian tube (four donor bodies) were used to assess whether or not processes of angiogenesis are guided by endothelial tip cells (ETCs), and if cytokine-receptors, such as CD117/c-kit and PDGFR-α, are expressed in the microenvironment of the endothelial tubes. CD34 labeled microvessels in the uterine wall (myometrium and endometrium) and in the wall of the uterine (fallopian) tube, and accurately identified ETCs in both organs. We conclude that sprouting angiogenesis in the developing human female tract is guided by ETCs. Moreover, CD117/c-kit antibodies labeled mural networks of pericytes, α-SMA-positive and desmin-negative, related to the endometrial (but not myometrial) microvessels, and similar labeling was identified in the wall of the uterine tube. PDGFR-α positive labeling, stromal and pericytary, was also found. Thus, sprouting angiogenesis in human fetal genital organs appears to be guided by tip cells and is influenced by tyrosine kinase receptor signaling.

In vivo monitoring of angiogenesis within Matrigel chambers using MRI

DEFF Research Database (Denmark)

Holm, David; Ley, Carsten Dan; Søgaard, Lise Vejby

2006-01-01

Angiogenesis is a critical process in tumour development and presents an important target for the development of a range of anti-cancer agents . To assess the in vivo efficacy of these ‘angiotherapeutics', a simple and reproducible in vivo model would be of significant value. Here we show...

Transforming growth factor β-regulated microRNA-29a promotes angiogenesis through targeting the phosphatase and tensin homolog in endothelium.

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Wang, Jun; Wang, Youliang; Wang, Yu; Ma, Ying; Lan, Yu; Yang, Xiao

2013-04-12

The TGF-β pathway plays an important role in physiological and pathological angiogenesis. MicroRNAs (miRNAs) are a class of 18- to 25-nucleotide, small, noncoding RNAs that function by regulating gene expression. A number of miRNAs have been found to be regulated by the TGF-β pathway. However, the role of endothelial miRNAs in the TGF-β-mediated control of angiogenesis is still largely unknown. Here we investigated the regulation of endothelial microRNA-29a (miR-29a) by TGF-β signaling and the potential role of miR-29a in angiogenesis. MiR-29a was directly up-regulated by TGF-β/Smad4 signaling in human and mice endothelial cells. In a chick chorioallantoic membrane assay, miR-29a overexpression promoted the formation of new blood vessels, and miR-29a suppression completely blocked TGF-β1-stimulated angiogenesis. Consistently, miR-29a overexpression increased tube formation and migration in endothelial cultures. Mechanistically, miR-29a directly targeted the phosphatase and tensin homolog (PTEN) in endothelial cells, leading to activation of the AKT pathway. PTEN knockdown recapitulated the role of miR-29a in endothelial migration, whereas AKT inhibition completely attenuated the stimulating role of miR-29a in angiogenesis. Taken together, these results reveal a crucial role of a TGF-β-regulated miRNA in promoting angiogenesis by targeting PTEN to stimulate AKT activity.

SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease

Energy Technology Data Exchange (ETDEWEB)

Hendrikx, Geert [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Voeoe, Stefan [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Bauwens, Matthias [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht (Netherlands); Post, Mark J. [Maastricht University, Department of Physiology, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Mottaghy, Felix M. [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); University Hospital, RWTH Aachen University, Department of Nuclear Medicine, Aachen (Germany)

2016-12-15

The extent of neovascularization determines the clinical outcome of coronary artery disease and other occlusive cardiovascular disorders. Monitoring of neovascularization is therefore highly important. This review article will elaborately discuss preclinical studies aimed at validating new nuclear angiogenesis and arteriogenesis tracers. Additionally, we will briefly address possible obstacles that should be considered when designing an arteriogenesis radiotracer. A structured medline search was the base of this review, which gives an overview on different radiopharmaceuticals that have been evaluated in preclinical models. Neovascularization is a collective term used to indicate different processes such as angiogenesis and arteriogenesis. However, while it is assumed that sensitive detection through nuclear imaging will facilitate translation of successful therapeutic interventions in preclinical models to the bedside, we still lack specific tracers for neovascularization imaging. Most nuclear imaging research to date has focused on angiogenesis, leaving nuclear arteriogenesis imaging largely overlooked. Although angiogenesis is the process which is best understood, there is no scarcity in theoretical targets for arteriogenesis imaging. (orig.)

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells12

OpenAIRE

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-01-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation ...

Examining cerebral angiogenesis in response to physical exercise.

Science.gov (United States)

Berggren, Kiersten L; Kay, Jacob J M; Swain, Rodney A

2014-01-01

Capillary growth and expansion (angiogenesis) is a prerequisite for many forms of neural and behavioral plasticity. It is commonly observed in both brain and muscle of aerobically exercising animals. As such, several histological methods have been used to quantify capillary density, including perfusion with India ink, various Nissl stains, and immunohistochemistry. In this chapter, we will describe these histological procedures and describe the stereological analysis used to quantify vessel growth in response to aerobic exercise.

Markers of angiogenesis and epidermal growth factor receptor signalling in patients with pancreatic and gastroesophageal junction cancer

DEFF Research Database (Denmark)

Rohrberg, Kristoffer Staal; Skov, Birgit Guldhammer; Lassen, Ulrik

2010-01-01

The epidermal growth factor receptor (EGFR) and angiogenesis are well established targets in anti-cancer therapy. Several targeted anti-cancer therapies are in clinical trials in pancreatic and gastroesophageal (GEJ) cancer. However, many patients do not respond to these targeted therapies...... in pancreatic and GEJ cancer patients, and could be investigated further as predictive biomarkers in such patients treated with EGFR or angiogenesis targeted therapies....

Angiogenesis stimulated by novel nanoscale bioactive glasses

International Nuclear Information System (INIS)

Mao, Cong; Chen, Xiaofeng; Miao, Guohou; Lin, Cai

2015-01-01

The ability of biomaterials to induce rapid vascular formation is critical in tissue regeneration. Combining recombinant angiogenic growth factors with bioengineered constructs have proven to be difficult due to several issues, including the instability of recombinant proteins, the need for sustained delivery and the dosage of factors. New formulations of bioactive glass, 58S nanosized bioactive glass (58S-NBG), have been reported to enhance wound healing in animal models better than the first generation of 45S5 Bioglass. Therefore, we investigated the effects of extracts of 58S-NBG and 80S-NBG on cultures of human umbilical vein endothelial cells (HUVECs). Cell viability was assessed by MTS assay. In vitro angiogenesis was measured using an ECM gel tube formation assay, and levels of mRNAs for five angiogenic related genes were measured by qRT-PCR. Extracts of 58S-NBG and 80S-NBG stimulated the proliferation of HUVECs, accelerated cell migration, up-regulated expression of the vascular endothelial growth factor, basic fibroblast growth factor, their receptors, and endothelial nitric oxide synthase, resulting in enhanced tube formation in vitro. The enhanced angiogenic response correlated with increased levels of Ca and Si in the extracts of 58S-NBG and 80S-NBG. The ability of 58S-NBG and 80S-NBG to stimulate angiogenesis in vitro provides alternative approaches for stimulating neovascularization of tissue-engineered constructs. (paper)

An osteogenesis/angiogenesis-stimulation artificial ligament for anterior cruciate ligament reconstruction.

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Li, Hong; Li, Jinyan; Jiang, Jia; Lv, Fang; Chang, Jiang; Chen, Shiyi; Wu, Chengtie

2017-05-01

To solve the poor healing of polyethylene terephthalate (PET) artificial ligament in bone tunnel, copper-containing bioactive glass (Cu-BG) nanocoatings on PET artificial ligaments were successfully prepared by pulsed laser deposition (PLD). It was hypothesized that Cu-BG coated PET (Cu-BG/PET) grafts could enhance the in vitro osteogenic and angiogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs) and in vivo graft-bone healing after anterior cruciate ligament (ACL) reconstruction in a goat model. Scanning electron microscope and EDS mapping analysis revealed that the prepared nanocoatings had uniform element distribution (Cu, Ca, Si and P) and nanostructure. The surface hydrophilicity of PET grafts was significantly improved after depositing Cu-BG nanocoatings. The in vitro study displayed that the Cu-BG/PET grafts supported the attachment and proliferation of rBMSCs, and significantly promoted the expression of HIF-1α gene, which up-regulated the osteogenesis-related genes (S100A10, BMP2, OCN) and angiogenesis-related genes (VEGF) in comparison with PET or BG coated PET (BG/PET) grafts which do not contain Cu element. Meanwhile, Cu-BG/PET grafts promoted the bone regeneration at the graft-host bone interface and decreased graft-bone interface width, thus enhancing the bonding strength as well as angiogenesis (as indicated by CD31 expression) in the goat model as compared with BG/PET and pure PET grafts. The study demonstrates that the Cu-containing biomaterials significantly promote osteogenesis and angiogenesis in the repair of bone defects of large animals and thus offering a promising method for ACL reconstruction by using Cu-containing nanobioglass modified PET grafts. It remains a significant challenge to develop an artificial graft with distinct osteogenetic/angiogenetic activity to enhance graft-bone healing for ligament reconstruction. To solve these problems, copper-containing bioactive glass (Cu-BG) nanocoatings on PET artificial

Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LHBETATAG retinoblastoma tumors

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Samuel K Houston

2011-01-01

Full Text Available Samuel K Houston1, Yolanda Piña1, Timothy G Murray1, Hinda Boutrid1, Colleen Cebulla2, Amy C Schefler1, Wei Shi1, Magda Celdran1, William Feuer1, Jaime Merchan3, Ted J Lampidis41Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Ophthalmology, The Ohio State University, Columbus, OH, USA; 3Division of Hematology/Oncology, Department of Medicine, 4Department of Cell Biology and Anatomy, University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center, Miami, FL, USAPurpose: The purpose of this study was to evaluate the effect of optimally timed combination treatment with angiogenic and glycolytic inhibitors on tumor burden, hypoxia, and angiogenesis in advanced retinoblastoma tumors.Methods: LHBETATAG mice (n = 30 were evaluated. Mice were divided into 5 groups (n = 6 and received injections at 16 weeks of age (advanced tumors with a saline, b anecortave acetate (AA, c 2-deoxyglucose (2-DG, d AA + 2-DG (1 day post-AA treatment, or e AA + 2-DG (1 week post-AA treatment. Eyes were enucleated at 21 weeks and tumor sections were analyzed for hypoxia, angiogenesis, and tumor burden.Results: Eyes treated with 2-DG 1 day post-AA injection showed a 23% (P = 0.03 reduction in tumor burden compared with 2-DG alone and a 61% (P < 0.001 reduction compared with saline-treated eyes. Eyes treated with 2-DG 1 week post-AA injection showed no significant decrease in tumor burden compared with 2-DG alone (P = 0.21 and a 56% (P < 0.001 decrease in comparison with saline-treated eyes. 2-DG significantly reduced the total density of new blood vessels in tumors by 44% compared to saline controls (P < 0.001, but did not affect the density of mature vasculature.Conclusions: Combination therapy with angiogenic and glycolytic inhibitors significantly enhanced tumor control. Synergistic effects were shown to be dependent on the temporal course of treatment

Increased Umbilical Cord PAI-1 Levels in Placental Insufficiency Are Associated with Fetal Hypoxia and Angiogenesis

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Maxim D. Seferovic

2016-01-01

Full Text Available In intrauterine growth restriction (IUGR, a subset of pregnancies undergoes placental vascular dysregulation resulting in restricted blood flow and fetal hypoxemia. Altered transcription of hypoxic regulated plasminogen activator inhibitor 1 (PAI-1 has been associated with pregnancy complications and angiogenic regulation. Here we assessed circulating PAI-1 as an indicator of placental insufficiency. Venous umbilical PAI-1 of hypoxemic (VpO2 20 versus 35 mmHg, p<0.0001 placental insufficient pregnancies (resistance index 0.9 versus 0.63, p<0.05 (n=18 was compared to controls (n=12. PAI-1 was increased (~10-fold, p<0.001 and had a positive predictive ratio of 6.7. Further, PAI-1 levels correlated to blood oxygen (r=-0.68, p<0.0001. The plasma’s angiogenic potency measured in vitro was associated with umbilical cord blood PAI-1 levels (r=0.65, p<0.01. This association was attenuated by PAI-1 inhibiting antibody (p<0.001. The results demonstrate PAI-1 as a potential marker of placental insufficiency and identify its close association with pathological hypoxia and angiogenesis in a subset of growth restricted pregnancies.

