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Sample records for angiogenesis markers vascular

  1. Vascular grading of angiogenesis

    DEFF Research Database (Denmark)

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

    2000-01-01

    was moderately reproduced (kappa = 0.59). Vascular grade was significantly associated with axillary node involvement, tumour size, malignancy grade, oestrogen receptor status and histological type. In univariate analyses vascular grade significantly predicted recurrence free survival and overall survival for all...... patients (P analysis showed that vascular grading contributed with independent prognostic value in all patients (P

  2. 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...

  3. Quantitative gene-expression of the tumor angiogenesis markers vascular endothelial growth factor, integrin alphaV and integrin beta3 in human neuroendocrine tumors

    DEFF Research Database (Denmark)

    Oxboel, Jytte; Binderup, Tina; Knigge, Ulrich;

    2009-01-01

    Anti-angiogenesis treatment is a promising new therapy for cancer that recently has also been suggested for patients with neuroendocrine tumors. The aim of the present study was therefore to investigate the level of tumor angiogenesis, and thereby the molecular basis for anti-angiogenesis treatment......, in neuroendocrine tumors. We used quantitative real-time PCR for measuring mRNA gene-expression of vascular endothelial growth factor (VEGF), integrin alphaV, and integrin beta3, and CD34 for a group of patients with neuroendocrine tumors (n=13). Tissue from patients with colorectal cancer liver metastases (n=14......) and normal liver tissues (n=16) was used as control. We found a lower mRNA level of VEGF in neuroendocrine tumors compared to both colorectal liver metastases (ptumors...

  4. VASCULAR REMODELING IN HYPERTENSION: ANGIOGENESIS FEATURES

    Directory of Open Access Journals (Sweden)

    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.

  5. 3D Multiscale Modelling of Angiogenesis and Vascular Tumour Growth

    KAUST Repository

    Perfahl, H.

    2012-11-01

    We present a three-dimensional, multiscale model of vascular tumour growth, which couples nutrient/growth factor transport, blood flow, angiogenesis, vascular remodelling, movement of and interactions between normal and tumour cells, and nutrient-dependent cell cycle dynamics within each cell. We present computational simulations which show how a vascular network may evolve and interact with tumour and healthy cells. We also demonstrate how our model may be combined with experimental data, to predict the spatio-temporal evolution of a vascular tumour.

  6. Angiogenesis: the genetic regulation of vascular development

    NARCIS (Netherlands)

    R.A. Haasdijk (Remco Anton)

    2014-01-01

    markdownabstract__Abstract__ For centuries, many scientists are fascinated by the organisation of the vascular network. The Greek philosopher and polymath Aristotle (384 BC) was one of the first man who described the vasculature. He wrote: “the system of blood vessels in the body may be compared to

  7. Vascular endothelial growth factor-dependent angiogenesis and dynamic vascular plasticity in the sensory circumventricular organs of adult mouse brain.

    Science.gov (United States)

    Morita, Shoko; Furube, Eriko; Mannari, Tetsuya; Okuda, Hiroaki; Tatsumi, Kouko; Wanaka, Akio; Miyata, Seiji

    2015-03-01

    The sensory circumventricular organs (CVOs), which comprise the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ (SFO) and the area postrema (AP), lack a typical blood-brain barrier (BBB) and monitor directly blood-derived information to regulate body fluid homeostasis, inflammation, feeding and vomiting. Until now, almost nothing has been documented about vascular features of the sensory CVOs except fenestration of vascular endothelial cells. We therefore examine whether continuous angiogenesis occurs in the sensory CVOs of adult mouse. The angiogenesis-inducing factor vascular endothelial growth factor-A (VEGF-A) and the VEGF-A-regulating transcription factor hypoxia-inducible factor-1α were highly expressed in neurons of the OVLT and SFO and in both neurons and astrocytes of the AP. Expression of the pericyte-regulating factor platelet-derived growth factor B was high in astrocytes of the sensory CVOs. Immunohistochemistry of bromodeoxyuridine and Ki-67, a nuclear protein that is associated with cellular proliferation, revealed active proliferation of endothelial cells. Moreover, immunohistochemistry of caspase-3 and the basement membrane marker laminin showed the presence of apoptosis and sprouting of endothelial cells, respectively. Treatment with the VEGF receptor-associated tyrosine kinase inhibitor AZD2171 significantly reduced proliferation and filopodia sprouting of endothelial cells, as well as the area and diameter of microvessels. The mitotic inhibitor cytosine-b-D-arabinofuranoside reduced proliferation of endothelial cells and the vascular permeability of blood-derived low-molecular-weight molecules without changing vascular area and microvessel diameter. Thus, our data indicate that continuous angiogenesis is dependent on VEGF signaling and responsible for the dynamic plasticity of vascular structure and permeability.

  8. Vascular endothelial growth factor-B promotes in vivo angiogenesis.

    Science.gov (United States)

    Silvestre, Jean-Sébastien; Tamarat, Radia; Ebrahimian, Teni G; Le-Roux, Aude; Clergue, Michel; Emmanuel, Florence; Duriez, Micheline; Schwartz, Bertrand; Branellec, Didier; Lévy, Bernard I

    2003-07-25

    Vascular endothelial growth factors (VEGFs) and their receptors have emerged as central regulators of the angiogenic process. However, involvement of VEGF-B, one of these factors, in angiogenesis remains obscure. Mice received subcutaneous injection of Matrigel alone or Matrigel with human recombinant protein rhVEGF-B167 or with rhVEGF-A165. After 14 days, cell ingrowth in the Matrigel plug was increased by 2.0- and 2.5-fold in rhVEGF-B167-treated and rhVEGF-A165-treated mice, respectively (P<0.01), in association with a raise in phospho-Akt/Akt (1.8-fold, P<0.01) and endothelial NO synthase (eNOS) (1.80- and 1.60-fold, respectively; P<0.05) protein levels measured by Western blot. VEGF-B-induced cell ingrowth was impaired by treatment with NOS inhibitor (NG-nitro-l-arginine methyl ester; L-NAME, 10 mg/kg per day). Treatment with neutralizing antibody directed against the VEGF-B receptor VEGF-R1 (anti-VEGFR1, 10 microg) completely abrogated VEGF-B-related effects. Proangiogenic effect of VEGF-B was confirmed in a mouse model of surgically induced hindlimb ischemia. Plasmids containing human form of VEGF-A (phVEGF-A165) or VEGF-B (phVEGF-B167 or phVEGF-B186) were administered by in vivo electrotransfer. Angiographic score at day 28 showed significant improvement in ischemic/nonischemic leg ratio by 1.4- and 1.5-fold in mice treated with phVEGF-B167 and phVEGF-B186, respectively (P<0.05). Laser Doppler perfusion data also evidenced a 1.5-fold increase in phVEGF-B167-treated and phVEGF-B186-treated mice (P<0.05). Such an effect was associated with an upregulation of phospho-Akt/Akt and eNOS protein levels in the ischemic legs and was hampered by treatment with anti-VEGFR1. This study demonstrates for the first time that VEGF-B, in part through its receptor VEGF-R1, promotes angiogenesis in association with an activation of Akt and eNOS-related pathways.

  9. Evaluation of angiogenesis in 77 pituitary adenomas using endoglin as a marker.

    Science.gov (United States)

    Pizarro, Cristina B; Oliveira, Miriam C; Pereira-Lima, Julia F S; Leães, Carolina G S; Kramer, Carolina K; Schuch, Tiago; Barbosa-Coutinho, Lígia M; Ferreira, Nelson P

    2009-02-01

    Angiogenesis, a fundamental process for the development and growth of a tumor, is less expressive in adenomas than in the normal pituitary tissue. There is controversy about the behavior of angiogenesis as a function of hormonal secretion or other characteristics of pituitary tumors. Endoglin (CD105) is a proliferation-associated antigen on endothelial cells, as well as an endothelial progenitor cell marker. We used the anti-endoglin antibody, a glycoprotein expressed in endothelial cells and conjunctive tissue, as a new marker particularly associated with neovascularization, in order to determine microvascular density (MVD) in pituitary adenomas. There were 77 samples, 31 males and 46 females, carriers of micro- (n = 24) or macroadenomas (n = 53). No significant difference was found in MVD concerning the variables of age, clinical presentation, and immunohistochemical phenotype or tumor size. MVD in males (median 5.4) was significantly higher (P = 0.001) than in females (median 3.0). Cell proliferation, as evaluated by the MIB-1 antibody (a cellular proliferation index [Ki-67 antigen], which is present in all stages of the cellular cycle except for the resting cells), ranged from 0% to 19.58%. No correlation was found between MIB-1 and MVD. It is possible to infer that the lower MVD found in pituitary adenomas in females reflects an inhibitory estrogen action on TGF-beta1, a protein involved in vascular remodeling. Because of its role as a TGF receptor ligand, endoglin proved to be sensitive in detecting this gender difference in pituitary tumor angiogenesis.

  10. The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells.

    Science.gov (United States)

    Savant, Soniya; La Porta, Silvia; Budnik, Annika; Busch, Katrin; Hu, Junhao; Tisch, Nathalie; Korn, Claudia; Valls, Aida Freire; Benest, Andrew V; Terhardt, Dorothee; Qu, Xianghu; Adams, Ralf H; Baldwin, H Scott; Ruiz de Almodóvar, Carmen; Rodewald, Hans-Reimer; Augustin, Hellmut G

    2015-09-22

    Tie1 is a mechanistically poorly characterized endothelial cell (EC)-specific orphan receptor. Yet, Tie1 deletion is embryonic lethal and Tie1 has been implicated in critical vascular pathologies, including atherosclerosis and tumor angiogenesis. Here, we show that Tie1 does not function independently but exerts context-dependent effects on the related receptor Tie2. Tie1 was identified as an EC activation marker that is expressed during angiogenesis by a subset of angiogenic tip and remodeling stalk cells and downregulated in the adult quiescent vasculature. Functionally, Tie1 expression by angiogenic EC contributes to shaping the tip cell phenotype by negatively regulating Tie2 surface presentation. In contrast, Tie1 acts in remodeling stalk cells cooperatively to sustain Tie2 signaling. Collectively, our data support an interactive model of Tie1 and Tie2 function, in which dynamically regulated Tie1 versus Tie2 expression determines the net positive or negative effect of Tie1 on Tie2 signaling.

  11. Identification of colorectal cancer metastasis markers by an angiogenesis-related cytokine-antibody array

    Institute of Scientific and Technical Information of China (English)

    Ana Abajo; Nerea Bitarte; Ruth Zarate; Valentina Boni; Ines Lopez; Marisol Gonzalez-Huarriz; Javier Rodriguez; Eva Bandres; Jesus Garcia-Foncillas

    2012-01-01

    AIM:To investigate the angiogenesis-related protein expression profile characterizing metastatic colorectal cancer (mCRC) with the aim of identifying prognostic markers.METHODS:The expression of 44 angiogenesissecreted factors was measured by a novel cytokine antibody array methodology.The study evaluated vascular endothelial growth factor (VEGF) and its soluble vascular endothelial growth factor receptor (sVEGFR)-1 protein levels by enzyme immunoassay (EIA) in a panel of 16 CRC cell lines.mRNA VEGF and VEGF-A isoforms were quantified by quantitative reverse-transcription polymerase chain reaction (Q-RT-PCR) and vascular endothelial growth factor receptor (VEGFR)-2 expression was analyzed by flow cytometry.RESULTS:Metastasis-derived CRC cell lines expressed a distinctive molecular profile as compared with those isolated from a primary tumor site.Metastatic CRC cell lines were characterized by higher expression of angiogenin-2 (Ang-2),macrophage chemoattractant proteins-3/4 (MCP-3/4),matrix metalloproteinase-1 (MMP-1),and the chemokines interferon γ inducible T cell α chemoattractant protein (I-TAC),monocyte chemoattractant protein 1-309,and interleukins interleukin (IL)-2 and IL-1α,as compared to primary tumor cell lines.In contrast,primary CRC cell lines expressed higher levels of interferon γ (IFN-γ),insulin-like growth factor-1 (IGF-1),IL-6,leptin,epidermal growth factor (EGF),placental growth factor (PIGF),thrombopoietin,transforming growth factor β1 (TGF-β1) and VEGF-D,as compared with the metastatic cell lines.VEGF expression does not significantly differ according to the CRC cellular origin in normoxia.Severe hypoxia induced VEGF expression up-regulation but contrary to expectations,metastatic CRC cell lines did not respond as much as primary cell lines to the hypoxic stimulus.In CRC primary-derived cell lines,we observed a twofold increase in VEGF expression between normoxia and hypoxia as compared to metastatic cell lines.CRC cell lines express a

  12. Impact of Endothelial Microparticles on Coagulation, Inflammation, and Angiogenesis in Age-Related Vascular Diseases

    Directory of Open Access Journals (Sweden)

    Margaret Markiewicz

    2013-01-01

    Full Text Available Endothelial microparticles (EMPs are complex vesicular structures that originate from plasma membranes of activated or apoptotic endothelial cells. EMPs play a significant role in vascular function by altering the processes of inflammation, coagulation, and angiogenesis, and they are key players in the pathogenesis of several vascular diseases. Circulating EMPs are increased in many age-related vascular diseases such as coronary artery disease, peripheral vascular disease, cerebral ischemia, and congestive heart failure. Their elevation in plasma has been considered as both a biomarker and bioactive effector of vascular damage and a target for vascular diseases. This review focuses on the pleiotropic roles of EMPs and the mechanisms that trigger their formation, particularly the involvement of decreased estrogen levels, thrombin, and PAI-1 as major factors that induce EMPs in age-related vascular diseases.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Garrido-Urbani, Sarah; Jemelin, Stephane; Deffert, Christine; Carnesecchi, Stéphanie; Basset, Olivier; Szyndralewiez, Cédric; Heitz, Freddy; Page, Patrick; Montet, Xavier; Michalik, Liliane; Arbiser, Jack; Rüegg, Curzio; Krause, Karl Heinz; Imhof, Beat A; Imhof, Beat

    2011-02-07

    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.

  15. Increased shear stress inhibits angiogenesis in veins and not arteries during vascular development.

    Science.gov (United States)

    Chouinard-Pelletier, Guillaume; Jahnsen, Espen D; Jones, Elizabeth A V

    2013-01-01

    Vascular development is believed to occur first by vasculogenesis followed by angiogenesis. Though angiogenesis is the formation of new vessels, we found that vascular density actually decreases during this second stage. The onset of the decrease coincided with the entry of erythroblasts into circulation. We therefore measured the level of shear stress at various developmental stages and found that it was inversely proportional to vascular density. To investigate whether shear stress was inhibitory to angiogenesis, we altered shear stress levels either by preventing erythroblasts from entering circulation ("low" shear stress) or by injection of a starch solution to increase the blood plasma viscosity ("high" shear stress). By time-lapse microscopy, we show that reverse intussusception (merging of two vessels) is inversely proportional to the level of shear stress. We also found that angiogenesis (both sprouting and splitting) was inversely proportional to shear stress levels. These effects were specific to the arterial or venous plexus however, such that the effect on reverse intussusception was present only in the arterial plexus and the effect on sprouting only in the venous plexus. We cultured embryos under altered shear stress in the presence of either DAPT, a Notch inhibitor, or DMH1, an inhibitor of the bone morphogenetic protein (BMP) pathway. DAPT treatment phenocopied the inhibition of erythroblast circulation ("low" shear stress) and the effect of DAPT treatment could be partially rescued by injection of starch. Inhibition of the BMP signaling prevented the reduction in vascular density that was observed when starch was injected to increase shear stress levels.

  16. Role of simvastatin and/or antioxidant vitamins in therapeutic angiogenesis in experimental diabetic hindlimb ischemia: effects on capillary density, angiogenesis markers, and oxidative stress.

    Science.gov (United States)

    El-Azab, Mona F; Hazem, Reem M; Moustafa, Yasser M

    2012-09-05

    Therapeutic angiogenesis has emerged as an attractive approach for the management of peripheral arterial disease in diabetic patients. Oxidative stress generated and aggravated by prolonged hyperglycemia may interfere with and destroy the newly formed blood vessels. Angiogenic effect of simvastatin has been reported; however, its exact mechanism is yet to be evaluated. In addition, the exact role of antioxidant vitamins in diabetic peripheral arterial disease is still controversial. The present study was undertaken to investigate the therapeutic potential of simvastatin and antioxidant vitamins (E and C) and their combined effects on angiogenesis in diabetic hind-limb ischemia. Streptozotocin diabetic rats were treated for 6 weeks with simvastatin either alone or in combination with vitamin E or vitamin C. Parameters of angiogenesis, nitric oxide, heme oxygenase-1 (HO-1), and oxidative stress markers were evaluated. CD31 immunostaining revealed an increased capillary density in ischemic gastrocnemious tissue of diabetic rats treated with either simvastatin or its combination with vitamin C. This effect was accompanied by up-regulated plasma levels of HO-1, nitric oxide, vascular endothelial growth factor (VEGF) and its intra-muscular receptor type-2 (Flk-1). Tissue reduced glutathione and antioxidant enzymes activities were normalized in groups treated with antioxidant vitamins or their combination with simvastatin with concomitant blunting of lipid peroxidation. Vitamins E and C, through their antioxidant effects, evidently enhanced the angiogenic effect of simvastatin in ischemic diabetic muscle. Hence, the use of antioxidant vitamins combined with statins to induce therapeutic angiogenesis is a promising strategy in the management of diabetes-associated peripheral arterial disease.

  17. Controlled angiogenesis in the heart by cell-based expression of specific vascular endothelial growth factor levels.

    Science.gov (United States)

    Melly, Ludovic F; Marsano, Anna; Frobert, Aurelien; Boccardo, Stefano; Helmrich, Uta; Heberer, Michael; Eckstein, Friedrich S; Carrel, Thierry P; Giraud, Marie-Noëlle; Tevaearai, Hendrik T; Banfi, Andrea

    2012-10-01

    Vascular endothelial growth factor (VEGF) can induce normal angiogenesis or the growth of angioma-like vascular tumors depending on the amount secreted by each producing cell because it remains localized in the microenvironment. In order to control the distribution of VEGF expression levels in vivo, we recently developed a high-throughput fluorescence-activated cell sorting (FACS)-based technique to rapidly purify transduced progenitors that homogeneously express a specific VEGF dose from a heterogeneous primary population. Here we tested the hypothesis that cell-based delivery of a controlled VEGF level could induce normal angiogenesis in the heart, while preventing the development of angiomas. Freshly isolated human adipose tissue-derived stem cells (ASC) were transduced with retroviral vectors expressing either rat VEGF linked to a FACS-quantifiable cell-surface marker (a truncated form of CD8) or CD8 alone as control (CTR). VEGF-expressing cells were FACS-purified to generate populations producing either a specific VEGF level (SPEC) or uncontrolled heterogeneous levels (ALL). Fifteen nude rats underwent intramyocardial injection of 10(7) cells. Histology was performed after 4 weeks. Both the SPEC and ALL cells produced a similar total amount of VEGF, and both cell types induced a 50%-60% increase in both total and perfused vessel density compared to CTR cells, despite very limited stable engraftment. However, homogeneous VEGF expression by SPEC cells induced only normal and stable angiogenesis. Conversely, heterogeneous expression of a similar total amount by the ALL cells caused the growth of numerous angioma-like structures. These results suggest that controlled VEGF delivery by FACS-purified ASC may be a promising strategy to achieve safe therapeutic angiogenesis in the heart.

  18. Angiogenesis impairment in diabetes: role of methylglyoxal-induced receptor for advanced glycation endproducts, autophagy and vascular endothelial growth factor receptor 2.

    Directory of Open Access Journals (Sweden)

    Hongtao Liu

    Full Text Available Diabetes impairs physiological angiogenesis by molecular mechanisms that are not fully understood. Methylglyoxal (MGO, a metabolite of glycolysis, is increased in patients with diabetes. This study defined the role of MGO in angiogenesis impairment and tested the mechanism in diabetic animals. Endothelial cells and mouse aortas were subjected to Western blot analysis of vascular endothelial growth factor receptor 2 (VEGFR2 protein levels and angiogenesis evaluation by endothelial cell tube formation/migration and aortic ring assays. Incubation with MGO reduced VEGFR2 protein, but not mRNA, levels in a time and dose dependent manner. Genetic knockdown of the receptor for advanced glycation endproducts (RAGE attenuated the reduction of VEGFR2. Overexpression of Glyoxalase 1, the enzyme that detoxifies MGO, reduced the MGO-protein adducts and prevented VEGFR2 reduction. The VEGFR2 reduction was associated with impaired angiogenesis. Suppression of autophagy either by inhibitors or siRNA, but not of the proteasome and caspase, normalized both the VEGFR2 protein levels and angiogenesis. Conversely, induction of autophagy either by rapamycin or overexpression of LC3 and Beclin-1 reduced VEGFR2 and angiogenesis. MGO increased endothelial LC3B and Beclin-1, markers of autophagy, which were accompanied by an increase of both autophagic flux (LC3 punctae and co-immunoprecipitation of VEGFR2 with LC3. Pharmacological or genetic suppression of peroxynitrite (ONOO(- generation not only blocked the autophagy but also reversed the reduction of VEGFR2 and angiogenesis. Like MGO-treated aortas from normglycemic C57BL/6J mice, aortas from diabetic db/db and Akita mice presented reductions of angiogenesis or VEGFR2. Administration of either autophagy inhibitor ex vivo or superoxide scavenger in vivo abolished the reductions. Taken together, MGO reduces endothelial angiogenesis through RAGE-mediated, ONOO(-dependent and autophagy-induced VEGFR2 degradation, which

  19. In vivo quantitative evaluation of vascular parameters for angiogenesis based on sparse principal component analysis and aggregated boosted trees

    Science.gov (United States)

    Zhao, Fengjun; Liu, Junting; Qu, Xiaochao; Xu, Xianhui; Chen, Xueli; Yang, Xiang; Cao, Feng; Liang, Jimin; Tian, Jie

    2014-12-01

    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.