Long non-coding RNA taurine upregulated 1 enhances tumor-induced angiogenesis through inhibiting microRNA-299 in human glioblastoma.

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Cai, H; Liu, X; Zheng, J; Xue, Y; Ma, J; Li, Z; Xi, Z; Li, Z; Bao, M; Liu, Y

2017-01-19

Angiogenesis is one of the critical biological elements affecting the development and progression of cancer. Long non-coding RNAs (lncRNAs) are important regulators and aberrantly expressed in various types of human cancer. Our previous studies indicated that lncRNA taurine upregulated 1 (TUG1) implicated in the regulation of blood-tumor barrier permeability; however, its role in glioblastoma angiogenesis still unclear. Here we demonstrated that TUG1 was up-expressed in human glioblastoma tissues and glioblastoma cell lines. Knockdown of TUG1 remarkably suppressed tumor-induced endothelial cell proliferation, migration and tube formation as well as reducing spheroid-based angiogenesis ability in vitro, which are the critical steps for tumor angiogenesis. Besides, knockdown of TUG1 significantly increased the expression of mircroRNA-299 (miR-299), which was down-expressed in glioblastoma tissues and glioblastoma cell lines. Bioinformatics analysis and luciferase reporter assay revealed that TUG1 influenced tumor angiogenesis via directly binding to the miR-299 and there was a reciprocal repression between TUG1 and miR-299 in the same RNA-induced silencing complex. Moreover, knockdown of TUG1 reduced the expression of vascular endothelial growth factor A (VEGFA), which was defined as a functional downstream target of miR-299. In addition, knockdown of TUG1, shown in the in vivo studies, has effects on suppressing tumor growth, reducing tumor microvessel density and decreasing the VEGFA expression by upregulating miR-299 in xenograft glioblastoma model. Overall, the results demonstrated that TUG1 enhances tumor-induced angiogenesis and VEGF expression through inhibiting miR-299. Also, the inhibition of TUG1 could provide a novel therapeutic target for glioblastoma treatment.

β-Elemene-Attenuated Tumor Angiogenesis by Targeting Notch-1 in Gastric Cancer Stem-Like Cells

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Bing Yan

2013-01-01

Full Text Available Emerging evidence suggests that cancer stem cells are involved in tumor angiogenesis. The Notch signaling pathway is one of the most important regulators of these processes. β-Elemene, a naturally occurring compound extracted from Curcumae Radix, has been used as an antitumor drug for various cancers in China. However, its underlying mechanism in the treatment of gastric cancer remains largely unknown. Here, we report that CD44+ gastric cancer stem-like cells (GCSCs showed enhanced proliferation capacity compared to their CD44− counterparts, and this proliferation was accompanied by the high expression of Notch-1 (in vitro. These cells were also more superior in spheroid colony formation (in vitro and tumorigenicity (in vivo and positively associated with microvessel density (in vivo. β-Elemene was demonstrated to effectively inhibit the viability of GCSCs in a dose-dependent manner, most likely by suppressing Notch-1 (in vitro. β-Elemene also contributed to growth suppression and attenuated the angiogenesis capacity of these cells (in vivo most likely by interfering with the expression of Notch-1 but not with Dll4. Our findings indicated that GCSCs play an important role in tumor angiogenesis, and Notch-1 is one of the most likely mediators involved in these processes. β-Elemene was effective at attenuating angiogenesis by targeting the GCSCs, which could be regarded as a potential mechanism for its efficacy in gastric cancer management in the future.

Identification of Padi2 as a novel angiogenesis-regulating gene by genome association studies in mice.

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Khajavi, Mehrdad; Zhou, Yi; Birsner, Amy E; Bazinet, Lauren; Rosa Di Sant, Amanda; Schiffer, Alex J; Rogers, Michael S; Krishnaji, Subrahmanian Tarakkad; Hu, Bella; Nguyen, Vy; Zon, Leonard; D'Amato, Robert J

2017-06-01

Recent findings indicate that growth factor-driven angiogenesis is markedly influenced by genetic variation. This variation in angiogenic responsiveness may alter the susceptibility to a number of angiogenesis-dependent diseases. Here, we utilized the genetic diversity available in common inbred mouse strains to identify the loci and candidate genes responsible for differences in angiogenic response. The corneal micropocket neovascularization assay was performed on 42 different inbred mouse strains using basic fibroblast growth factor (bFGF) pellets. We performed a genome-wide association study utilizing efficient mixed-model association (EMMA) mapping using the induced vessel area from all strains. Our analysis yielded five loci with genome-wide significance on chromosomes 4, 8, 11, 15 and 16. We further refined the mapping on chromosome 4 within a haplotype block containing multiple candidate genes. These genes were evaluated by expression analysis in corneas of various inbred strains and in vitro functional assays in human microvascular endothelial cells (HMVECs). Of these, we found the expression of peptidyl arginine deiminase type II (Padi2), known to be involved in metabolic pathways, to have a strong correlation with a haplotype shared by multiple high angiogenic strains. In addition, inhibition of Padi2 demonstrated a dosage-dependent effect in HMVECs. To investigate its role in vivo, we knocked down Padi2 in transgenic kdrl:zsGreen zebrafish embryos using morpholinos. These embryos had disrupted vessel formation compared to control siblings. The impaired vascular pattern was partially rescued by human PADI2 mRNA, providing evidence for the specificity of the morphant phenotype. Taken together, our study is the first to indicate the potential role of Padi2 as an angiogenesis-regulating gene. The characterization of Padi2 and other genes in associated pathways may provide new understanding of angiogenesis regulation and novel targets for diagnosis and

Identification of Padi2 as a novel angiogenesis-regulating gene by genome association studies in mice.

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Mehrdad Khajavi

2017-06-01

Full Text Available Recent findings indicate that growth factor-driven angiogenesis is markedly influenced by genetic variation. This variation in angiogenic responsiveness may alter the susceptibility to a number of angiogenesis-dependent diseases. Here, we utilized the genetic diversity available in common inbred mouse strains to identify the loci and candidate genes responsible for differences in angiogenic response. The corneal micropocket neovascularization assay was performed on 42 different inbred mouse strains using basic fibroblast growth factor (bFGF pellets. We performed a genome-wide association study utilizing efficient mixed-model association (EMMA mapping using the induced vessel area from all strains. Our analysis yielded five loci with genome-wide significance on chromosomes 4, 8, 11, 15 and 16. We further refined the mapping on chromosome 4 within a haplotype block containing multiple candidate genes. These genes were evaluated by expression analysis in corneas of various inbred strains and in vitro functional assays in human microvascular endothelial cells (HMVECs. Of these, we found the expression of peptidyl arginine deiminase type II (Padi2, known to be involved in metabolic pathways, to have a strong correlation with a haplotype shared by multiple high angiogenic strains. In addition, inhibition of Padi2 demonstrated a dosage-dependent effect in HMVECs. To investigate its role in vivo, we knocked down Padi2 in transgenic kdrl:zsGreen zebrafish embryos using morpholinos. These embryos had disrupted vessel formation compared to control siblings. The impaired vascular pattern was partially rescued by human PADI2 mRNA, providing evidence for the specificity of the morphant phenotype. Taken together, our study is the first to indicate the potential role of Padi2 as an angiogenesis-regulating gene. The characterization of Padi2 and other genes in associated pathways may provide new understanding of angiogenesis regulation and novel targets for

ADAM-17 regulates endothelial cell morphology, proliferation, and in vitro angiogenesis

International Nuclear Information System (INIS)

Goeoz, Pal; Goeoz, Monika; Baldys, Aleksander; Hoffman, Stanley

2009-01-01

Modulation of angiogenesis is a promising approach for treating a wide variety of human diseases including ischemic heart disease and cancer. In this study, we show that ADAM-17 is an important regulator of several key steps during angiogenesis. Knocking down ADAM-17 expression using lentivirus-delivered siRNA in HUVECs inhibited cell proliferation and the ability of cells to form close contact in two-dimensional cultures. Similarly, ADAM-17 depletion inhibited the ability of HUVECs to form capillary-like networks on top of three-dimensional Matrigel as well as in co-culture with fibroblasts within a three-dimensional scaffold. In mechanistic studies, both baseline and VEGF-induced MMP-2 activation and Matrigel invasion were inhibited by ADAM-17 depletion. Based on our findings we propose that ADAM-17 is part of a novel pro-angiogenic pathway leading to MMP-2 activation and vessel formation.

Protein Phosphotyrosine Phosphatase 1B (PTP1B) in Calpain-dependent Feedback Regulation of Vascular Endothelial Growth Factor Receptor (VEGFR2) in Endothelial Cells: IMPLICATIONS IN VEGF-DEPENDENT ANGIOGENESIS AND DIABETIC WOUND HEALING.

Science.gov (United States)

Zhang, Yixuan; Li, Qiang; Youn, Ji Youn; Cai, Hua

2017-01-13

The VEGF/VEGFR2/Akt/eNOS/NO pathway is essential to VEGF-induced angiogenesis. We have previously discovered a novel role of calpain in mediating VEGF-induced PI3K/AMPK/Akt/eNOS activation through Ezrin. Here, we sought to identify possible feedback regulation of VEGFR2 by calpain via its substrate protein phosphotyrosine phosphatase 1B (PTP1B), and the relevance of this pathway to VEGF-induced angiogenesis, especially in diabetic wound healing. Overexpression of PTP1B inhibited VEGF-induced VEGFR2 and Akt phosphorylation in bovine aortic endothelial cells, while PTP1B siRNA increased both, implicating negative regulation of VEGFR2 by PTP1B. Calpain inhibitor ALLN induced VEGFR2 activation, which can be completely blocked by PTP1B overexpression. Calpain activation induced by overexpression or Ca/A23187 resulted in PTP1B cleavage, which can be blocked by ALLN. Moreover, calpain activation inhibited VEGF-induced VEGFR2 phosphorylation, which can be restored by PTP1B siRNA. These data implicate calpain/PTP1B negative feedback regulation of VEGFR2, in addition to the primary signaling pathway of VEGF/VEGFR2/calpain/PI3K/AMPK/Akt/eNOS. We next examined a potential role of PTP1B in VEGF-induced angiogenesis. Endothelial cells transfected with PTP1B siRNA showed faster wound closure in response to VEGF. Aortic discs isolated from PTP1B siRNA-transfected mice also had augmented endothelial outgrowth. Importantly, PTP1B inhibition and/or calpain overexpression significantly accelerated wound healing in STZ-induced diabetic mice. In conclusion, our data for the first time demonstrate a calpain/PTP1B/VEGFR2 negative feedback loop in the regulation of VEGF-induced angiogenesis. Modulation of local PTP1B and/or calpain activities may prove beneficial in the treatment of impaired wound healing in diabetes. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Histopathological growth pattern, proteolysis and angiogenesis in chemonaive patients resected for multiple colorectal liver metastases

DEFF Research Database (Denmark)

Eefsen, Rikke Løvendahl; Van den Eynden, Gert G; Høyer-Hansen, Gunilla

2012-01-01

The purpose of this study was to characterise growth patterns, proteolysis, and angiogenesis in colorectal liver metastases from chemonaive patients with multiple liver metastases. Twenty-four patients were included in the study, resected for a median of 2.6 metastases. The growth pattern......-type plasminogen activator receptor (P = 0.0008). Angiogenesis was most pronounced in metastases with a pushing growth pattern in comparison to those with desmoplastic (P = 0.0007) and replacement growth pattern (P = 0.021). Although a minor fraction of the patients harboured metastases with different growth...