  20. Role of Copper and Vascular Endothelial Growth Factor (VEGF on Endometrial Angiogenesis

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    Yousef Rezaei Chianeh

    2013-07-01

    Full Text Available The formation of new blood vessels is the ini-tial step in neovascularisation. The first stagein angiogenesis is the activation of endothelialcells. Copper ions stimulate proliferation andimmigration of endothelial cells. It has beenshown that serum copper concentration in-creases as the cancer disease progresses andcorrelates with tumour incidence and burden.Copper ions also activate several proangiogenicfactors, e.g., vascular endothelial growth fac-tor, basic fibroblast growth factor, andinterleukin 1. This review concerns a brief in-troduction into the basics of blood vessel de-velopment as well as the regulatory mecha-nisms of this process. The role of copper ionsin angiogenesis is discussed.

  1. Effects of cellular iron deficiency on the formation of vascular endothelial growth factor and angiogenesis. Iron deficiency and angiogenesis

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    Eckard Jonathan

    2010-08-01

    Full Text Available Abstract Background Young women diagnosed with breast cancer are known to have a higher mortality rate from the disease than older patients. Specific risk factors leading to this poorer outcome have not been identified. In the present study, we hypothesized that iron deficiency, a common ailment in young women, contributes to the poor outcome by promoting the hypoxia inducible factor-1α (HIF-1α and vascular endothelial growth factor (VEGF formation. This hypothesis was tested in an in vitro cell culture model system. Results Human breast cancer MDA-MB-231 cells were transfected with transferrin receptor-1 (TfR1 shRNA to constitutively impair iron uptake. Cellular iron status was determined by a set of iron proteins and angiogenesis was evaluated by levels of VEGF in cells as well as by a mouse xenograft model. Significant decreases in ferritin with concomitant increases in VEGF were observed in TfR1 knockdown MDA-MB-231 cells when compared to the parental cells. TfR1 shRNA transfectants also evoked a stronger angiogenic response after the cells were injected subcutaneously into nude mice. The molecular mechanism appears that cellular iron deficiency elevates VEGF formation by stabilizing HIF-1α. This mechanism is also true in human breast cancer MCF-7 and liver cancer HepG2 cells. Conclusions Cellular iron deficiency increased HIF-1α, VEGF, and angiogenesis, suggesting that systemic iron deficiency might play an important part in the tumor angiogenesis and recurrence in this young age group of breast cancer patients.

  2. Vascular Function and Angiogenesis in Aging and Essential Hypertension

    DEFF Research Database (Denmark)

    Gliemann, Lasse

    markers of basal oxidative stress and inflammation in skeletal muscle. The effect of training on markers of oxidative stress was likely, at least in part, due to a increase in skeletal muscle levels of SOD2, as the potential for ROS formation actually increased as evidenced by an increase...... age and inactivity, muscle capillarization is decreased, which may contribute to decreased muscle function and physical capacity. In agreement with previous observations, the present work shows that exercise training induces a marked angiogenic response and increases capillarization in skeletal muscle...... capillary lumen area and a tendency for increased basement membrane thickness in the skeletal muscle. The physiological consequences of these alterations are unknown but may constitute a limitation for diffusion of oxygen and nutrients. Increased basement membrane thickness has also been associated...

  3. Endothelial-mural cell signaling in vascular development and angiogenesis.

    Science.gov (United States)

    Gaengel, Konstantin; Genové, Guillem; Armulik, Annika; Betsholtz, Christer

    2009-05-01

    Mural cells are essential components of blood vessels and are necessary for normal development, homeostasis, and organ function. Alterations in mural cell density or the stable attachment of mural cells to the endothelium is associated with several human diseases such as diabetic retinopathy, venous malformation, and hereditary stroke. In addition mural cells are implicated in regulating tumor growth and have thus been suggested as potential antiangiogenic targets in tumor therapy. In recent years our knowledge of mural cell function and endothelial-mural cell signaling has increased dramatically, and we now begin to understand the mechanistic basis of the key signaling pathways involved. This is mainly thanks to sophisticated in vivo experiments using a broad repertoire of genetic technologies. In this review, we summarize the five currently best understood signaling pathways implicated in mural cell biology. We discuss PDGFB/PDGFRbeta- dependent pericyte recruitment, as well as the role of angiopoietins and Tie receptors in vascular maturation. In addition, we highlight the effects of sphingosine-1-phosphate signaling on adherens junction assembly and vascular stability, as well as the role of TGF-beta-signaling in mural cell differentiation. We further reflect recent data suggesting an important function for Notch3 signaling in mural cell maturation.

  4. Microultrasound Molecular Imaging of Vascular Endothelial Growth Factor Receptor 2 in a Mouse Model of Tumor Angiogenesis

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    Joshua J. Rychak

    2007-09-01

    Full Text Available High-frequency microultrasound imaging of tumor progression in mice enables noninvasive anatomic and functional imaging at excellent spatial and temporal resolution, although microultrasonography alone does not offer molecular scale data. In the current study, we investigated the use of microbubble ultrasound contrast agents bearing targeting ligands specific for molecular markers of tumor angiogenesis using high-frequency microultrasound imaging. A xenograft tumor model in the mouse was used to image vascular endothelial growth factor receptor 2 (VEGFR-2 expression with microbubbles conjugated to an anti-VEGFR-2 monoclonal antibody or an isotype control. Microultrasound imaging was accomplished at a center frequency of 40 MHz, which provided lateral and axial resolutions of 40 and 90 μm, respectively. The B-mode (two-dimensional mode acoustic signal from microbubbles bound to the molecular target was determined by an ultrasound-based destruction-subtraction scheme. Quantification of the adherent microbubble fraction in nine tumor-bearing mice revealed significant retention of VEGFR-2-targeted microbubbles relative to control-targeted microbubbles. These data demonstrate that contrast-enhanced microultrasound imaging is a useful method for assessing molecular expression of tumor angiogenesis in mice at high resolution.

  5. The Orphan Receptor Tie1 Controls Angiogenesis and Vascular Remodeling by Differentially Regulating Tie2 in Tip and Stalk Cells

    Directory of Open Access Journals (Sweden)

    Soniya Savant

    2015-09-01

    Full Text Available Tie1 is a mechanistically poorly characterized endothelial cell (EC-specific orphan receptor. Yet, Tie1 deletion is embryonic lethal and Tie1 has been implicated in critical vascular pathologies, including atherosclerosis and tumor angiogenesis. Here, we show that Tie1 does not function independently but exerts context-dependent effects on the related receptor Tie2. Tie1 was identified as an EC activation marker that is expressed during angiogenesis by a subset of angiogenic tip and remodeling stalk cells and downregulated in the adult quiescent vasculature. Functionally, Tie1 expression by angiogenic EC contributes to shaping the tip cell phenotype by negatively regulating Tie2 surface presentation. In contrast, Tie1 acts in remodeling stalk cells cooperatively to sustain Tie2 signaling. Collectively, our data support an interactive model of Tie1 and Tie2 function, in which dynamically regulated Tie1 versus Tie2 expression determines the net positive or negative effect of Tie1 on Tie2 signaling.

  6. Angiogenesis and vascular malformations: Antiangiogenic drugs for treatment of gastrointestinal bleeding

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Treatment of gastrointestinal bleeding in patients with angiodysplasias and Osler's disease (hereditary hemorrhagic teleangiectasia) is clinically challenging.Frequently, vascular malformations occur as multiple disseminated lesions, making local treatment an unfavorable choice or impossible. After local therapy,lesions often recur at other sites of the intestine.However, as there are few therapeutic alternatives,repeated endoscopic coagulations or surgical resections are still performed to prevent recurrent bleeding.Hormonal therapy has been employed for more than 50 years but has recently been shown to be ineffective.Therefore, new therapeutic strategies are required.Understanding of the pathophysiology of angiogenesis and vascular malformations has recently substantially increased. Currently, multiple inhibitors of angiogenesis are under development for treatment of malignant diseases. Experimental and clinical data suggest that antiangiogenic substances, which were originally developed for treatment of malignant diseases, may also represent long-awaited specific drugs for the treatment of vascular malformations. However, antiangiogenics display significantly different actions and side-effects.Although antiangiogenics like thalidomide seem to inhibit gastrointestinal bleeding, other substances like bevacizumab can cause mucosal bleeding. Therefore differential and cautious evaluation of this therapeutic strategy is necessary.

  7. Diagnostic Value of Serum Angiogenesis Markers in Ovarian Cancer Using Multiplex Immunoassay

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    Agnieszka Horala

    2017-01-01

    Full Text Available As cancer development involves pathological vessel formation, 16 angiogenesis markers were evaluated as potential ovarian cancer (OC biomarkers. Blood samples collected from 172 patients were divided based on histopathological result: OC (n = 38, borderline ovarian tumours (n = 6, non-malignant ovarian tumours (n = 62, healthy controls (n = 50 and 16 patients were excluded. Sixteen angiogenesis markers were measured using BioPlex Pro Human Cancer Biomarker Panel 1 immunoassay. Additionally, concentrations of cancer antigen 125 (CA125 and human epididymis protein 4 (HE4 were measured in patients with adnexal masses using electrochemiluminescence immunoassay. In the comparison between OC vs. non-OC, osteopontin achieved the highest area under the curve (AUC of 0.79 (sensitivity 69%, specificity 78%. Multimarker models based on four to six markers (basic fibroblast growth factor—FGF-basic, follistatin, hepatocyte growth factor—HGF, osteopontin, platelet-derived growth factor AB/BB—PDGF-AB/BB, leptin demonstrated higher discriminatory ability (AUC 0.80–0.81 than a single marker (AUC 0.79. When comparing OC with benign ovarian tumours, six markers had statistically different expression (osteopontin, leptin, follistatin, PDGF-AB/BB, HGF, FGF-basic. Osteopontin was the best single angiogenesis marker (AUC 0.825, sensitivity 72%, specificity 82%. A three-marker panel consisting of osteopontin, CA125 and HE4 better discriminated the groups (AUC 0.958 than HE4 or CA125 alone (AUC 0.941 and 0.932, respectively. Osteopontin should be further investigated as a potential biomarker in OC screening and differential diagnosis of ovarian tumours. Adding osteopontin to a panel of already used biomarkers (CA125 and HE4 significantly improves differential diagnosis between malignant and benign ovarian tumours.

  8. Oscillation of Angiogenesis with Vascular Dropout in Diabetic Retinopathy by VESsel GENeration Analysis (VESGEN)

    Science.gov (United States)

    Parsons-Wingerter, Patricia; Radbakrishnan, Krisbnan; Vickerman, Mary B.; Kaiser, Peter K.

    2010-01-01

    PURPOSE. Vascular dropout and angiogenesis are hallmarks of the progression of diabetic retinopathy (DR). However, current evaluation of DR relies on grading of secondary vascular effects, such as microaneurysms and hemorrhages, by clinical examination instead of by evaluation of actual vascular changes. The purpose of this study was to map and quantify vascular changes during progression of DR by VESsel GENeration Analysis (VESGEN). METHODS. In this prospective cross-sectional study, 15 eyes with DR were evaluated with fluorescein angiography (FA) and color fundus photography, and were graded using modified Early Treatment Diabetic Retinopathy Study criteria. FA images were separated by semiautomatic image processing into arterial and venous trees. Vessel length density (L(sub v)), number density (N(sub v)), and diameter (D(sub v)) were analyzed in a masked fashion with VESGEN software. Each vascular tree was automatically segmented into branching generations (G(sub 1)...G(sub 8) or G(sub 9)) by vessel diameter and branching. Vascular remodeling status (VRS) for N(sub v) and L(sub v) was graded 1 to 4 for increasing severity of vascular change. RESULTS. By N(sub v) and L(sub v), VRS correlated significantly with the independent clinical diagnosis of mild to proliferative DR (13/15 eyes). N(sub v) and L(sub v) of smaller vessels (G(sub >=6) increased from VRS1 to VRS2 by 2.4 X and 1.6 X, decreased from VRS2 to VRS3 by 0.4 X and 0.6X, and increased from VRS3 to VRS4 by 1.7 X and 1.5 X (P < 0.01). Throughout DR progression, the density of larger vessels (G(sub 1-5)) remained essentially unchanged, and D(sub v1-5) increased slightly. CONCLUSIONS. Vessel density oscillated with the progression of DR. Alternating phases of angiogenesis/neovascularization and vascular dropout were dominated first by remodeling of arteries and subsequently by veins.

  9. The role of vascular endothelial growth factors and fibroblast growth factors in angiogenesis during otitis media.

    Science.gov (United States)

    Husseman, Jacob; Palacios, Sean D; Rivkin, Alexander Z; Oehl, Heinz; Ryan, Allen F

    2012-01-01

    The middle ear response to otitis media includes transformation and hyperplasia of the mucosal epithelium and subepithelial connective tissue. Significant neovascularization is also noted, which occurs both to support the hypertrophied mucosa and to mediate the increased trafficking of leukocytes. We investigated the role of two known potent angiogenic growth factor families, the fibroblast growth factors (FGFs) and vascular endothelial growth factors (VEGFs), in middle ear mucosal angiogenesis. DNA microarrays were used to evaluate the expression of FGFs and VEGFs, as well as their receptors and unique signaling proteins, in the middle ears of mice undergoing a complete course of acute bacterial otitis media. In addition, a member of each family was introduced to the middle ear submucosal compartment of the normal middle ears of guinea pigs, by a continuous-release osmotic minipump system over 1 week. During the course of bacterial otitis media, a significant regulation of a number of genes important for angiogenesis was identified. Histologic evaluation of middle ear mucosa following micropump infusion of both FGF1 and VEGF-A showed significant angiogenesis at the site of infusion in comparison to control saline infusion. These results support a role for FGFs and VEGFs in the neovascularization of the middle ear mucosa during otitis media, and offer a potential avenue for therapeutic intervention.

  10. SNS-032 Prevents Tumor Cell-Induced Angiogenesis By Inhibiting Vascular Endothelial Growth Factor

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    M. Aktar Ali

    2007-05-01

    Full Text Available Cell proliferation, migration, and capillary network formation of endothelial cells are the fundamental steps for angiogenesis, which involves the formation of new blood vessels. The purpose of this study is to investigate the effect of a novel aminothiazole SNS-032 on these critical steps for in vitro angiogenesis using a coculture system consisting of human umbilical vein endothelial cells (HUVECs and human glioblastoma cells (U87MG. SNS-032 is a potent selective inhibitor of cyclin-dependent kinases 2, 7, and 9, and inhibits both transcription and cell cycle. In this study, we examined the proliferation and viability of HUVECs and U87MG cells in the presence of SNS-032 and observed a dose-dependent inhibition of cellular proliferation in both cell lines. SNS-032 inhibited threedimensional capillary network formations of endothelial cells. In a coculture study, SNS-032 completely prevented U87MG cell-mediated capillary formation of HUVECs. This inhibitor also prevented the migration of HUVECs when cultured alone or cocultured with U87MG cells. In addition, SNS-032 significantly prevented the production of vascular endothelial growth factor (VEGF in both cell lines, whereas SNS-032 was less effective in preventing capillary network formation and migration of endothelial cells when an active recombinant VEGF was added to the medium. In conclusion, SNS-032 prevents in vitro angiogenesis, and this action is attributable to blocking of VEGF.

  11. 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.

  12. Markers of angiogenesis and epidermal growth factor receptor signalling in patients with pancreatic and gastroesophageal junction cancer.

    Science.gov (United States)

    Rohrberg, Kristoffer Staal; Skov, Birgit Guldhammer; Lassen, Ulrik; Christensen, Ib Jarle; Høyer-Hansen, Gunilla; Buysschaert, Ian; Pappot, Helle

    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 and there is therefore an increasing need for biomarkers for selection of patients to these therapies. We investigated the expression of EGFR, vascular endothelial growth factor A (VEGF-A), and VEGF receptor 2 (VEGFR-2) in tumour tissue by immunohistochemistry, and soluble EGFR (sEGFR), soluble VEGFR-2 (sVEGFR-2), basic fibroblast growth factor (bFGF), placental growth factor (PlGF), plasminogen activator inhibitor 1 (PAI-1), and different forms of the urokinase plasminogen activator receptor (uPAR): uPAR (I), uPAR (I-III), and uPAR (I-III)+(II-III) in plasma by quantitative immunoassays in 14 patients with pancreatic and GEJ cancer. We found expression in tumour tissue and the plasma levels to be similar to those found in patients with other tumour types. No correlation was found between the blood levels of soluble receptors and the corresponding tumour tissue levels. We conclude that these markers are present in pancreatic and GEJ cancer patients, and could be investigated further as predictive biomarkers in such patients treated with EGFR or angiogenesis targeted therapies.

  13. Micro-CT imaging of tumor angiogenesis: quantitative measures describing micromorphology and vascularization.

    Science.gov (United States)

    Ehling, Josef; Theek, Benjamin; Gremse, Felix; Baetke, Sarah; Möckel, Diana; Maynard, Juliana; Ricketts, Sally-Ann; Grüll, Holger; Neeman, Michal; Knuechel, Ruth; Lederle, Wiltrud; Kiessling, Fabian; Lammers, Twan

    2014-02-01

    Angiogenesis is a hallmark of cancer, and its noninvasive visualization and quantification are key factors for facilitating translational anticancer research. Using four tumor models characterized by different degrees of aggressiveness and angiogenesis, we show that the combination of functional in vivo and anatomical ex vivo X-ray micro-computed tomography (μCT) allows highly accurate quantification of relative blood volume (rBV) and highly detailed three-dimensional analysis of the vascular network in tumors. Depending on the tumor model, rBV values determined using in vivo μCT ranged from 2.6% to 6.0%, and corresponds well with the values assessed using IHC. Using ultra-high-resolution ex vivo μCT, blood vessels as small as 3.4 μm and vessel branches up to the seventh order could be visualized, enabling a highly detailed and quantitative analysis of the three-dimensional micromorphology of tumor vessels. Microvascular parameters such as vessel size and vessel branching correlated very well with tumor aggressiveness and angiogenesis. In rapidly growing and highly angiogenic A431 tumors, the majority of vessels were small and branched only once or twice, whereas in slowly growing A549 tumors, the vessels were much larger and branched four to seven times. Thus, we consider that combining highly accurate functional with highly detailed anatomical μCT is a useful tool for facilitating high-throughput, quantitative, and translational (anti-) angiogenesis and antiangiogenesis research.

  14. Effects of vascular endothelial growth factor on angiogenesis of the endothelial cells isolated from cavernous malformations

    Institute of Scientific and Technical Information of China (English)

    TAN YuZhen; ZHAO Yao; WANG HaiJie; ZHOU LiangFu; MAO Ying; LIU Rui; SHU Jia; WANG YongFei

    2008-01-01

    Human cerebral cavernous malformation (CM) is a common vascular malformation of the central nervous system. We have investigated the biological characteristics of CM endothelial cells and the cellular and molecular mechanisms of CM angiogenesis to offer new insights into exploring effective measures for treatment of this disease. The endothelial cells were isolated from CM tissue masses dissected during operation and expanded in vitro. Expression of VEGFR-1 and VEGFR-2 was examined with immunocytochemical staining. Proliferation, migration and tube formation of CM endothelial cells were determined using MTT, wounding and transmigration assays, and three-dimensional collagen type Ⅰ gel respectively. The endothelial cells were successfully isolated from the tissue specimens of 25 CMs dissected without dipolar electrocoagulation. The cells show the general characteristics of the vascular endothelial cells. Expression of VEGFR-1 and VEGFR-2 on the cells is higher than that on the normal cerebral microvascular endothelial cells. After treatment with VEGF, numbers of the proliferated and migrated cells, the maximal distance of cell migration and the length and area of capillary-like struc-tures formed in the three-dimensional collagen gel increase significantly. These results demonstrate that expression of VEGFR-1 and VEGFR-2 on CM endothelial cells is up-regulated. By binding to re-ceptors, VEGF may activate the downstream signaling pathways and promote proliferation, migration and tube formation of CM endothelial cells. VEGF/VEGFR signaling pathways play important regulating roles in CM angiogenesis.

  15. Desert Hedgehog/Patch2 Axis Contributes to Vascular Permeability and Angiogenesis in Glioblastoma.

    Science.gov (United States)

    Azzi, Sandy; Treps, Lucas; Leclair, Héloïse M; Ngo, Hai-Mi; Harford-Wright, Elizabeth; Gavard, Julie

    2015-01-01

    Glioblastoma multiforme (GBM) constitutes the most common and the most aggressive type of human tumors affecting the central nervous system. Prognosis remains dark due to the inefficiency of current treatments and the rapid relapse. Paralleling other human tumors, GBM contains a fraction of tumor initiating cells with the capacity to self-renew, initiate and maintain the tumor mass. These cells were found in close proximity to brain vasculature, suggesting functional interactions between brain tumor-initiating cells (BTICs) and endothelial cells within the so-called vascular niche. However, the mechanisms by which these cells impact on the endothelium plasticity and function remain unclear. Using culture of BTICs isolated from a cohort of 14 GBM patients, we show that BTICs secretome promotes brain endothelial cell remodeling in a VEGF-independent manner. Gene array analysis unmasked that BTICs-released factors drove the expression of Ptch2 in endothelial cells. Interestingly, BTICs produce desert hedgehog (DHH) ligand, enabling a paracrine DHH/Ptch2 signaling cascade that conveys elevated permeability and angiogenesis. Finally, DHH silencing in BTICs dramatically reduced tumor growth, as well as vascularization and intra-tumor permeability. Collectively, our data unveil a role for DHH in exacerbated tumor angiogenesis and permeability, which may ultimately favor glioblastoma growth, and thus place the DHH/Ptch2 nexus as a molecular target for novel therapies.