Interplay between VEGF and Nrf2 regulates angiogenesis due to intracranial venous hypertension.

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Li, Liwen; Pan, Hao; Wang, Handong; Li, Xiang; Bu, Xiaomin; Wang, Qiang; Gao, Yongyue; Wen, Guodao; Zhou, Yali; Cong, Zixiang; Yang, Youqing; Tang, Chao; Liu, Zhengwei

2016-11-21

Venous hypertension(VH) plays an important role in the pathogenesis of cerebral arteriovenous malformations (AVMs) and is closely associated with the HIF-1α/VEGF signaling pathway. Nuclear factor erythroid 2-related factor 2(Nrf2) significantly influences angiogenesis; however, the interplay between Nrf2 and VEGF under VH in brain AVMs remains unclear. Therefore, our study aimed to investigate the interplay between Nrf2 and VEGF due to VH in brain AVMs. Immunohistochemistry indicated that Nrf2 and VEGF were highly expressed in human brain AVM tissues. In vivo, we established a VH model in both wild-type (WT) and siRNA-mediated Nrf2 knockdown rats. VH significantly increased the expression of Nrf2 and VEGF. Loss of Nrf2 markedly inhibited the upregulation of VEGF, as determined by Western blot analysis and qRT-PCR. In vitro, primary brain microvascular endothelial cells (BMECs) were isolated from WT and Nrf2 -/- mice, and a VEGF-Nrf2 positive feed-back loop was observed in BMECs. By trans well assay and angiogenesis assay, Nrf2 knockout significantly inhibited the migration and vascular tube formation of BMECs. These findings suggest that the interplay between Nrf2 and VEGF can contribute to VH-induced angiogenesis in brain AVMs pathogenesis.

Targeted microbubbles for imaging tumor angiogenesis: assessment of whole-body biodistribution with dynamic micro-PET in mice

DEFF Research Database (Denmark)

Willmann, Jürgen K; Cheng, Zhen; Davis, Corrine

2008-01-01

To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice.......To evaluate in vivo whole-body biodistribution of microbubbles (MBs) targeted to tumor angiogenesis-related vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2) by using dynamic micro-positron emission tomography (PET) in living mice....

Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis.

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Gao, Jin-Hang; Wen, Shi-Lei; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Huang, Zhi-Yin; Liu, Zhang-Xu; Tang, Cheng-Wei

2013-01-01

Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2) in the cirrhotic liver might be a potential target to ameliorate portal hypertension. To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and related signal molecules were quantitated. Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, pportal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, pprotein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1α (HIF-1α), and c-fos were also down-regulated after celecoxib treatment. Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its modulation on VEGF/VEGFR-2 through the down-regulation of integrated signal pathways involving PGE2- HIF-1α- VEGF and p-ERK- c-fos- VEGFR-2.

Study of the Impact of Uterine Artery Embolization (UAE) on Endometrial Microvessel Density (MVD) and Angiogenesis

International Nuclear Information System (INIS)

Tan Guosheng; Xiang Xianhong; Guo Wenbo; Zhang Bing; Chen Wei; Yang Jianyong

2013-01-01

PurposeTo investigate the influence of uterine artery embolization (UAE) on endometrial microvessel density (MVD) and angiogenesis.MethodsSixty female guinea pigs were divided into two groups, the control group (n = 15) and the UAE treatment group (n = 45). In the UAE group, tris–acryl gelatin microspheres were used to generate embolization. Animals were further divided into three subgroups, A1, A2, and A3 (n = 15 for each subgroup), with uterine specimens collected at 7–15, 16–30, and 31–45 days after UAE, respectively. Immunostaining for factor VIII and CD105 was performed to identify total endometrial MVD (MVD FVIII ) and CD105-positive angiogenesis (MVD CD105 ) at the indicated time points after UAE.ResultsQuantitative analysis revealed that MVD FVIII significantly decreased in the A1 (11.40 ± 2.76, p CD105 -positive angiogenesis in the A1 group (9.33 ± 2.37, p CD105 value returned to normal in the A3 group (8.07 ± 1.97).ConclusionUAE caused a temporal decrease in endometrial MVD that reversed over time as a result of the increase of CD105-positive angiogenesis. Although the UAE-induced reduction of endometrial MVD was reversible, its long-term effect on endometrial receptivity still needs further study

In vivo angiogenesis screening and mechanism of action of novel tanshinone derivatives produced by one-pot combinatorial modification of natural tanshinone mixture from Salvia miltiorrhiza.

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Zhe-Rui Zhang

Full Text Available Natural products present in low quantity in herb medicines constitute an important source of chemical diversity. However, the isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemical entities for drug discovery and development. And, pro-angiogenic therapies are being explored as options to treat cardio-cerebral vascular diseases and wound healing recently. The present study investigates the pro-angiogenic potential of tanshinone derivatives produced by one-pot synthesis using zebrafish model.In order to address the difficulty of chemical modification of low abundant constituents in herb medicines, a novel one-pot combinatorial modification was used to diversify a partially purified tanshinone mixture from Salvia miltiorrhiza. This led to the isolation of ten new imidazole-tanshinones (Compounds 1-10 and one oxazole-tanshinone (Compound 11, the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. The angiogenesis activities of the new tanshinone derivatives were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested new derivatives, compound 10 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 µM. Moreover, the mechanism underlying the pro-angiogenesis effect of 10 probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signalling pathways by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors.Taken together, our study demonstrated the more distinctive pro-angiogenic properties of 10 than other tanshinones and revealed 10 has potential for development as a pro-angiogenic agent for diseases associated with insufficient angiogenesis. Our results highlighted the great

miRNA let-7b modulates macrophage polarization and enhances tumor-associated macrophages to promote angiogenesis and mobility in prostate cancer.

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Wang, Zhigang; Xu, Lu; Hu, Yinying; Huang, Yanqin; Zhang, Yujuan; Zheng, Xiufen; Wang, Shanshan; Wang, Yifan; Yu, Yanrong; Zhang, Meng; Yuan, Keng; Min, Weiping

2016-05-09

Macrophage polarization is a highly plastic physiological process that responds to a variety of environmental factors by changing macrophage phenotype and function. Tumor-associated macrophages (TAMs) are generally recognized as promoting tumor progression. As universal regulators, microRNAs (miRNAs) are functionally involved in numerous critical cellular processes including macrophage polarization. Let-7b, a miRNA, has differential expression patterns in inflamed tissues compared with healthy controls. However, whether and how miRNA let-7b regulates macrophage phenotype and function is unclear. In this report, we find that up-regulation of let-7b is characteristic of prostatic TAMs, and down-regulation of let-7b in TAMs leads to changes in expression profiles of inflammatory cytokines, such as IL-12, IL-23, IL-10 and TNF-α. As a result, TAMs treated with let-7b inhibitors reduce angiogenesis and prostate carcinoma (PCa) cell mobility. Let-7b may play a vital role in regulating macrophage polarization, thus modulating the prognosis of prostate cancer.

Soluble Tie2 overrides the heightened invasion induced by anti-angiogenesis therapies in gliomas.

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Cortes-Santiago, Nahir; Hossain, Mohammad B; Gabrusiewicz, Konrad; Fan, Xuejun; Gumin, Joy; Marini, Frank C; Alonso, Marta M; Lang, Frederick; Yung, W K; Fueyo, Juan; Gomez-Manzano, Candelaria

2016-03-29

Glioblastoma recurrence after treatment with the anti-vascular endothelial growth factor (VEGF) agent bevacizumab is characterized by a highly infiltrative and malignant behavior that renders surgical excision and chemotherapy ineffective. Our group has previously reported that Tie2-expressing monocytes (TEMs) are aberrantly present at the tumor/normal brain interface after anti-VEGF therapies and their significant role in the invasive outgrowth of these tumors. Here, we aimed to further understand the mechanisms leading to this pro-invasive tumor microenvironment. Examination of a U87MG xenogeneic glioma model and a GL261 murine syngeneic model showed increased tumor expression of angiopoietin 2 (Ang2), a natural ligand of Tie2, after anti-angiogenesis therapies targeting VEGF or VEGF receptor (VEGFR), as assessed by immunohistochemical analysis, immunofluorescence analysis, and enzyme-linked immunosorbent assays of tumor lysates. Migration and gelatinolytic assays showed that Ang2 acts as both a chemoattractant of TEMs and an enhancing signal for their tumor-remodeling properties. Accordingly, in vivo transduction of Ang2 into intracranial gliomas increased recruitment of TEMs into the tumor. To reduce invasive tumor outgrowth after anti-angiogenesis therapy, we targeted the Ang-Tie2 axis using a Tie2 decoy receptor. Using syngeneic models, we observed that overexpression of soluble Tie2 within the tumor prevented the recruitment of TEMs to the tumor and the development of invasion after anti-angiogenesis treatment. Taken together, these data indicate an active role for the Ang2-Tie2 pathway in invasive glioma recurrence after anti-angiogenesis treatment and provide a rationale for testing the combined targeting of VEGF and Ang-Tie2 pathways in patients with glioblastoma.

Physiologic ischaemic training induces endothelial progenitor cell mobilization and myocardial angiogenesis via endothelial nitric oxide synthase related pathway in rabbits.

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Xiao, Mingyue; Lu, Xiao; Li, Jianan; Li, Ling; Li, Yongxue

2014-04-01

Ischaemia-induced angiogenesis promises to improve neovascularization by delivery of angiogenic factors or endothelial progenitor cells (EPCs) to cardiac ischaemic areas. In order to avoid the risk of excessive myocardial ischaemia, therefore, we hypothesized that physiological ischaemic training (PIT) of normal skeletal muscle might contribute to myocardial angiogenesis via nitric oxide mediated mobilization of EPCs from the bone marrow in the established rabbit model of controllable myocardial ischaemia. The rabbits were grouped by sham-operation, myocardial ischaemia without PIT, PIT and PIT with pretreatment with the endothelial nitric oxide synthase (eNOS) inhibitor L-nitroarginine methyl ester (L-NAME). Controlled myocardial ischaemia was modelled by a water balloon constrictor implanted on the left ventricular branch in a rabbit. The PIT procedure included three cycles of 3 min of cuff inflation followed by 5 min of deflation on hind limbs of the rabbits for 4 weeks. At the endpoints, circulating EPCs (CD34/Flk-1) were measured by fluorescence-activated cell sorter; capillary density, by immunohistochemistry; blood flow, by a microsphere technique; endothelial nitric oxide synthase (eNOS) mRNA and protein, by real-time reverse transcriptase (RT)-PCR and Western blotting. The mRNA levels of eNOS were significantly higher in the PIT and L-NAME groups than in the sham-operation group (P < 0.05). Phospho-eNOS protein expression was higher in the PIT group than in the sham-operation and myocardial ischaemia without PIT groups (P < 0.05), and the effect was inhibited by L-NAME pretreatment (P < 0.05). Compared with sham-operation and myocardial ischaemia without PIT groups, the PIT group had the highest EPC count (P < 0.001), and the increase of capillary density (P < 0.01) and collateral blood flow (P < 0.05) in the ischaemic myocardium was consistent with the finding of EPC count. These effects were also inhibited by pretreatment with

Ets2 in tumor fibroblasts promotes angiogenesis in breast cancer.