  16. Desert Hedgehog/Patch2 axis contributes to vascular permeability and angiogenesis in glioblastoma

    Directory of Open Access Journals (Sweden)

    Sandy eAzzi

    2015-11-01

    Full Text Available Glioblastoma multiforme (GBM constitutes the most common and the most aggressive type of human tumors affecting the central nervous system. Prognosis remains dark due to the inefficiency of current treatments and the rapid relapse. Paralleling other human tumors, GBM contains a fraction of tumor initiating cells with the capacity to self-renew, initiate and maintain the tumor mass. These cells were found in close proximity to brain vasculature, suggesting functional interactions between brain tumor-initiating cells (BTICs and endothelial cells within the so-called vascular niche. However, the mechanisms by which these cells impact on the endothelium plasticity and function remain unclear. Using culture of BTICs isolated from a cohort of 14 GBM patients, we show that BTIC secretome promotes brain endothelial cell remodeling in a VEGF-independent manner. Gene array analysis unmasked that BTIC-released factors drove the expression of Ptch2 in endothelial cells. Interestingly, BTICs produce Desert Hedgehog (DHH ligand, enabling a paracrine DHH/Ptch2 signaling cascade that conveys elevated permeability and angiogenesis. Finally, DHH silencing in BTICs dramatically reduced tumor growth, as well as vascularization and intra-tumor permeability. Collectively, our data unveil a role for DHH in exacerbated tumor angiogenesis and permeability, which may ultimately favor glioblastoma growth, and thus place the DHH/Ptch2 nexus as a molecular target for novel therapies.

  17. Identification of Chemical Vascular Disruptors During Development Using An Integrative Predictive Toxicity Model and Zebrafish and in Vitro Functional Angiogenesis Assays.

    Science.gov (United States)

    Identification of chemical vascular disruptors during development using an integrative predictive toxicity model and zebrafish and in vitro functional angiogenesis assays Chemically-induced vascular toxicity during embryonic development can result in a wide range of adverse pre...

  18. Brain-derived neurotrophic factor increases vascular endothelial growth factor expression and enhances angiogenesis in human chondrosarcoma cells.

    Science.gov (United States)

    Lin, Chih-Yang; Hung, Shih-Ya; Chen, Hsien-Te; Tsou, Hsi-Kai; Fong, Yi-Chin; Wang, Shih-Wei; Tang, Chih-Hsin

    2014-10-15

    Chondrosarcomas are a type of primary malignant bone cancer, with a potent capacity for local invasion and distant metastasis. Brain-derived neurotrophic factor (BDNF) is commonly upregulated during neurogenesis. The aim of the present study was to examine the mechanism involved in BDNF-mediated vascular endothelial growth factor (VEGF) expression and angiogenesis in human chondrosarcoma cells. Here, we knocked down BDNF expression in chondrosarcoma cells and assessed their capacity to control VEGF expression and angiogenesis in vitro and in vivo. We found knockdown of BDNF decreased VEGF expression and abolished chondrosarcoma conditional medium-mediated angiogenesis in vitro as well as angiogenesis effects in vivo in the chick chorioallantoic membrane and Matrigel plug nude mouse models. In addition, in the xenograft tumor angiogenesis model, the knockdown of BDNF significantly reduced tumor growth and tumor-associated angiogenesis. BDNF increased VEGF expression and angiogenesis through the TrkB receptor, PLCγ, PKCα, and the HIF-1α signaling pathway. Finally, we analyzed samples from chondrosarcoma patients by immunohistochemical staining. The expression of BDNF and VEGF protein in 56 chondrosarcoma patients was significantly higher than in normal cartilage. In addition, the high level of BDNF expression correlated strongly with VEGF expression and tumor stage. Taken together, our results indicate that BDNF increases VEGF expression and enhances angiogenesis through a signal transduction pathway that involves the TrkB receptor, PLCγ, PKCα, and the HIF-1α. Therefore, BDNF may represent a novel target for anti-angiogenic therapy for human chondrosarcoma.

  19. Angiogenesis and inflammation signaling are targets of beer polyphenols on vascular cells.

    Science.gov (United States)

    Negrão, Rita; Costa, Raquel; Duarte, Delfim; Taveira Gomes, Tiago; Mendanha, Mário; Moura, Liane; Vasques, Luísa; Azevedo, Isabel; Soares, Raquel

    2010-12-01

    Emerging evidence indicates that chronic inflammation and oxidative stress cluster together with angiogenic imbalance in a wide range of pathologies. In general, natural polyphenols present health-protective properties, which are likely attributed to their effect on oxidative stress and inflammation. Hops used in beer production are a source of polyphenols such as xanthohumol (XN), and its metabolites isoxanthohumol (IXN) and phytoestrogen 8-prenylnaringenin (8PN). Our study aimed to evaluate XN, IXN, and 8PN effects on angiogenesis and inflammation processes. Opposite in vitro effects were observed between 8PN, stimulating endothelial and smooth muscle cell (SMC) growth, motility, invasion and capillary-like structures formation, and XN and IXN, which inhibited them. Mouse matrigel plug and rat skin wound-healing assays confirmed that XN and IXN treatments reduced vessel number as well as serum macrophage enzymatic activity, whereas 8PN increased blood vessels formation in both assays and enzyme activity in the wound-healing assay. A similar profile was found for serum inflammatory interleukin-1β quantification, in the wound-healing assay. Our data indicate that whereas 8PN stimulates angiogenesis, XN and IXN manifested anti-angiogenic and anti-inflammatory effects in identical conditions. These findings suggest that the effects observed for individual compounds on vascular wall cells must be carefully taken into account, as these polyphenols are metabolized after in vivo administration. The modulation of SMC proliferation and migration is also of special relevance, given the role of these cells in many pathological conditions. Furthermore, these results may provide clues for developing useful therapeutic agents against inflammation- and angiogenesis-associated pathologies.

  20. Human BCAS3 expression in embryonic stem cells and vascular precursors suggests a role in human embryogenesis and tumor angiogenesis.

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    Kavitha Siva

    Full Text Available Cancer is often associated with multiple and progressive genetic alterations in genes that are important for normal development. BCAS3 (Breast Cancer Amplified Sequence 3 is a gene of unknown function on human chromosome 17q23, a region associated with breakpoints of several neoplasms. The normal expression pattern of BCAS3 has not been studied, though it is implicated in breast cancer progression. Rudhira, a murine WD40 domain protein that is 98% identical to BCAS3 is expressed in embryonic stem (ES cells, erythropoiesis and angiogenesis. This suggests that BCAS3 expression also may not be restricted to mammary tissue and may have important roles in other normal as well as malignant tissues. We show that BCAS3 is also expressed in human ES cells and during their differentiation into blood vascular precursors. We find that BCAS3 is aberrantly expressed in malignant human brain lesions. In glioblastoma, hemangiopericytoma and brain abscess we note high levels of BCAS3 expression in tumor cells and some blood vessels. BCAS3 may be associated with multiple cancerous and rapidly proliferating cells and hence the expression, function and regulation of this gene merits further investigation. We suggest that BCAS3 is mis-expressed in brain tumors and could serve as a human ES cell and tumor marker.

  1. Vascular endothelial growth factor induced angiogenesis following focal cerebral ischemia/reperfusion injury in rabbits

    Institute of Scientific and Technical Information of China (English)

    Huaijun Liu; Jiping Yang; Fenghai Liu; Qiang Zhang; Hui Li

    2006-01-01

    BACKGROUND: Therapeutic angiogenesis has opened up new pathway for the treatment of ischemic cerebrovascular disease in recent years. The exploration of the effect of vascular endothelial growth factor (VEGF) on inducing angiogenesis following ischemia/reperfusion injury can provide better help for the long-term treatment of cerebrovascular disease in clinic.OBJECTIVE: To observe the effect of VEGF on inducing angiogenesis following focal cerebral ischemia/reperfusion injury in rabbits through the angiogenesis of microvessels reflected by the expression of the factors of vascular pseudohemophilia.DESIGN: A randomized controlled animal trial.SETTING: Department of Medical Imaging, Second Hospital of Hebei Medical University.MATERIALS: Sixty-five healthy male New Zealand rabbits of clean degree, weighing (2.6±0.2) kg, aged4.5-5 months, were used. The polyclonal antibody against vascular pseudohemophilia (Beijing Zhongshan Company), recombinant VEGF165 (Peprotech Company, USA), biotinylated second antibody and ABC compound (Wuhan Boster Company) were applied.METHODS: The experiments were carried out in the Laboratory of Neuromolecular Imaging and Neuropathy,Second Hospital of Hebei Medical University from May to August in 2005. ① The rabbits were randomly divided into three groups: sham-operated group (n=15), control group (n=25) and VEGF-treated group(n=25). In the control group and VEGF-treated group, models were established by middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia/reperfusion. In the VEGF-treated group, VEGF165(2.5 mg/L) was stereotactically injected into the surrounding regions of the infarcted sites immediately after the 2-hour ischemia/reperfusion; Saline of the same dosage was injected in the control group. But the rabobserved on the 3rd, 7th, 14th, 28th and 70th days of the experiment respectively, 3 rabbits in the sham-operated group and 5 in the control group and VEGF-treated group were observed at each time point. The

  2. Co-option of pre-existing vascular beds in adipose tissue controls tumor growth rates and angiogenesis.

    Science.gov (United States)

    Lim, Sharon; Hosaka, Kayoko; Nakamura, Masaki; Cao, Yihai

    2016-06-21

    Many types of cancer develop in close association with highly vascularized adipose tissues. However, the role of adipose pre-existing vascular beds on tumor growth and angiogenesis is unknown. Here we report that pre-existing microvascular density in tissues where tumors originate is a crucial determinant for tumor growth and neovascularization. In three independent tumor types including breast cancer, melanoma, and fibrosarcoma, inoculation of tumor cells in the subcutaneous tissue, white adipose tissue (WAT), and brown adipose tissue (BAT) resulted in markedly differential tumor growth rates and angiogenesis, which were in concordance with the degree of pre-existing vascularization in these tissues. Relative to subcutaneous tumors, WAT and BAT tumors grew at accelerated rates along with improved neovascularization, blood perfusion, and decreased hypoxia. Tumor cells implanted in adipose tissues contained leaky microvessel with poor perivascular cell coverage. Thus, adipose vasculature predetermines the tumor microenvironment that eventually supports tumor growth.

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

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    Chen, Pei-Lin, E-mail: pchen@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Easton, Alexander S., E-mail: alexander.easton@dal.ca [Department of Pathology, Dalhousie University, Halifax, Nova Scotia (Canada); Department of Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia (Canada); Division of Neurosurgery, Department of Surgery, Dalhousie University, Halifax, Nova Scotia (Canada)

    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{sup -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.

  4. Low Concentration of S100A8/9 Promotes Angiogenesis-Related Activity of Vascular Endothelial Cells: Bridges among Inflammation, Angiogenesis, and Tumorigenesis?

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    Changyou Li

    2012-01-01

    Full Text Available Previous studies showed that several members of the S100A family are involved in neovascularization and tumor development. This study checked whether low concentrations of S100A8 or S100A9 has any effect on the behaviour of vascular endothelial cells. A human umbilical vascular endothelial cell (HUVEC line was used to measure vascular endothelial cell bioactivity related to angiogenesis, such as cell proliferation, migration, and vessel formation. In the low concentration range up to 10 μg/mL, either each alone or in combination, S100A8 and S100A9 proteins promoted proliferation of HUVEC cells in a dose-dependent manner. The presence of both proteins in culture showed additive effects over each single protein. Both proteins enhanced HUVEC cells to migrate across the transwell membrane and to form tube-like structures on the Matrigel surface. When mixed in Matrigel and injected subcutaneously in Balb/c mice, both proteins increased vessel development in the gel plugs. Microarray assay of HUVEC cells treated with 10 μg/mL S100A8 revealed that ribosome pathway, pathogenic Escherichia coli infection pathway, apoptosis, and stress response genes were modulated by S100A8 treatment. We propose that S100A8 and S100A9 proteins from either infiltrating inflammatory cells or tumor cells play an important role in the interplay among inflammation, angiogenesis, and tumorigenesis.

  5. REGULATING EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND ANGⅡ ON FROG'S PERICARDIAL STOMATA, MESOTHELIUM AND ANGIOGENESIS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To observe the regulating effects of vascular endothelial growth factor (VEGF) and angiotensinⅡ (ANG II) on the frog's pericardium, lymphatic stomata and angiogenesis so as to reveal their effects and mechanism on the mesothelial permeability, lymphatic stoma regulation and myocardial hypertrophy. Methods. VEGF and ANGⅡ were injected into the frog's peritoneal cavity so as to examine the changes of the pericardial stromata by using transmission electron microscopy, scanning electron microscopy and computerized imaging analysis. Results. Scattered distributed pericardial stomata were found on the parietal pericardium of the frog with a few sinusoid mesothelial cells, whose blood supply was directly from the cardiac chambers flowing into the trabecular spaces of the myocardium (because there are no blood vessels in the myocardium of the frog). The average diameters of the pericardial stomata in VEGF and ANGⅡ groups were 1.50 μ m and 1.79 μ m respectively, which were much larger than those in the control group (0.72 μ m, P< 0.01); the average distribution densities of the stomata were 8.25/0.1 mm2 and 12.80/0.1 mm2 in VEGF and ANGⅡ groups, which were also much higher than those in the control group (3.57/0.1 mm2, P< 0.01); the sinusoid areas in VEGF and ANGⅡ groups were 2442.95 μ m2/0.1 mm2 and 2121.79 μ m2/0.1 mm2, which were larger than that in the control group (995.08 μ m2 /0.1 mm2 , P< 0.01); no angiogenesis was found in the frogs of the experimental groups. Conclusions. VEGF and ANGⅡ could strongly regulate the pericardial stomata by increasing their numbers and openings with larger diameters and higher distribution density. They could also increase the sinusoid areas with the result of the higher permeability of the pericardium, which clearly indicated that VEGF and ANGⅡ could speed up the material transfer of the pericardial cavity and play an important role in preventing myocardial interstitial edema. Yet there was no strong

  6. CCL5/CCR5 axis induces vascular endothelial growth factor-mediated tumor angiogenesis in human osteosarcoma microenvironment.

    Science.gov (United States)

    Wang, Shih-Wei; Liu, Shih-Chia; Sun, Hui-Lung; Huang, Te-Yang; Chan, Chia-Han; Yang, Chen-Yu; Yeh, Hung-I; Huang, Yuan-Li; Chou, Wen-Yi; Lin, Yu-Min; Tang, Chih-Hsin

    2015-01-01

    Chemokines modulate angiogenesis and metastasis that dictate cancer development in tumor microenvironment. Osteosarcoma is the most frequent bone tumor and is characterized by a high metastatic potential. Chemokine CCL5 (previously called RANTES) has been reported to facilitate tumor progression and metastasis. However, the crosstalk between chemokine CCL5 and vascular endothelial growth factor (VEGF) as well as tumor angiogenesis in human osteosarcoma microenvironment has not been well explored. In this study, we found that CCL5 increased VEGF expression and production in human osteosarcoma cells. The conditioned medium (CM) from CCL5-treated osteosarcoma cells significantly induced tube formation and migration of human endothelial progenitor cells. Pretreatment of cells with CCR5 antibody or transfection with CCR5 specific siRNA blocked CCL5-induced VEGF expression and angiogenesis. CCL5/CCR5 axis demonstrably activated protein kinase Cδ (PKCδ), c-Src and hypoxia-inducible factor-1 alpha (HIF-1α) signaling cascades to induce VEGF-dependent angiogenesis. Furthermore, knockdown of CCL5 suppressed VEGF expression and attenuated osteosarcoma CM-induced angiogenesis in vitro and in vivo. CCL5 knockdown dramatically abolished tumor growth and angiogenesis in the osteosarcoma xenograft animal model. Importantly, we demonstrated that the expression of CCL5 and VEGF were correlated with tumor stage according the immunohistochemistry analysis of human osteosarcoma tissues. Taken together, our findings provide evidence that CCL5/CCR5 axis promotes VEGF-dependent tumor angiogenesis in human osteosarcoma microenvironment through PKCδ/c-Src/HIF-1α signaling pathway. CCL5 may represent a potential therapeutic target against human osteosarcoma.

  7. FGFR3 promotes angiogenesis-dependent metastasis of hepatocellular carcinoma via facilitating MCP-1-mediated vascular formation.

    Science.gov (United States)

    Liu, Xinyu; Jing, Xiaoqian; Cheng, Xi; Ma, Ding; Jin, Zhijian; Yang, Weiping; Qiu, Weihua

    2016-05-01

    The biological role of fibroblast growth factor receptor 3 (FGFR3) in tumor angiogenesis of hepatocellular carcinoma (HCC) has not been discussed before. Our previous work had indicated FGFR3 was overexpressed in HCC, and silencing FGFR3 in Hu7 cells could regulate tumorigenesis via down-regulating the phosphorylation level of key members of classic signaling pathways including ERK and AKT. In the present work, we explored the role of FGFR3 in angiogenesis-dependent metastasis by using SMMC-7721 and QGY-7703 stable cell lines. Our results indicated FGFR3 could regulate in vitro cell migration ability and in vivo lung metastasis ability of HCC, which was in accordance with increased angiogenesis ability in vitro and in vivo. Using the supernatant from SMMC-7721/FGFR3 cells, we conducted a human angiogenesis protein microarray including 43 angiogenesis factors and found that FGFR3 modulated angiogenesis and metastasis of HCC mainly by promoting the protein level of monocyte chemotactic protein 1 (MCP-1). Silencing FGFR3 by short hairpin RNA (shRNA) could reduce MCP-1 level in lysates and supernatant of QGY-7703 cells and SMMC-7721 cells. Silencing MCP-1 in QGY-7703 or SMMC-7721 cells could induce similar phenotypes compared with silencing FGFR3. Our results suggested FGFR3 promoted metastasis potential of HCC, at least partially if not all, via facilitating MCP-1-mediated angiogenesis, in addition to previously found cell growth and metastasis. MCP-1, a key medium between HCC cells and HUVECs, might be a novel anti-vascular target in HCC.

  8. Expression and Purification of Functional Human Vascular Endothelial Growth Factor-A121; the Most Important Angiogenesis Factor

    Directory of Open Access Journals (Sweden)

    Fatemeh Kazemi-Lomedasht

    2014-12-01

    Full Text Available Purpose: Angiogenesis or formation of new blood vessels is an essential process for tumor growth, invasion and metastasis. Vascular Endothelial Growth Factor (VEGF and its receptors play an important role in angiogenesis-dependent tumors. VEGF-A is the most important factor in angiogenesis process. Human VEGF-A gene consists of eight exons that undergoes alternative exon splicing and produce five different proteins consisting of 121, 145, 165, 189 and 206 amino acids (named VEGF121, VEGF145, VEGF165, VEGF189, and VEGF206. Methods: In this study, VEGF121 gene synthesized and cloned into the pET-26b plasmid. The recombinant plasmid was transferred into appropriate expression strain of BL-21. Expression of VEGF121 induced by IPTG (Isopropyl β-D-1-thiogalactopyranoside and confirmed by SDS-PAGE and Western-Blotting. Recombinant VEGF121 was purified by nickel affinity chromatography. HUVECs (Human Umbilical Vein Endothelia Cells cells were isolated from umbilical vein and the effect of VEGF121 on tube formation of endothelial cells was investigated. Results: SDS-PAGE and Western-Blotting results verified the purification of VEGF121. The final yield of recombinant protein was about 5mg per liter. Endothelial cell tube formation assay results showed that VEGF121 leads to tube formation of endothelial cell on matrix and induces angiogenesis in vitro. Conclusion: Recombinant VEGF121 is important factor in tube formation of endothelial cell, so it could be used in different cancer researches and angiogenesis assay.

  9. Vascular Basement Membrane-derived Multifunctional Peptide, a Novel Inhibitor of Angiogenesis and Tumor Growth

    Institute of Scientific and Technical Information of China (English)

    Jian-Guo CAO; Shu-Ping PENG; Li SUN; Hui LI; Li WANG; Han-Wu DENG

    2006-01-01

    Vascular basement membrane-derived multifunctional peptide (VBMDMP) gene (fusion gene of the human immunoglobulin G3 upper hinge region and two tumstatin-derived fragments) obtained by chemical synthesis was cloned into vector pUC 19, and introduced into the expression vector pGEX-4T-1 to construct a prokaryotic expression vector pGEX-4T-1-VBMDMP. Recombinant VBMDMP produced in Escherichia coli has been shown to have significant activity of antitumor growth and antimetastasis in Lewis lung carcinoma transplanted into mouse C57B1/6. In the present study, we have studied the ability of rVBMDMP to inhibit endothelial cell tube formation and proliferation, to induce apoptosis in vitro, and to suppress tumor growth in vivo. The experimental results showed that rVBMDMP potently inhibited proliferation of human endothelial (HUVEC-12) cells and human colon cancer (SW480) cells in vitro, with no inhibition of proliferation in Chinese hamster ovary (CHO-K1) cells. rVBMDMP also significantly inhibited human endothelial cell tube formation and suppressed tumor growth of SW480 cells in a mouse xenograft model. These results suggest that rVBMDMP is a powerful therapeutic agent for suppressing angiogenesis and tumor growth.