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Julie A Wallace

Full Text Available Tumor fibroblasts are active partners in tumor progression, but the genes and pathways that mediate this collaboration are ill-defined. Previous work demonstrates that Ets2 function in stromal cells significantly contributes to breast tumor progression. Conditional mouse models were used to study the function of Ets2 in both mammary stromal fibroblasts and epithelial cells. Conditional inactivation of Ets2 in stromal fibroblasts in PyMT and ErbB2 driven tumors significantly reduced tumor growth, however deletion of Ets2 in epithelial cells in the PyMT model had no significant effect. Analysis of gene expression in fibroblasts revealed a tumor- and Ets2-dependent gene signature that was enriched in genes important for ECM remodeling, cell migration, and angiogenesis in both PyMT and ErbB2 driven-tumors. Consistent with these results, PyMT and ErbB2 tumors lacking Ets2 in fibroblasts had fewer functional blood vessels, and Ets2 in fibroblasts elicited changes in gene expression in tumor endothelial cells consistent with this phenotype. An in vivo angiogenesis assay revealed the ability of Ets2 in fibroblasts to promote blood vessel formation in the absence of tumor cells. Importantly, the Ets2-dependent gene expression signatures from both mouse models were able to distinguish human breast tumor stroma from normal stroma, and correlated with patient outcomes in two whole tumor breast cancer data sets. The data reveals a key function for Ets2 in tumor fibroblasts in signaling to endothelial cells to promote tumor angiogenesis. The results highlight the collaborative networks that orchestrate communication between stromal cells and tumor cells, and suggest that targeting tumor fibroblasts may be an effective strategy for developing novel anti-angiogenic therapies.

Angiogenesis in alkaptonuria.

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Millucci, Lia; Bernardini, Giulia; Marzocchi, Barbara; Braconi, Daniela; Geminiani, Michela; Gambassi, Silvia; Laschi, Marcella; Frediani, Bruno; Galvagni, Federico; Orlandini, Maurizio; Santucci, Annalisa

2016-11-01

Alkaptonuria (AKU) is a rare genetic disease that affects the entire joint. Current standard of AKU treatment is palliative and little is known about its physiopathology. Neovascularization is involved in the pathogenesis of systemic inflammatory rheumatic diseases, a family of related disorders that includes AKU. Here, we investigated the presence of neoangiogenesis in AKU synovium and healthy controls. Synovium from AKU patients, who had undergone total joint replacement or arthroscopy, or from healthy patients without any history of rheumatic diseases, who underwent surgical operation following sport trauma was subjected to hematoxylin and eosin staining. Histologic grades were assigned for clinical disease activity and synovitis based on cellular content of the synovium. By immunofluorescence microscopy, using different endothelial cell markers, we observed large vascularization in AKU but not in healthy synovium. Moreover, Western blotting and quantification analyses confirmed strong expression of endothelial cell markers in AKU synovial tissues. Importantly, AKU synovium vascular endothelium expressed high levels of β-dystroglycan, a protein previously involved in the regulation of angiogenesis in osteoarthritic synovium. This is the first report providing experimental evidences that new blood vessels are formed in AKU synovial tissues, opening new perspectives for AKU therapy.

Atrial Natriuretic Peptide Accelerates Human Endothelial Progenitor Cell-Stimulated Cutaneous Wound Healing and Angiogenesis.

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Lee, Tae Wook; Kwon, Yang Woo; Park, Gyu Tae; Do, Eun Kyoung; Yoon, Jung Won; Kim, Seung-Chul; Ko, Hyun-Chang; Kim, Moon-Bum; Kim, Jae Ho

2018-05-26

Atrial natriuretic peptide (ANP) is a powerful vasodilating peptide secreted by cardiac muscle cells, and endothelial progenitor cells (EPCs) have been reported to stimulate cutaneous wound healing by mediating angiogenesis. To determine whether ANP can promote the EPC-mediated repair of injured tissues, we examined the effects of ANP on the angiogenic properties of EPCs and on cutaneous wound healing. In vitro, ANP treatment enhanced the migration, proliferation, and endothelial tube-forming abilities of EPCs. Furthermore, small interfering RNA-mediated silencing of natriuretic peptide receptor-1, which is a receptor for ANP, abrogated ANP-induced migration, tube formation, and proliferation of EPCs. In a murine cutaneous wound model, administration of either ANP or EPCs had no significant effect on cutaneous wound healing or angiogenesis in vivo, whereas the co-administration of ANP and EPCs synergistically potentiated wound healing and angiogenesis. In addition, ANP promoted the survival and incorporation of transplanted EPCs into newly formed blood vessels in wounds. These results suggest ANP accelerates EPC-mediated cutaneous wound healing by promoting the angiogenic properties and survival of transplanted EPCs. This article is protected by copyright. All rights reserved. © 2018 by the Wound Healing Society.

Quercetin inhibits angiogenesis through thrombospondin-1 upregulation to antagonize human prostate cancer PC-3 cell growth in vitro and in vivo.

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Yang, Feiya; Jiang, Xian; Song, Liming; Wang, Huiping; Mei, Zhu; Xu, Zhiqing; Xing, Nianzeng

2016-03-01

The rapid growth, morbidity and mortality of prostate cancer, and the lack of effective treatment have attracted great interests of researchers to find novel cancer therapies aiming to inhibit angiogenesis and tumor growth. Quercetin is a flavonoid compound that widely exists in the nature. Our previous study preliminarily demonstrated that quercetin effectively inhibited human prostate cancer cell xenograft tumor growth by inhibiting angiogenesis. Thrombospondin-1 (TSP-1) is the first reported endogenous anti-angiogenic factor that can inhibit angiogenesis and tumorigenesis. However, the relationship between quercetin inhibiting angiogenesis and TSP-1 upregulation in prostate cancer has not been determined. Thus, we explored the important role of TSP-1 upregulation in reducing angiogenesis and anti-prostate cancer effect of quercetin both in vitro and in vivo for the first time. After the selected doses were used for a certain time, quercetin i) significantly inhibited PC-3 and human umbilical vein endothelial cells (HUVECs) proliferation, migration and invasion in a dose-dependent manner; ⅱ) effectively inhibited prostate cancer PC-3 cell xenograft tumor growth by 37.5% with 75 mg/kg as compared to vehicle control group, more effective than 25 (22.85%) and 50 mg/kg (29.6%); ⅲ) was well tolerated by BALB/c mice and no obvious toxic reactions were observed; ⅳ) greatly reduced angiogenesis and led to higher TSP-1 protein and mRNA expression both in vitro and in vivo in a dose-dependent manner. Therefore, quercetin could increase TSP-1 expression to inhibit angiogenesis resulting in antagonizing prostate cancer PC-3 cell and xenograft tumor growth. The present study can lay a good basis for the subsequent concrete mechanism study and raise the possibility of applying quercetin to clinical for human prostate cancer in the near future.

Celiac Disease-Specific TG2-Targeted Autoantibodies Inhibit Angiogenesis Ex Vivo and In Vivo in Mice by Interfering with Endothelial Cell Dynamics.

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Suvi Kalliokoski

Full Text Available A characteristic feature of celiac disease is the presence of circulating autoantibodies targeted against transglutaminase 2 (TG2, reputed to have a function in angiogenesis. In this study we investigated whether TG2-specific autoantibodies derived from celiac patients inhibit angiogenesis in both ex vivo and in vivo models and sought to clarify the mechanism behind this phenomenon. We used the ex vivo murine aorta-ring and the in vivo mouse matrigel-plug assays to address aforementioned issues. We found angiogenesis to be impaired as a result of celiac disease antibody supplementation in both systems. Our results also showed the dynamics of endothelial cells was affected in the presence of celiac antibodies. In the in vivo angiogenesis assays, the vessels formed were able to transport blood despite impairment of functionality after treatment with celiac autoantibodies, as revealed by positron emission tomography. We conclude that celiac autoantibodies inhibit angiogenesis ex vivo and in vivo and impair vascular functionality. Our data suggest that the anti-angiogenic mechanism of the celiac disease-specific autoantibodies involves extracellular TG2 and inhibited endothelial cell mobility.

Celiac Disease–Specific TG2-Targeted Autoantibodies Inhibit Angiogenesis Ex Vivo and In Vivo in Mice by Interfering with Endothelial Cell Dynamics

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Kalliokoski, Suvi; Sulic, Ana-Marija; Korponay-Szabó, Ilma R.; Szondy, Zsuzsa; Frias, Rafael; Perez, Mileidys Alea; Martucciello, Stefania; Roivainen, Anne; Pelliniemi, Lauri J.; Esposito, Carla; Griffin, Martin; Sblattero, Daniele; Mäki, Markku; Kaukinen, Katri; Lindfors, Katri; Caja, Sergio

2013-01-01

A characteristic feature of celiac disease is the presence of circulating autoantibodies targeted against transglutaminase 2 (TG2), reputed to have a function in angiogenesis. In this study we investigated whether TG2-specific autoantibodies derived from celiac patients inhibit angiogenesis in both ex vivo and in vivo models and sought to clarify the mechanism behind this phenomenon. We used the ex vivo murine aorta-ring and the in vivo mouse matrigel-plug assays to address aforementioned issues. We found angiogenesis to be impaired as a result of celiac disease antibody supplementation in both systems. Our results also showed the dynamics of endothelial cells was affected in the presence of celiac antibodies. In the in vivo angiogenesis assays, the vessels formed were able to transport blood despite impairment of functionality after treatment with celiac autoantibodies, as revealed by positron emission tomography. We conclude that celiac autoantibodies inhibit angiogenesis ex vivo and in vivo and impair vascular functionality. Our data suggest that the anti-angiogenic mechanism of the celiac disease-specific autoantibodies involves extracellular TG2 and inhibited endothelial cell mobility. PMID:23824706

Aloe Gel Enhances Angiogenesis in Healing of Diabetic Wound

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Djanggan Sargowo

2011-12-01

Full Text Available BACKGROUND: Diabetic micro and macroangiophathy lead to the incident of diabetic foot ulcers characterized by an increased number of circulating endothelial cells (CECs and decreased function of endothelial progenitor cells (EPCs. This fact is correlated with ischemia and diabetic wound healing failure. Aloe vera gel is known to be able to stimulate vascular endothelial growth factor (VEGF expression and activity by enhancing nitric oxide (NO production as a result of nitric oxide synthase (NOS enzyme activity. Aloe vera is a potential target to enhancing angiogenesis in wound healing. OBJECTIVE: The objective of this study was to explore the major role of Aloe vera gel in wound healing of diabetic ulcers by increasing the level of EPCs, VEGF, and endothelial nitric oxide synthase (eNOS, as well as by reducing the level of CECs involved in angiogenesis process of diabetic ulcers healing. METHODS: The experimental groups was divided into five subgroups consisting of non diabetic wistar rats, diabetic rats without oral administration of aloe gel, and treatment subgroup (diabetic rats with 30, 60 and 120 mg/day of aloe gel doses for 14 days. All subgroups were wounded and daily observation was done on the wounds areas. Measurement of the number of EPCs (CD34, and CECs (CD45 and CD146 was done by flow cytometry, followed by measurement of VEGF and eNOS expression on dermal tissue by immunohistochemical method on day 0 and day 14 after treatment. The quantitative data were analyzed by One-Way ANOVA and Linear Regression, with a confidence interval 5% and significance level (p<0.05 using SPSS 16 software to compare the difference and correlation between wound diameters, number of EPCs and CECs as well as the levels of VEGF and eNOS. RESULTS: The results of this study showed that aloe gel oral treatment in diabetic wistar rats was able to accelerate the wound healing process. It was shown by significant reduction of wound diameter (0.27±0.02; the

Marine Cyclotripeptide X-13 Promotes Angiogenesis in Zebrafish and Human Endothelial Cells via PI3K/Akt/eNOS Signaling Pathways

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Zhong Pei

2012-06-01

Full Text Available Cyclotripeptide X-13 is a core of novel marine compound xyloallenoide A isolated from mangrove fungus Xylaria sp. (no. 2508. We found that X-13 dose-dependently induced angiogenesis in zebrafish embryos and in human endothelial cells, which was accompanied by increased phosphorylation of eNOS and Akt and NO release. Inhibition of PI3K/Akt/eNOS by LY294002 or l-NAME suppressed X-13-induced angiogenesis. The present work demonstrates that X-13 promotes angiogenesis via PI3K/Akt/eNOS pathways.

The regulatory mechanism of Hsp90α secretion from endothelial cells and its role in angiogenesis during wound healing

International Nuclear Information System (INIS)

Song, Xiaomin; Luo, Yongzhang

2010-01-01

Research highlights: → Growth factors such as bFGF, VEGF, PDGF and SDF-1 stimulate Hsp90α secretion from endothelial cells. → Secreted Hsp90α localizes on the leading edge of activated endothelial cells. → Secreted Hsp90α promotes angiogenesis in wound healing. -- Abstract: Heat shock protein 90α (Hsp90α) is a ubiquitously expressed molecular chaperone, which is essential for the maintenance of eukaryote homeostasis. Hsp90α can also be secreted extracellularly and is associated with several physiological and pathological processes including wound healing, cancer, infectious diseases and diabetes. Angiogenesis, defined as the sprouting of new blood vessels from pre-existing capillaries via endothelial cell proliferation and migration, commonly occurs in and contributes to the above mentioned processes. However, the secretion of Hsp90α from endothelial cells and also its function in angiogenesis are still unclear. Here we investigated the role of extracellular Hsp90α in angiogenesis using dermal endothelial cells in vitro and a wound healing model in vivo. We find that the secretion of Hsp90α but not Hsp90β is increased in activated endothelial cells with the induction of angiogenic factors and matrix proteins. Secreted Hsp90α localizes on the leading edge of endothelial cells and promotes their angiogenic activities, whereas Hsp90α neutralizing antibodies reverse the effect. Furthermore, using a mouse skin wound healing model in vivo, we demonstrate that extracellular Hsp90α localizes on blood vessels in granulation tissues of wounded skin and promotes angiogenesis during wound healing. Taken together, our study reveals that Hsp90α can be secreted by activated endothelial cells and is a positive regulator of angiogenesis, suggesting the potential application of Hsp90α as a stimulator for wound repair.

The regulatory mechanism of Hsp90{alpha} secretion from endothelial cells and its role in angiogenesis during wound healing

Energy Technology Data Exchange (ETDEWEB)

Song, Xiaomin [National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084 (China); Luo, Yongzhang, E-mail: yluo@tsinghua.edu.cn [National Engineering Laboratory for Anti-tumor Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, Beijing 100084 (China); Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, Beijing 100084 (China)

2010-07-16

Research highlights: {yields} Growth factors such as bFGF, VEGF, PDGF and SDF-1 stimulate Hsp90{alpha} secretion from endothelial cells. {yields} Secreted Hsp90{alpha} localizes on the leading edge of activated endothelial cells. {yields} Secreted Hsp90{alpha} promotes angiogenesis in wound healing. -- Abstract: Heat shock protein 90{alpha} (Hsp90{alpha}) is a ubiquitously expressed molecular chaperone, which is essential for the maintenance of eukaryote homeostasis. Hsp90{alpha} can also be secreted extracellularly and is associated with several physiological and pathological processes including wound healing, cancer, infectious diseases and diabetes. Angiogenesis, defined as the sprouting of new blood vessels from pre-existing capillaries via endothelial cell proliferation and migration, commonly occurs in and contributes to the above mentioned processes. However, the secretion of Hsp90{alpha} from endothelial cells and also its function in angiogenesis are still unclear. Here we investigated the role of extracellular Hsp90{alpha} in angiogenesis using dermal endothelial cells in vitro and a wound healing model in vivo. We find that the secretion of Hsp90{alpha} but not Hsp90{beta} is increased in activated endothelial cells with the induction of angiogenic factors and matrix proteins. Secreted Hsp90{alpha} localizes on the leading edge of endothelial cells and promotes their angiogenic activities, whereas Hsp90{alpha} neutralizing antibodies reverse the effect. Furthermore, using a mouse skin wound healing model in vivo, we demonstrate that extracellular Hsp90{alpha} localizes on blood vessels in granulation tissues of wounded skin and promotes angiogenesis during wound healing. Taken together, our study reveals that Hsp90{alpha} can be secreted by activated endothelial cells and is a positive regulator of angiogenesis, suggesting the potential application of Hsp90{alpha} as a stimulator for wound repair.

Proinflammatory mediators stimulate neutrophil-directed angiogenesis.

LENUS (Irish Health Repository)

McCourt, M

2012-02-03

BACKGROUND: Vascular endothelial growth factor (VEGF; vascular permeability factor) is one of the most potent proangiogenic cytokines, and it plays a central role in mediating the process of angiogenesis or new blood vessel formation. Neutrophils (PMNs) recently have been shown to produce VEGF. HYPOTHESIS: The acute inflammatory response is a potent stimulus for PMN-directed angiogenesis. METHODS: Neutrophils were isolated from healthy volunteers and stimulated with lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and anti-human Fas monoclonal antibody. Culture supernatants were assayed for VEGF using enzyme-linked immunosorbent assays. Culture supernatants from LPS- and TNF-alpha-stimulated PMNs were then added to human umbilical vein endothelial cells and human microvessel endothelial cells and assessed for endothelial cell proliferation using 5-bromodeoxyuridine labeling. Tubule formation was also assessed on MATRIGEL basement membrane matrix. Neutrophils were lysed to measure total VEGF release, and VEGF expression was detected using Western blot analysis. RESULTS: Lipopolysaccharide and TNF-alpha stimulation resulted in significantly increased release of PMN VEGF (532+\\/-49 and 484+\\/-80 pg\\/mL, respectively; for all, presented as mean +\\/- SEM) compared with control experiments (32+\\/-4 pg\\/mL). Interleukin 6 and Fas had no effect. Culture supernatants from LPS- and TNF-alpha-stimulated PMNs also resulted in significant increases (P<.005) in macrovascular and microvascular endothelial cell proliferation and tubule formation. Adding anti-human VEGF-neutralizing polyclonal antibody to stimulated PMN supernatant inhibited these effects. Total VEGF release following cell lysis and Western blot analysis suggests that the VEGF is released from an intracellular store. CONCLUSION: Activated human PMNs are directly angiogenic by releasing VEGF, and this has important implications for inflammation, capillary leak syndrome

Particular features of angiogenesis in lesions in patients suffering from basal cell epithelioma

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A. N. Khlebnikova

2014-01-01

Full Text Available Basal cell epithelioma is one of the most frequent malignant skin neoplasms. Angiogenesis plays an important part in the development of basal cell epithelioma. The article presents a review of the angiogenesis of this tumor with the help the immunohistochemistry analysis using CD31 and CD34 markers. The authors established a reliable relationship between the number of vessels expressing CD31 and those expressing CD34 in the superficial and nodular forms of the tumor as well as superficial, multi-center, nodular and infiltrative basal cell epitheliomas. A comparison of the number of vessels expressing CD31 and CD34 markers in different histological types made revealed a trend to their growth in the infiltrative type vs. superficial, multi-center and nodular ones.

Centchroman regulates breast cancer angiogenesis via inhibition of HIF-1α/VEGFR2 signalling axis.

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Dewangan, Jayant; Kaushik, Shweta; Rath, Srikanta Kumar; Balapure, Anil K

2018-01-15

Angiogenesis is a recognized hallmark of cancer which promotes cancer cell progression and metastasis. Inhibition of angiogenesis to attenuate cancer growth is becoming desirable strategy for breast cancer management. The present study is aimed to investigate the antiangiogenic efficacy of a novel selective estrogen receptor modulator Centchroman (CC) on human breast cancer cells. Effect of CC on cell viability was evaluated using Sulforhodamine B assay. Endothelial cell proliferation, wound healing, Boyden chamber cell invasion, tube formation and chorioallantoic membrane (CAM) assays were performed to assess the effect of CC on migration, invasion and angiogenesis. Apoptosis, reactive oxygen species generation, caspase-3/7 and intracellular calcium ion level were measured through flow cytometry. Expression levels of HIF-1α, VEGF, VEGFR2, AKT and ERK were assessed by western blot analysis. CC selectively induces apoptosis in human breast cancer cells without affecting non-tumorigenic breast epithelial cells MCF-10A. Moreover, it inhibits migratory, invasive and mammosphere forming potential of breast cancer. Furthermore, CC also inhibited VEGF-induced migration, invasion and tube formation of HUVECs in vitro. CC effectively inhibited neovasculature formation in chicken CAM. Western blot analysis demonstrated that CC inhibited expression of HIF-1α and its downstream target VEGF. Interestingly, CC also suppressed VEGFR2 phosphorylation and consequently attenuated AKT and ERK phosphorylation. Our findings suggest that CC downregulates VEGF-induced angiogenesis by modulating HIF-1α/VEGFR2 pathway and recommend it (CC) as a potential therapeutic drug for breast cancer treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells.

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Ruma, I Made Winarsa; Putranto, Endy Widya; Kondo, Eisaku; Watanabe, Risayo; Saito, Ken; Inoue, Yusuke; Yamamoto, Ken-Ichi; Nakata, Susumu; Kaihata, Masaji; Murata, Hitoshi; Sakaguchi, Masakiyo

2014-07-01

Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor-derived angiogenesis and commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering insights into the successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and tumor growth of a human malignant melanoma cell line. We demonstrated that Cordyceps militaris extract remarkably suppressed tumor growth via induction of apoptotic cell death in culture that links to the abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3β activation, while p38α phosphorylation levels were increased. Extract treatment in mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

A Specific Inhibitor of TGF-β Receptor Kinase, SB-431542, as a Potent Antitumor Agent for Human Cancers

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Sunil K. Halder

2005-05-01

Full Text Available Small molecule inhibitors of signaling pathways have proven to be extremely useful for the development of therapeutic strategies for human cancers. Blocking the tumor-promoting effects of transforming growth factor-β (TGF-β in advanced stage carcinogenesis provides a potentially interesting drug target for therapeutic intervention. Although very few TGF-β receptor kinase inhibitors (TRKI are now emerging in preclinical studies, nothing is known about how these inhibitors might regulate the tumor-suppressive or tumor-promoting effects of TGF-β, or when these inhibitors might be useful for treatment during cancer progression. We have investigated the potential of TRKI in new therapeutic approaches in preclinical models. Here, we demonstrate that the TRKI, SB-431542, inhibits TGF-β-induced transcription, gene expression, apoptosis, and growth suppression. We have observed that SB-431542 attenuates the tumor-promoting effects of TGF-β, including TGF-β-induced EMT, cell motility, migration and invasion, and vascular endothelial growth factor secretion in human cancer cell lines. Interestingly, SB-431542 induces anchorage independent growth of cells that are growth-inhibited by TGF-β, whereas it reduces colony formation by cells that are growth-promoted by TGF-β. However, SB-431542 has no effect on a cell line that failed to respond to TGF-β. This represents a novel potential application of these inhibitors as therapeutic agents for human cancers with the goal of blocking tumor invasion, angiogenesis, and metastasis, when tumors are refractory to TGF-β-induced tumor-suppressor functions but responsive to tumor-promoting effects of TGF-β.