  10. alphaB-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis.

    Science.gov (United States)

    Dimberg, Anna; Rylova, Svetlana; Dieterich, Lothar C; Olsson, Anna-Karin; Schiller, Petter; Wikner, Charlotte; Bohman, Svante; Botling, Johan; Lukinius, Agneta; Wawrousek, Eric F; Claesson-Welsh, Lena

    2008-02-15

    Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alphaB-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alphaB-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alphaB-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alphaB-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alphaB-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alphaB-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of angiogenic modulators.

  11. Hyperosmotic stimulus induces reversible angiogenesis within the hypothalamic magnocellular nuclei of the adult rat: a potential role for neuronal vascular endothelial growth factor

    Directory of Open Access Journals (Sweden)

    Vincent Anne

    2005-03-01

    Full Text Available Abstract Background In mammals, the CNS vasculature is established during the postnatal period via active angiogenesis, providing different brain regions with capillary networks of various densities that locally supply adapted metabolic support to neurons. Thereafter this vasculature remains essentially quiescent excepted for specific pathologies. In the adult rat hypothalamus, a particularly dense network of capillary vessels is associated with the supraoptic (SON and paraventricular (PVN nuclei containing the magnocellular neurons secreting vasopressin and oxytocin, two neurohormones involved in the control of the body fluid homoeostasis. In the seventies, it was reported that proliferation of astrocytes and endothelial cells occurs within these hypothalamic nuclei when strong metabolic activation of the vasopressinergic and oxytocinergic neurons was induced by prolonged hyperosmotic stimulation. The aim of the present study was to determine whether such proliferative response to osmotic stimulus is related to local angiogenesis and to elucidate the cellular and molecular mechanisms involved. Results Our results provide evidence that cell proliferation occurring within the SON of osmotically stimulated adult rats corresponds to local angiogenesis. We show that 1 a large majority of the SON proliferative cells is associated with capillary vessels, 2 this proliferative response correlates with a progressive increase in density of the capillary network within the nucleus, and 3 SON capillary vessels exhibit an increased expression of nestin and vimentin, two markers of newly formed vessels. Contrasting with most adult CNS neurons, hypothalamic magnocellular neurons were found to express vascular endothelial growth factor (VEGF, a potent angiogenic factor whose production was increased by osmotic stimulus. When VEGF was inhibited by dexamethasone treatment or by the local application of a blocking antibody, the angiogenic response was strongly

  12. Proliferation, angiogenesis and differentiation related markers in compact and follicular-compact thyroid carcinomas in dogs

    Science.gov (United States)

    Pessina, P.; Castillo, V.A.; César, D.; Sartore, I.; Meikle, A.

    2016-01-01

    Immunohistochemical markers (IGF-1, IGF-1R, VEGF, FGF-2, RARα and RXR) were evaluated in healthy canine thyroid glands (n=8) and in follicular-compact (n=8) and compact thyroid carcinomas (n=8). IGF-1, IGF-1R and VEGF expression was higher in fibroblasts and endothelial cells of compact carcinoma than in healthy glands (P < 0.05). Compared to follicular-compact carcinoma, compact carcinoma had higher IGF-1R expression in fibroblasts, and higher FGF-2 expression in endothelial cells (P < 0.05). RARα expression was higher in endothelial cells of compact carcinoma than in those of other groups (P < 0.05). The upregulation of these proliferation- and angiogenesis-related factors in endothelial cells and/or fibroblasts and not in follicular cells of compact carcinoma compared to healthy glands supports the relevance of stromal cells in cancer progression. PMID:28116249

  13. Total saponins from Albizia julibrissin inhibit vascular endothelial growth factor-mediated angiogenesis in vitro and in vivo.

    Science.gov (United States)

    Cai, Weiwei; Li, Yue; Yi, Qingqing; Xie, Fengshan; Du, Bin; Feng, Lei; Qiu, Liying

    2015-05-01

    Dried stem bark from Albizia julibrissin (AJ) is a highly valued Traditional Chinese Medicine, which has been shown to suppress tumor growth and angiogenesis. Total saponins from AJ (TSAJ) are one of the most bioactive components of AJ extract. The present study evaluated the anti‑tumor and anti‑angiogenic effects of TSAJ in vitro and in vivo. The anti‑angiogenic activity of TSAJ was investigated by measuring the effects on vascular endothelial growth factor (VEGF)‑induced proliferation, migration and tube formation of Ea.hy926 endothelial cells in vitro. The expression levels of proteins associated with VEGF‑induced angiogenesis were determined by western blotting. Furthermore, in vivo Matrigel™ plug and H22 hepatoma tumor models were used to verify the anti‑angiogenic effects of TSAJ. The present study demonstrated that TSAJ significantly inhibited VEGF‑mediated endothelial cell proliferation, migration and tube formation of Ea.hy926 cells in vitro. The anti‑angiogenic effects of TSAJ were modulated by suppression of phosphorylated‑(p‑) focal adhesion kinase, p‑Akt, and p‑extracellular signal‑regulated kinase in the VEGF/VEGF receptor 2 (R2) signaling pathway. Furthermore, oral administration of TSAJ significantly inhibited tumor growth and tumor‑induced angiogenesis, as well as the formation of functional vessels, in the Matrigel™ plug model. These results suggest that TSAJ may be a potential anti‑angiogenic agent that targets the VEGF/VEGFR2 signaling pathway, and inhibits tumor‑induced angiogenesis.

  14. Fucoidan reduces secretion and expression of vascular endothelial growth factor in the retinal pigment epithelium and reduces angiogenesis in vitro.

    Directory of Open Access Journals (Sweden)

    Michaela Dithmer

    Full Text Available Fucoidan is a polysaccharide isolated from brown algae which is of current interest for anti-tumor therapy. In this study, we investigated the effect of fucoidan on the retinal pigment epithelium (RPE, looking at physiology, vascular endothelial growth factor (VEGF secretion, and angiogenesis, thus investigating a potential use of fucoidan for the treatment of exudative age-related macular degeneration. For this study, human RPE cell line ARPE-19 and primary porcine RPE cells were used, as well as RPE/choroid perfusion organ cultures. The effect of fucoidan on RPE cells was investigated with methyl thiazolyl tetrazolium--assay, trypan blue exclusion assay, phagocytosis assay and a wound healing assay. VEGF expression was evaluated in immunocytochemistry and Western blot, VEGF secretion was evaluated in ELISA. The effect of fucoidan on angiogenesis was tested in a Matrigel assay using calcein-AM vital staining, evaluated by confocal laser scanning microcopy and quantitative image analysis. Fucoidan displays no toxicity and does not diminish proliferation or phagocytosis, but reduces wound healing in RPE cells. Fucoidan decreases VEGF secretion in RPE/choroid explants and RPE cells. Furthermore, it diminishes VEGF expression in RPE cells even when co-applied with bevacizumab. Furthermore, fucoidan reduces RPE-supernatant- and VEGF-induced angiogenesis of peripheral endothelial cells. In conclusion, fucoidan is a non-toxic agent that reduces VEGF expression and angiogenesis in vitro and may be of interest for further studies as a potential therapy against exudative age-related macular degeneration.

  15. Detection of the Hematopoietic Stem and Progenitor Cell Marker CD133 during Angiogenesis in Three-Dimensional Collagen Gel Culture

    Directory of Open Access Journals (Sweden)

    Masumi Akita

    2013-01-01

    Full Text Available We detected the hematopoietic stem and progenitor cell marker CD133 using immunogold labeling during angiogenesis in a three-dimensional collagen gel culture. CD133-positive cells were present in capillary tubes newly formed from aortic explants in vitro. The CD133-positive cell population had the capacity to form capillary tubes. Lovastatin strongly inhibited cell migration from aortic explants and caused the degradation of the capillary tubes. The present study provides insight into the function of CD133 during angiogenesis as well as an explanation for the antiangiogenic effect of statins.

  16. 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....... and there is therefore an increasing need for biomarkers for selection of patients to these therapies. We investigated the expression of EGFR, vascular endothelial growth factor A (VEGF-A), and VEGF receptor 2 (VEGFR-2) in tumour tissue by immunohistochemistry, and soluble EGFR (sEGFR), soluble VEGFR-2 (sVEGFR-2), basic...

  17. Lanthanum prevents high phosphate-induced vascular calcification by preserving vascular smooth muscle lineage markers.

    Science.gov (United States)

    Ciceri, Paola; Elli, Francesca; Brenna, Irene; Volpi, Elisa; Romagnoli, Solange; Tosi, Delfina; Braidotti, Paola; Brancaccio, Diego; Cozzolino, Mario

    2013-06-01

    Vascular calcification (VC) represents a major cardiovascular risk factor in chronic kidney disease patients. High phosphate (Pi) levels are strongly associated with VC in this population. Therefore, Pi binders are commonly used to control high Pi levels. The aim of this work was to study the mechanism of action of lanthanum chloride (LaCl3) on the progression of Pi-induced VC through its direct effect on vascular smooth muscle cells (VSMCs) in vitro. High Pi induced VSCM Ca deposition. We evaluated the action of LaCl3, compared to gadolinium chloride (GdCl3), and found different effects on the modulation of VSMC lineage markers, such as α-actin and SM22α. In fact, only LaCl3 preserved the expression of both VSMC lineage markers compared to high Pi-treated cells. Interestingly, both LaCl3 and GdCl3 reduced the high Pi-induced elevations of bone morphogenic protein 2 mRNA expression, with no reduction of the high core binding factor-alpha 1 mRNA levels observed in calcified VSMCs. Furthermore, we also found that only LaCl3 completely prevented the matrix GLA protein mRNA levels and osteonectin protein expression elevations induced by high Pi compared to GdCl3. Finally, LaCl3, in contrast to GdCl3, prevented the high Pi-induced downregulation of Axl, a membrane tyrosine kinase receptor involved in apoptosis. Thus, our results suggest that LaCl3 prevents VC by preserving VSMC lineage markers and by decreasing high Pi-induced osteoblastic differentiation.

  18. Safety of ranibizumab therapy in wet AMD and the role of vascular endothelial growth factors in physiological angiogenesis.