A Selenium Containing Inhibitor for the Treatment of Hepatocellular Cancer

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Hephzibah Rani S. Tagaram

2016-03-01

Full Text Available Hepatocellular carcinoma (HCC is the third most deadly cancer in the world. New treatment strategies are desperately needed due to limited standard therapies. Activation of the Erk, Akt, and STAT3pathways is implicated in the prognosis of HCC. The Se,Se′-1,4-phenylenebis(1,2-ethanediyl bisisoselenourea (PBISe, is a selenium-containing MAPK and PI3 kinase inhibitor, effectively inhibit tumorigenesis in a variety of experimental models. The aim of our study is to demonstrate the potential role of PBISe in the treatment of HCC. The anti-proliferative and pro-apoptotic ability of PBISe is studied in vitro in four human HCC cell lines and in vivo in a spontaneous murine HCC model. Inhibition of cancer growth was performed by cell viability assay and apoptosis by caspase 3/7, PARP cleavage, annexin-V, and TUNEL assays. Role of PBISe on PI3 kinase, MAPK and STAT3 signaling is determined by Western blotting. In vivo effects of PBISe on tumor sizes were monitored using MRI in a spontaneous murine HCC. Liver tissues from the PBISe-treated mice are analyzed for angiogenesis, proliferation, and signaling pathway markers. Overall, PBISe activated caspase-3/7 and increased DNA fragmentation, which is positively correlated with the increased PARP cleavage. PBISe promoted apoptosis by inhibiting PI3K, MAPK, and STAT3 signaling with significant reduction in the tumor sizes (p < 0.007. PBISe-treated tumors reduced survival marker PCNA, and angiogenesis markers Vegf-A, Vegf-R3 and CD34. These results demonstrate the chemotherapeutic effects of PBISe, by inhibiting tumor growth and facilitating tumor apoptosis for HCC treatment.

Mechanisms of lumen formation during sprouting angiogenesis in vivo

OpenAIRE

Gebala, V. M.

2016-01-01

During development, vascular networks expand following a process known as sprouting angiogenesis. New vascular branches arise from pre-existing vessels through the coordinated migration and proliferation of endothelial cells, and eventually connect to form new vascular loops. The functionality of these new vessel segments is dependent on the opening of a central lumen to allow perfusion. While mechanisms of lumen formation during the establishment of the primary vasculature by vasculogenesis ...

Platelet factor-4 and its p17-70 peptide inhibit myeloma proliferation and angiogenesis in vivo

International Nuclear Information System (INIS)

Yang, Longjiang; Du, Juan; Hou, Jian; Jiang, Hua; Zou, Jianfeng

2011-01-01

Angiogenesis plays an important role in the development of multiple myeloma (MM). The interaction between MM cells and the bone marrow microenvironment stimulates the proliferation and migration of endothelial progenitor cells (EPCs). Vascular endothelial growth factor (VEGF) contributes to the formation of new blood vessels by actively recruiting circulating EPCs. The production of proangiogenic and antiangiogenic factors is also dysregulated in MM. Platelet factor 4 (PF4) is a potent angiostatic cytokine that inhibits angiogenesis and tumor growth in several animal models. In this study, we stably transfected human myeloma cell lines with the PF4 gene or the sequence encoding its more potent p17-70 peptide and investigated the effects of PF4 and p17-70 on angiogenesis and tumor growth in vitro and in a SCID-rab myeloma model. PF4 and p17-70 significantly attenuated VEGF production, both in vitro and in vivo. In a migration study using a Transwell system, PF4 or p17-70 markedly suppressed the migration of co-cultured human endothelial progenitor cells. PF4 or p17-70 also caused a significant reduction in microvessel densities in myeloma xenografts and markedly reduced the tumor volume in the SCID mice. Kaplan-Meier analysis demonstrated that PF4 and p17-70 significantly extended the overall survival of SCID mice bearing human myeloma xenografts. Our findings indicate that PF4 or p17-70 could be valuable in combating multiple myeloma by disrupting tumor angiogenesis

The expression of miR-125b regulates angiogenesis during the recovery of heat-denatured HUVECs.

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Zhou, Situo; Zhang, Pihong; Liang, Pengfei; Huang, Xiaoyuan

2015-06-01

In previous studies we found that miR-125b was down-regulated in denatured dermis of deep partial thickness burn patients. Moreover, miR-125b inhibited tumor-angiogenesis associated with the decrease of ERBB2 and VEGF expression in ovarian cancer cells and breast cancer cells, etc. In this study, we investigated the expression patterns and roles of miR-125b during the recovery of denatured dermis and heat-denatured human umbilical vein endothelial cells (HUVECs). Deep partial thickness burns in Sprague-Dawley rats and the heat-denatured cells (52°C, 35 s) were used for analysis. Western blot analysis and real-time PCR were applied to evaluate the expression of miR-125b and ERBB2 and VEGF. The ability of angiogenesis in heat-denatured HUVECs was analyzed by scratch wound healing and tube formation assay after pri-miR-125b or anti-miR-125b transfection. miR-125b expression was time-dependent during the recovery of heat-denatured dermis and HUVECs. Moreover, miR-125b regulated ERBB2 mRNA and Protein Expression and regulated angiogenesis association with regulating the expression of VEGF in heat-denatured HUVECs. Taken together our results show that the expression of miR-125b is time-dependent and miR-125b plays a regulatory role of angiogenesis during wound healing after burns. Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.

Evaluation of Tumor Angiogenesis with a Second-Generation US Contrast Medium in a Rat Breast Tumor Model

International Nuclear Information System (INIS)

Ko, Eun Young; Lee, Sang Hoon; Kim, Hak Hee; Kim, Sung Moon; Shin, Myung Jin; Kim, Nam Kug; Gong, Gyung Yub

2008-01-01

Tumor angiogenesis is an important factor for tumor growth, treatment response and prognosis. Noninvasive imaging methods for the evaluation of tumor angiogenesis have been studied, but a method for the quantification of tumor angiogenesis has not been established. This study was designed to evaluate tumor angiogenesis in a rat breast tumor model by the use of a contrast enhanced ultrasound (US) examination with a second-generation US contrast agent. The alkylating agent 19N-ethyl-N-nitrosourea (ENU) was injected into the intraperitoneal cavity of 30-day-old female Sprague-Dawley rats. Three to four months later, breast tumors were detected along the mammary lines of the rats. A total of 17 breast tumors larger than 1 cm in nine rats were evaluated by gray-scale US, color Doppler US and contrast-enhanced US using SonoVue. The results were recorded as digital video images; time-intensity curves and hemodynamic parameters were analyzed. Pathological breast tumor specimens were obtained just after the US examinations. The tumor specimens were stained with hematoxylin and eosin (H and E) and the expression of CD31, an endothelial cell marker, was determined by immunohistochemical staining. We also evaluated the pathological diagnosis of the tumors and the microvessel density (MVD). Spearman's correlation and the Kruskal-Wallis test were used for the analysis. The pathological diagnoses were 11 invasive ductal carcinomas and six benign intraductal epithelial proliferations. The MVD did not correlate with the pathological diagnosis. However, blood volume (BV) showed a statistically significant correlation with MVD (Spearman's correlation, p < 0.05). Contrast-enhanced US using a second-generation US contrast material was useful for the evaluation of tumor angiogenesis of breast tumors in the rat

The role of CD27-CD70-mediated T cell co-stimulation in vasculogenesis, arteriogenesis and angiogenesis.

Science.gov (United States)

Simons, K H; Aref, Z; Peters, H A B; Welten, S P; Nossent, A Y; Jukema, J W; Hamming, J F; Arens, R; de Vries, M R; Quax, P H A

2018-06-01

T cells have a distinctive role in neovascularization, which consists of arteriogenesis and angiogenesis under pathological conditions and vasculogenesis under physiological conditions. However, the role of co-stimulation in T cell activation in neovascularization has yet to be established. The aim of this study was to investigate the role T cell co-stimulation and inhibition in angiogenesis, arteriogenesis and vasculogenesis. Hind limb ischemia was induced by double ligation of the left femoral artery in mice and blood flow recovery was measured with Laser Doppler Perfusion Imaging in control, CD70 -/- , CD80/86 -/- , CD70/80/86 -/- and CTLA4 +/- mice. Blood flow recovery was significantly impaired in mice lacking CD70 compared to control mice, but was similar in CD80/86 -/- , CTLA4 +/- and control mice. Mice lacking CD70 showed impaired vasculogenesis, since the number of pre-existing collaterals was reduced as observed in the pia mater compared to control mice. In vitro an impaired capability of vascular smooth muscle cells (VSMC) to activate T cells was observed in VSMC lacking CD70. Furthermore, CD70 -/- , CD80/86 -/- and CD70/80/86 -/- mice showed reduced angiogenesis in the soleus muscle 10 days after ligation. Arteriogenesis was also decreased in CD70 -/- compared to control mice 10 and 28 days after surgery. The present study is the first to describe an important role for T cell activation via co-stimulation in angiogenesis, arteriogenesis and vasculogenesis, where the CD27-CD70 T cell co-stimulation pathway appears to be the most important co-stimulation pathway in pre-existing collateral formation and post-ischemic blood flow recovery, by arteriogenesis and angiogenesis. Copyright © 2018 Elsevier B.V. All rights reserved.

TIE2-expressing monocytes as a diagnostic marker for hepatocellular carcinoma correlates with angiogenesis.

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Matsubara, Tokuhiro; Kanto, Tatsuya; Kuroda, Shoko; Yoshio, Sachiyo; Higashitani, Koyo; Kakita, Naruyasu; Miyazaki, Masanori; Sakakibara, Mitsuru; Hiramatsu, Naoki; Kasahara, Akinori; Tomimaru, Yoshito; Tomokuni, Akira; Nagano, Hiroaki; Hayashi, Norio; Takehara, Tetsuo

2013-04-01

Angiogenesis is a critical step in the development and progression of hepatocellular carcinoma (HCC). Myeloid lineage cells, such as macrophages and monocytes, have been reported to regulate angiogenesis in mouse tumor models. TIE2, a receptor of angiopoietins, conveys pro-angiogenic signals and identifies a monocyte/macrophage subset with pro-angiogenic activity. Here, we analyzed the occurrence and kinetics of TIE2-expressing monocytes/macrophages (TEMs) in HCC patients. This study enrolled 168 HCV-infected patients including 89 with HCC. We examined the frequency of TEMs, as defined as CD14+CD16+TIE2+ cells, in the peripheral blood and liver. The localization of TEMs in the liver was determined by immunofluorescence staining. Micro-vessel density in the liver was measured by counting CD34+ vascular structures. We found that the frequency of circulating TEMs was significantly higher in HCC than non-HCC patients, while being higher in the liver than in the blood. In patients who underwent local radio-ablation or resection of HCC, the frequency of TEMs dynamically changed in the blood in parallel with HCC recurrence. Most TEMs were identified in the perivascular areas of tumor tissue. A significant positive correlation was observed between micro-vessel density in HCC and frequency of TEMs in the blood or tumors, suggesting that TEMs are involved in HCC angiogenesis. Receiver operating characteristic analyses revealed the superiority of TEM frequency to AFP, PIVKA-II and ANG-2 serum levels as diagnostic marker for HCC. TEMs increase in patients with HCC and their frequency changes with the therapeutic response or recurrence. We thus suggest that TEM frequency can be used as a diagnostic marker for HCC, potentially reflecting angiogenesis in the liver. Copyright © 2012 American Association for the Study of Liver Diseases.

Mesenchymal stem/stromal cells as a pharmacological and therapeutic approach to accelerate angiogenesis.

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Bronckaers, Annelies; Hilkens, Petra; Martens, Wendy; Gervois, Pascal; Ratajczak, Jessica; Struys, Tom; Lambrichts, Ivo

2014-08-01

Mesenchymal stem cells or multipotent stromal cells (MSCs) have initially captured attention in the scientific world because of their differentiation potential into osteoblasts, chondroblasts and adipocytes and possible transdifferentiation into neurons, glial cells and endothelial cells. This broad plasticity was originally hypothesized as the key mechanism of their demonstrated efficacy in numerous animal models of disease as well as in clinical settings. However, there is accumulating evidence suggesting that the beneficial effects of MSCs are predominantly caused by the multitude of bioactive molecules secreted by these remarkable cells. Numerous angiogenic factors, growth factors and cytokines have been discovered in the MSC secretome, all have been demonstrated to alter endothelial cell behavior in vitro and induce angiogenesis in vivo. As a consequence, MSCs have been widely explored as a promising treatment strategy in disorders caused by insufficient angiogenesis such as chronic wounds, stroke and myocardial infarction. In this review, we will summarize into detail the angiogenic factors found in the MSC secretome and their therapeutic mode of action in pathologies caused by limited blood vessel formation. Also the application of MSC as a vehicle to deliver drugs and/or genes in (anti-)angiogenesis will be discussed. Furthermore, the literature describing MSC transdifferentiation into endothelial cells will be evaluated critically. Copyright © 2014 Elsevier Inc. All rights reserved.

Anti-angiogenesis and anti-tumor activity of recombinant anginex

International Nuclear Information System (INIS)

Brandwijk, Ricardo J.M.G.E.; Dings, Ruud P.M.; Linden, Edith van der; Mayo, Kevin H.; Thijssen, Victor L.J.L.; Griffioen, Arjan W.

2006-01-01

Anginex, a synthetic 33-mer angiostatic peptide, specifically inhibits vascular endothelial cell proliferation and migration along with induction of apoptosis in endothelial cells. Here we report on the in vivo characterization of recombinant anginex and use of the artificial anginex gene for gene therapy approaches. Tumor growth of human MA148 ovarian carcinoma in athymic mice was inhibited by 80% when treated with recombinant anginex. Histological analysis of the tumors showed an approximate 2.5-fold reduction of microvessel density, suggesting that angiogenesis inhibition is the cause of the anti-tumor effect. Furthermore, there was a significant correlation between the gene expression patterns of 16 angiogenesis-related factors after treatment with both recombinant and synthetic anginex. To validate the applicability of the anginex gene for gene therapy, stable transfectants of murine B16F10 melanoma cells expressing recombinant anginex were made. Supernatants of these cells inhibited endothelial cell proliferation in vitro. Furthermore, after subcutaneous injection of these cells in C57BL/6 mice, an extensive delay in tumor growth was observed. These data show that the artificial anginex gene can be used to produce a recombinant protein with similar activity as its synthetic counterpart and that the gene can be applied in gene therapy approaches for cancer treatment

Sunitinib significantly suppresses the proliferation, migration, apoptosis resistance, tumor angiogenesis and growth of triple-negative breast cancers but increases breast cancer stem cells.

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Chinchar, Edmund; Makey, Kristina L; Gibson, John; Chen, Fang; Cole, Shelby A; Megason, Gail C; Vijayakumar, Srinivassan; Miele, Lucio; Gu, Jian-Wei

2014-01-01

innovative therapeutic strategy in TNBC therapy by using sunitinib plus γ-secretase inhibitor to simultaneously target angiogenesis and CSC.

Human tumor cells induce angiogenesis through positive feedback between CD147 and insulin-like growth factor-I.

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Yanke Chen

Full Text Available Tumor angiogenesis is a complex process based upon a sequence of interactions between tumor cells and endothelial cells. Previous studies have shown that CD147 was correlated with tumor angiogenesis through increasing tumor cell secretion of vascular endothelial growth factor (VEGF and matrix metalloproteinases (MMPs. In this study, we made a three-dimensional (3D tumor angiogenesis model using a co-culture system of human hepatocellular carcinoma cells SMMC-7721 and humanumbilical vein endothelial cells (HUVECs in vitro. We found that CD147-expressing cancer cells could promote HUVECs to form net-like structures resembling the neo-vasculature, whereas the ability of proliferation, migration and tube formation of HUVECs was significantly decreased in tumor conditioned medium (TCM of SMMC-7721 cells transfected with specific CD147-siRNA. Furthermore, by assaying the change of pro-angiogenic factors in TCM, we found that the inhibition of CD147 expression led to significant decrease of VEGF and insulin-like growth factor-I (IGF-I secretion. Interestingly, we also found that IGF-I up-regulated the expression of CD147 in both tumor cells and HUVECs. These findings suggest that there is a positive feedback between CD147 and IGF-I at the tumor-endothelial interface and CD147 initiates the formation of an angiogenesis niche.

iNOS Activity Modulates Inflammation, Angiogenesis, and Tissue Fibrosis in Polyether-Polyurethane Synthetic Implants.

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Cassini-Vieira, Puebla; Araújo, Fernanda Assis; da Costa Dias, Filipi Leles; Russo, Remo Castro; Andrade, Silvia Passos; Teixeira, Mauro Martins; Barcelos, Luciola Silva

2015-01-01

There is considerable interest in implantation techniques and scaffolds for tissue engineering and, for safety and biocompatibility reasons, inflammation, angiogenesis, and fibrosis need to be determined. The contribution of inducible nitric oxide synthase (iNOS) in the regulation of the foreign body reaction induced by subcutaneous implantation of a synthetic matrix was never investigated. Here, we examined the role of iNOS in angiogenesis, inflammation, and collagen deposition induced by polyether-polyurethane synthetic implants, using mice with targeted disruption of the iNOS gene (iNOS(-/-)) and wild-type (WT) mice. The hemoglobin content and number of vessels were decreased in the implants of iNOS(-/-) mice compared to WT mice 14 days after implantation. VEGF levels were also reduced in the implants of iNOS(-/-) mice. In contrast, the iNOS(-/-) implants exhibited an increased neutrophil and macrophage infiltration. However, no alterations were observed in levels of CXCL1 and CCL2, chemokines related to neutrophil and macrophage migration, respectively. Furthermore, the implants of iNOS(-/-) mice showed boosted collagen deposition. These data suggest that iNOS activity controls inflammation, angiogenesis, and fibrogenesis in polyether-polyurethane synthetic implants and that lack of iNOS expression increases foreign body reaction to implants in mice.

Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis.

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Rosmorduc, O; Wendum, D; Corpechot, C; Galy, B; Sebbagh, N; Raleigh, J; Housset, C; Poupon, R

1999-10-01

We tested the potential role of vascular endothelial growth factor (VEGF) and of fibroblast growth factor-2 (FGF-2) in the angiogenesis associated with experimental liver fibrogenesis induced by common bile duct ligation in Sprague-Dawley rats. In normal rats, VEGF and FGF-2 immunoreactivities were restricted to less than 3% of hepatocytes. One week after bile duct ligation, hypoxia was demonstrated by the immunodetection of pimonidazole adducts unevenly distributed throughout the lobule. After 2 weeks, hypoxia and VEGF expression were detected in >95% of hepatocytes and coexisted with an increase in periportal vascular endothelial cell proliferation, as ascertained by Ki67 immunolabeling. Subsequently, at 3 weeks the density of von Willebrand-labeled vascular section in fibrotic areas significantly increased. Semiquantitative reverse transcription polymerase chain reaction showed that VEGF(120) and VEGF(164) transcripts, that correspond to secreted isoforms, increased within 2 weeks, while VEGF(188) transcripts remained unchanged. FGF-2 mainly consisting of a 22-kd isoform, according to Western blot, was identified by immunohistochemistry in 49% and 100% of hepatocytes at 3 and 7 weeks, respectively. Our data provide evidence that in biliary-type liver fibrogenesis, angiogenesis is stimulated primarily by VEGF in response to hepatocellular hypoxia while FGF-2 likely contributes to the maintenance of angiogenesis at later stages.

iNOS Activity Modulates Inflammation, Angiogenesis, and Tissue Fibrosis in Polyether-Polyurethane Synthetic Implants

Science.gov (United States)

Cassini-Vieira, Puebla; Araújo, Fernanda Assis; da Costa Dias, Filipi Leles; Russo, Remo Castro; Andrade, Silvia Passos; Teixeira, Mauro Martins; Barcelos, Luciola Silva

2015-01-01

There is considerable interest in implantation techniques and scaffolds for tissue engineering and, for safety and biocompatibility reasons, inflammation, angiogenesis, and fibrosis need to be determined. The contribution of inducible nitric oxide synthase (iNOS) in the regulation of the foreign body reaction induced by subcutaneous implantation of a synthetic matrix was never investigated. Here, we examined the role of iNOS in angiogenesis, inflammation, and collagen deposition induced by polyether-polyurethane synthetic implants, using mice with targeted disruption of the iNOS gene (iNOS−/−) and wild-type (WT) mice. The hemoglobin content and number of vessels were decreased in the implants of iNOS−/− mice compared to WT mice 14 days after implantation. VEGF levels were also reduced in the implants of iNOS−/− mice. In contrast, the iNOS−/− implants exhibited an increased neutrophil and macrophage infiltration. However, no alterations were observed in levels of CXCL1 and CCL2, chemokines related to neutrophil and macrophage migration, respectively. Furthermore, the implants of iNOS−/− mice showed boosted collagen deposition. These data suggest that iNOS activity controls inflammation, angiogenesis, and fibrogenesis in polyether-polyurethane synthetic implants and that lack of iNOS expression increases foreign body reaction to implants in mice. PMID:26106257

Role of Microvessel Density and Vascular Endothelial Growth Factor in Angiogenesis of Hematological Malignancies

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Rashika Chand

2016-01-01

Full Text Available Angiogenesis plays an important role in progression of tumor with vascular endothelial growth factor (VEGF being key proangiogenic factor. It was intended to study angiogenesis in different hematological malignancies by quantifying expression of VEGF and MVD in bone marrow biopsy along with serum VEGF levels and observing its change following therapy. The study included 50 cases of hematological malignancies which were followed for one month after initial therapy along with 30 controls. All of them were subjected to immunostaining by anti-VEGF and factor VIII antibodies on bone marrow biopsy along with the measurement of serum VEGF levels. Significantly higher pretreatment VEGF scores, serum VEGF levels, and MVD were observed in cases as compared to controls (p<0.05. The highest VEGF score and serum VEGF were observed in chronic myeloid leukemia and maximum MVD in Non-Hodgkin’s Lymphoma. Significant decrease in serum VEGF levels after treatment was observed in all hematological malignancies except for AML. To conclude angiogenesis plays an important role in pathogenesis of all the hematological malignancies as reflected by increased VEGF expression and MVD in bone marrow biopsy along with increased serum VEGF level. The decrease in serum VEGF level after therapy further supports this view and also lays the importance of anti angiogenic therapy.

Angiomodulin is a specific marker of vasculature and regulates VEGF-A dependent neo-angiogenesis

Science.gov (United States)

Hooper, Andrea T.; Shmelkov, Sergey V.; Gupta, Sunny; Milde, Till; Bambino, Kathryn; Gillen, Kelly; Goetz, Mollie; Chavala, Sai; Baljevic, Muhamed; Murphy, Andrew J.; Valenzuela, David M.; Gale, Nicholas W.; Thurston, Gavin; Yancopoulos, George D.; Vahdat, Linda; Evans, Todd; Rafii, Shahin

2010-01-01

Blood vessel formation is controlled by the balance between pro- and anti-angiogenic pathways. Although much is known about the factors that drive sprouting of neovessels, the factors that stabilize and pattern neovessels are undefined. The expression of angiomodulin (AGM), a VEGF-A binding protein, was increased in the vasculature of several human tumors as compared to normal tissue, raising the hypothesis that AGM may modulate VEGF-A-dependent vascular patterning. To elucidate the expression pattern of AGM, we developed an AGM knockin reporter mouse (AGMlacZ/+) wherein we demonstrate that AGM is predominantly expressed in the vasculature of developing embryos and adult organs. During physiological and pathological angiogenesis, AGM is upregulated in the angiogenic vasculature. Using the zebrafish model, we found that AGM is restricted to developing vasculature by 17-22 hpf. Blockade of AGM activity with morpholino oligomers (MO) results in prominent angiogenesis defects in vascular sprouting and remodeling. Concurrent knockdown of both AGM and VEGF-A results in synergistic angiogenesis defects. When VEGF-A is overexpressed, the compensatory induction of the VEGF-A receptor, VEGFR-2/flk-1, is blocked by the simultaneous injection of AGM MO. These results demonstrate that the vascular-specific marker AGM modulates vascular remodeling in part by temporizing the pro-angiogenic effects of VEGF-A. PMID:19542015

Brassinosteroids inhibit in vitro angiogenesis in human endothelial cells

Czech Academy of Sciences Publication Activity Database

Rárová, L.; Zahler, S.; Liebl, J.; Kryštof, Vladimír; Sedlák, David; Bartůněk, Petr; Kohout, Ladislav; Strnad, Miroslav

2012-01-01

Roč. 77, č. 13 (2012), s. 1502-1509 ISSN 0039-128X R&D Projects: GA MŠk(CZ) LC06077 Grant - others:GA MŠk(CZ) ED0007/01/01 Program:ED Institutional research plan: CEZ:AV0Z50380511; CEZ:AV0Z50520514; CEZ:AV0Z40550506 Keywords : Angiogenesis * Human umbilical vein endothelial cells * Migration Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.803, year: 2012

Hypoxia-induced mitogenic factor enhances angiogenesis by promoting proliferation and migration of endothelial cells

International Nuclear Information System (INIS)

Tong Qiangsong; Zheng Liduan; Li Bo; Wang Danming; Huang Chuanshu; Matuschak, George M.; Li Dechun

2006-01-01

Our previous studies have indicated that hypoxia-induced mitogenic factor (HIMF) has angiogenic properties in an in vivo matrigel plug model and HIMF upregulates expression of vascular endothelial growth factor (VEGF) in mouse lungs and cultured lung epithelial cells. However, whether HIMF exerts angiogenic effects through modulating endothelial cell function remains unknown. In this study, mouse aortic rings cultured with recombinant HIMF protein resulted in enhanced vascular sprouting and increased endothelial cell spreading as confirmed by Dil-Ac-LDL uptake, von Willebrand factor and CD31 staining. In cultured mouse endothelial cell line SVEC 4-10, HIMF dose-dependently enhanced cell proliferation, in vitro migration and tubulogenesis, which was not attenuated by SU1498, a VEGFR2/Flk-1 receptor tyrosine kinase inhibitor. Moreover, HIMF stimulation resulted in phosphorylation of Akt, p38 and ERK1/2 kinases in SVEC 4-10 cells. Treatment of mouse aortic rings and SVEC 4-10 cells with LY294002, but not SB203580, PD098059 or U0126, abolished HIMF-induced vascular sprouting and angiogenic responses. In addition, transfection of a dominant-negative mutant of phosphatidylinositol 3-kinase (PI-3K), Δp85, blocked HIMF-induced phosphorylation of Akt, endothelial activation and tubulogenesis. These results indicate that HIMF enhances angiogenesis by promoting proliferation and migration of endothelial cells via activation of the PI-3K/Akt pathways

Control of Cross Talk between Angiogenesis and Inflammation by Mesenchymal Stem Cells for the Treatment of Ocular Surface Diseases

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Fei Li

2016-01-01

Full Text Available Angiogenesis is beneficial in the treatment of ischemic heart disease and peripheral artery disease. However, it facilitates inflammatory cell filtration and inflammation cascade that disrupt the immune and angiogenesis privilege of the avascular cornea, resulting in ocular surface diseases and even vision loss. Although great progress has been achieved, healing of severe ocular surface injury and immunosuppression of corneal transplantation are the most difficult and challenging step in the treatment of ocular surface disorders. Mesenchymal stem cells (MSCs, derived from various adult tissues, are able to differentiate into different cell types such as endothelial cells and fat cells. Although it is still under debate whether MSCs could give rise to functional corneal cells, recent results from different study groups showed that MSCs could improve corneal disease recovery through suppression of inflammation and modulation of immune cells. Thus, MSCs could become a promising tool for ocular surface disorders. In this review, we discussed how angiogenesis and inflammation are orchestrated in the pathogenesis of ocular surface disease. We overviewed and updated the knowledge of MSCs and then summarized the therapeutic potential of MSCs via control of angiogenesis, inflammation, and immune response in the treatment of ocular surface disease.

In vivo quantitative evaluation of vascular parameters for angiogenesis based on sparse principal component analysis and aggregated boosted trees

International Nuclear Information System (INIS)

Zhao, Fengjun; Liu, Junting; Qu, Xiaochao; Xu, Xianhui; Chen, Xueli; Yang, Xiang; Liang, Jimin; Tian, Jie; Cao, Feng

2014-01-01

To solve the multicollinearity issue and unequal contribution of vascular parameters for the quantification of angiogenesis, we developed a quantification evaluation method of vascular parameters for angiogenesis based on in vivo micro-CT imaging of hindlimb ischemic model mice. Taking vascular volume as the ground truth parameter, nine vascular parameters were first assembled into sparse principal components (PCs) to reduce the multicolinearity issue. Aggregated boosted trees (ABTs) were then employed to analyze the importance of vascular parameters for the quantification of angiogenesis via the loadings of sparse PCs. The results demonstrated that vascular volume was mainly characterized by vascular area, vascular junction, connectivity density, segment number and vascular length, which indicated they were the key vascular parameters for the quantification of angiogenesis. The proposed quantitative evaluation method was compared with both the ABTs directly using the nine vascular parameters and Pearson correlation, which were consistent. In contrast to the ABTs directly using the vascular parameters, the proposed method can select all the key vascular parameters simultaneously, because all the key vascular parameters were assembled into the sparse PCs with the highest relative importance. (paper)

Silencing cathepsin S gene expression inhibits growth, invasion and angiogenesis of human hepatocellular carcinoma in vitro

International Nuclear Information System (INIS)

Fan, Qi; Wang, Xuedi; Zhang, Hanguang; Li, Chuanwei; Fan, Junhua; Xu, Jing

2012-01-01

Highlights: ► Cat S is highly expressed in HCC cells with high metastatic potential. ► Knockdown of Cat S inhibits growth and invasion of HCC cells. ► Knockdown of Cat S inhibits HCC-associated angiogenesis. ► Cat S might be a potential target for HCC therapy. -- Abstract: Cathepsin S (Cat S) plays an important role in tumor invasion and metastasis by its ability to degrade extracellular matrix (ECM). Our previous study suggested there could be a potential association between Cat S and hepatocellular carcinoma (HCC) metastasis. The present study was designed to determine the role of Cat S in HCC cell growth, invasion and angiogenesis, using RNA interference technology. Small interfering RNA (siRNA) sequences for the Cat S gene were synthesized and transfected into human HCC cell line MHCC97-H. The Cat S gene targeted siRNA-mediated knockdown of Cat S expression, leading to potent suppression of MHCC97-H cell proliferation, invasion and angiogenesis. These data suggest that Cat S might be a potential target for HCC therapy.

EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome.

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Sato, Mototaka; Nakai, Yasutomo; Nakata, Wataru; Yoshida, Takahiro; Hatano, Koji; Kawashima, Atsunari; Fujita, Kazutoshi; Uemura, Motohide; Takayama, Hitoshi; Nonomura, Norio

2013-01-01

Extracellular matrix metalloproteinase inducer (EMMPRIN) has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC) is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC. EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined. EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA) in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni). EMMPRIN-overexpressing RCC cells were resistant to sunitinib. Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.

EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome.

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Mototaka Sato

Full Text Available Extracellular matrix metalloproteinase inducer (EMMPRIN has been reported to play crucial roles, including in angiogenesis, in several carcinomas. However, the correlation between EMMPRIN levels and angiogenesis expression profile has not been reported, and the role of EMMPRIN in renal cell carcinoma (RCC is unclear. In the present study, we evaluated the association of EMMPRIN with angiogenesis, its value in prognosis, and its roles in RCC.EMMPRIN expression was examined in 50 RCC patients treated with radical nephrectomy. Angiogenesis, proliferation, and invasion activity were evaluated using EMMPRIN knockdown RCC cell lines. The size of EMMPRIN-overexpressing xenografts was measured and the degree of angiogenesis was quantified. EMMPRIN expression was evaluated in RCC patients who received sunitinib therapy and in sunitinib-resistant cells. Further, the relation between EMMPRIN expression and sensitivity to sunitinib was examined.EMMPRIN score was significantly associated with clinicopathological parameters in RCC patients, as well as being significantly correlated with microvessel area (MVA in immature vessels and with prognosis. Down-regulation of EMMPRIN by siRNA led to decreased VEGF and bFGF expression, cell proliferation, and invasive potential. EMMPRIN over-expressing xenografts showed accelerated growth and MVA of immature vessels. EMMPRIN expression was significantly increased in patients who received sunitinib therapy as well as in sunitinib-resistant 786-O cells (786-suni. EMMPRIN-overexpressing RCC cells were resistant to sunitinib.Our findings indicate that high expression of EMMPRIN in RCC plays important roles in tumor progression and sunitinib resistance. Therefore, EMMPRIN could be a novel target for the treatment of RCC.

Toward angiogenesis of implanted bio-artificial liver using scaffolds with type I collagen and adipose tissue-derived stem cells.

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Lee, Jae Geun; Bak, Seon Young; Nahm, Ji Hae; Lee, Sang Woo; Min, Seon Ok; Kim, Kyung Sik

2015-05-01

Stem cell therapies for liver disease are being studied by many researchers worldwide, but scientific evidence to demonstrate the endocrinologic effects of implanted cells is insufficient, and it is unknown whether implanted cells can function as liver cells. Achieving angiogenesis, arguably the most important characteristic of the liver, is known to be quite difficult, and no practical attempts have been made to achieve this outcome. We carried out this study to observe the possibility of angiogenesis of implanted bio-artificial liver using scaffolds. This study used adipose tissue-derived stem cells that were collected from adult patients with liver diseases with conditions similar to the liver parenchyma. Specifically, microfilaments were used to create an artificial membrane and maintain the structure of an artificial organ. After scratching the stomach surface of severe combined immunocompromised (SCID) mice (n=4), artificial scaffolds with adipose tissue-derived stem cells and type I collagen were implanted. Expression levels of angiogenesis markers including vascular endothelial growth factor (VEGF), CD34, and CD105 were immunohistochemically assessed after 30 days. Grossly, the artificial scaffolds showed adhesion to the stomach and surrounding organs; however, there was no evidence of angiogenesis within the scaffolds; and VEGF, CD34, and CD105 expressions were not detected after 30 days. Although implantation of cells into artificial scaffolds did not facilitate angiogenesis, the artificial scaffolds made with type I collagen helped maintain implanted cells, and surrounding tissue reactions were rare. Our findings indicate that type I collagen artificial scaffolds can be considered as a possible implantable biomaterial.

General Information about Rectal Cancer

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... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... VEGF inhibitors and angiogenesis inhibitors . Epidermal growth factor receptor (EGFR) inhibitor therapy: EGFRs are proteins found on ...

Stages of Rectal Cancer

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... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... VEGF inhibitors and angiogenesis inhibitors . Epidermal growth factor receptor (EGFR) inhibitor therapy: EGFRs are proteins found on ...

Treatment Options by Stage (Rectal Cancer)

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... Common Cancer Types Recurrent Cancer Common Cancer Types Bladder Cancer Breast Cancer Colorectal Cancer Kidney (Renal Cell) Cancer ... VEGF inhibitors and angiogenesis inhibitors . Epidermal growth factor receptor (EGFR) inhibitor therapy: EGFRs are proteins found on ...

General Information about Colon Cancer

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