    Science.gov (United States)

    Figurska, Małgorzata; Robaszkiewicz, Jacek; Wierzbowska, Joanna

    2010-01-01

    Vascular endothelial growth factor - A (VEGF-A), is a major factor implicated in choroidal neovascularisation (CNV) and therefore a target for therapeutic agents in wet age related macular degeneration (AMD). Ranibiuzumab (Lucentis) blocks all active isoforms of VEGF-A and the products of their degradation. It penetrates through all layers of the retina in order to reach the target tissue. It is quickly removed from the system and it is characterised by low level of immunogenicity. The essence of angiogenesis is formation of new vessels by branching and expansion of already existing ones. Angiogenesis is an important physiological process that takes place during the healing of wounds, reconstruction of hypoxic injury and reproduction. However some diseases such as cancer, arthritis, diabetes and neovascular AMD are associated with persistent unregulated angiogenesis. There is an important question whether binding vascular-endothelial growth factors in wet AMD therapies using ranibizumab is correlated with the increase of the incidence of systematic adverse effects (AEs), such as cardiovascular episodes or thrombosis. The aim of this article is to present ranibizumab as a safe drug in treating wet AMD patients. Even though the concentration of Lucentis administered in a dose of 0.3 or 0.5 mg into the vitreous body in the organism is very low, the incidence of AEs during the anti-VEGF therapy was traced. In MARINA and ANCHOR studies, occurrence of possible AEs was observed. No statistically significant differences were shown in the AEs frequency between the patients treated with ranibizumab and the control group, and in correlation with the general population of patients suffering from wet AMD.

  19. Hepatic proliferation and angiogenesis markers are increased after portal deprivation in rats: a study of molecular, histological and radiological changes.

    Directory of Open Access Journals (Sweden)

    Florent Guérin

    Full Text Available To determine the pathogenesis of liver nodules, and lesions similar to obliterative portal venopathy, observed after portosystemic shunts or portal vein thrombosis in humans.We conducted an experimental study comparing portacaval shunt (PCS, total portal vein ligation (PVL, and sham (S operated rats. Each group were either sacrificed at 6 weeks (early or 6 months (late. Arterial liver perfusion was studied in vivo using CT, and histopathological changes were noted. Liver mRNA levels were quantified by RT-QPCR for markers of inflammation (Il10, Tnfa, proliferation (Il6st, Mki67, Hgf, Hnf4a, angiogenesis: (Vegfa, Vegfr 1, 2 and 3; Pgf, oxidative stress (Nos2, and 3, Hif1a, and fibrosis (Tgfb. PCS and PVL were compared to the S group.Periportal fibrosis and arterial proliferation was observed in late PCS and PVL groups. CT imaging demonstrated increased arterial liver perfusion in the PCS group. RT-QPCR showed increased inflammatory markers in PCS and PVL early groups. Tnfa and Il10 were increased in PCS and PVL late groups respectively. All proliferative markers increased in the PCS, and Hnf4a in the PVL early groups. Mki67 and Hnf4a were increased in the PCS late group. Nos3 was increased in the early and late PCS groups, and Hif1a was decreased in the PVL groups. Markers of angiogenesis were all increased in the early PCS group, and Vegfr3 and Pgf in the late PCS group. Only Vegfr3 was increased in the PVL groups. Tgf was increased in the PCS groups.Portal deprivation in rats induces a sustained increase in intrahepatic markers of inflammation, angiogenesis, proliferation, and fibrosis.

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

    Science.gov (United States)

    2007-02-01

    Progenitor Cells for Cardiovascular Tissue-Engineering Juan Melero-Martin, Seminar, Centro Andaluz de Biologia Molecular y Medicina Regenerativa...homepage: http://www.blah.net Access to this links box is available online. Figure 1| Key steps in tumour angiogenesis. Angiopoietin-1, expressed by

  1. Ultrasound Molecular Imaging of Angiogenesis Using Vascular Endothelial Growth Factor-Conjugated Microbubbles

    Science.gov (United States)

    Wang, Jianjun; Qin, Bin; Chen, Xucai; Wagner, William R.; Villanueva, Flordeliza S.

    2017-01-01

    Imaging of angiogenesis receptors could provide a sensitive and clinically useful method for detecting neovascularization such as occurs in malignant tumors, and responses to anti-angiogenic therapies for such tumors. We tested the hypothesis that microbubbles (MB) tagged with human VEGF121 (MBVEGF) bind to the kinase insert domain receptor (KDR) in vitro and angiogenic endothelium in vivo, and that this specific binding can be imaged on a clinical ultrasound system. In this work, targeted adhesion of MBVEGF was evaluated in vitro using a parallel plate flow system containing adsorbed recombinant human KDR. There was more adhesion of MBVEGF to KDR-coated plates when the amount of VEGF121 on each MB or KDR density on the plate was increased. MBVEGF adhesion to KDR-coated plates decreased with increasing wall shear rate. On intravital microscopic imaging of bFGF-stimulated rat cremaster muscle, there was greater microvascular adhesion of MBVEGF compared to that of isotype IgG-conjugated control MB (MBCTL). To determine if MBVEGF could be used to ultrasonically image angiogenesis, ultrasound imaging was performed in mice bearing squamous cell carcinoma after intravenous injection of MBVEGF. Ultrasound videointensity enhancement in tumor was significantly higher for MBVEGF (17.3±9.7 dB) compared to MBCTL (3.8±4.4 dB, n=6, ptumor angiogenesis and could be extended to other applications such as molecular monitoring of therapeutic angiogenesis or anti-angiogenic therapies in cardiovascular disease or cancer. PMID:28165246

  2. Vascular Endothelial Growth Factor (VEGF) Bioavailability Regulates Angiogenesis and Intestinal Stem and Progenitor Cell Proliferation during Postnatal Small Intestinal Development

    Science.gov (United States)

    Holoyda, Kathleen A.; Hou, Xiaogang; Fowler, Kathryn L.; Grikscheit, Tracy C.

    2016-01-01

    Background Vascular endothelial growth factor (VEGF) is a highly conserved, master regulatory molecule required for endothelial cell proliferation, organization, migration and branching morphogenesis. Podocoryne carnea and drosophila, which lack endothelial cells and a vascular system, express VEGF homologs, indicating potential roles beyond angiogenesis and vasculogenesis. The role of VEGF in the development and homeostasis of the postnatal small intestine is unknown. We hypothesized regulating VEGF bioavailability in the postnatal small intestine would exhibit effects beyond the vasculature and influence epithelial cell stem/progenitor populations. Methods VEGF mutant mice were created that overexpressed VEGF in the brush border of epithelium via the villin promotor following doxycycline treatment. To decrease VEGF bioavailability, sFlt-1 mutant mice were generated that overexpressed the soluble VEGF receptor sFlt-1 upon doxycycline administration in the intestinal epithelium. Mice were analyzed after 21 days of doxycycline administration. Results Increased VEGF expression was confirmed by RT-qPCR and ELISA in the intestine of the VEGF mutants compared to littermates. The VEGF mutant duodenum demonstrated increased angiogenesis and vascular leak as compared to littermate controls. The VEGF mutant duodenum revealed taller villi and increased Ki-67-positive cells in the transit-amplifying zone with reduced Lgr5 expression. The duodenum of sFlt-1 mutants revealed shorter villi and longer crypts with reduced proliferation in the transit-amplifying zone, reduced expression of Dll1, Bmp4 and VE-cadherin, and increased expression of Sox9 and EphB2. Conclusions Manipulating VEGF bioavailability leads to profound effects on not only the intestinal vasculature, but epithelial stem and progenitor cells in the intestinal crypt. Elucidation of the crosstalk between VEGF signaling in the vasculature, mesenchyme and epithelial stem/progenitor cell populations may direct future

  3. 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...... and GEJ cancer. We found expression in tumour tissue and the plasma levels to be similar to those found in patients with other tumour types. No correlation was found between the blood levels of soluble receptors and the corresponding tumour tissue levels. We conclude that these markers are present...... in pancreatic and GEJ cancer patients, and could be investigated further as predictive biomarkers in such patients treated with EGFR or angiogenesis targeted therapies....

  4. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    OpenAIRE

    Laila C. Roudsari; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-01-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted...

  5. [Genetic engineering technologies of stimulating angiogenesis as an innovation trend in angiology and vascular surgery].

    Science.gov (United States)

    Gavrilenko, A V; Voronov, D A

    2015-01-01

    Presented herein is a review of the principles, fundamental concepts, and possibilities of genetic engineering technologies of stimulating angiogenesis for treatment of patients with lower limb chronic ischaemia. This is followed by a detailed discussion of the structure and results of Russian and foreign studies on this direction, also considering the causes of differences of their results. Outlined is a circle of clinical situations in relation to which these technologies may be regarded as most promising.

  6. Two Dimensional Mathematical Model of Tumor Angiogenesis: Coupling of Avascular Growth and Vascularization

    Directory of Open Access Journals (Sweden)

    Farideh Hosseini

    2015-09-01

    Full Text Available Introduction As a tumor grows, the demand for oxygen and nutrients increases and it grows further if acquires the ability to induce angiogenesis. In this study, we aimed to present a two-dimensional continuous mathematical model for avascular tumor growth, coupled with a discrete model of angiogenesis. Materials and Methods In the avascular growth model, tumor is considered as a single mass, which uptakes oxygen through diffusion and invades the extracellular matrix (ECM. After the tumor reaches its maximum size in the avascular growth phase, tumor cells may be in three different states (proliferative, quiescent and apoptotic, depending on oxygen availability. Quiescent cells are assumed to secrete tumor angiogenic factors, which diffuse into the surrounding tissue until reaching endothelial cells. The mathematical model for tumor angiogenesis is consisted of a five-point finite difference scheme to simulate the progression of endothelial cells in ECM and their penetration into the tumor. Results The morphology of produced networks was investigated, based on various ECM degradation patterns. The generated capillary networks involved the rules of microvascular branching and anastomosis. Model predictions were in qualitative agreement with experimental observations and might have implications as a supplementary model to facilitate mathematical analyses for anti-cancer therapies. Conclusion Our numerical simulations could facilitate the qualitative comparison between three layers of tumor cells, their TAF-producing abilities and subsequent penetration of micro-vessels in order to determine the dynamics of microvascular branching and anastomosis in ECM and three different parts of the tumor.

  7. NITRIC OXIDE SYNTHASE AND VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION IN HEPATOCELLULAR CARCINOMA AND THE CORRELATION WITH ANGIOGENESIS

    Institute of Scientific and Technical Information of China (English)

    王鲁; 汤钊猷; 孙惠川; 叶胜龙; 纪元; 陆洪芬; 施达仁

    2001-01-01

    Objective: To analyze the expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC) and its relation to angiogenesis. Methods: Tissue sections from 71 HCC patients were examined immunohistochemically for protein expression of iNOS, eNOS, and VEGF. Microvessal density (MVD) was counted by endothelial cells immunostained by anti-CD34 antibody. Results: Positive immunostaining for iNOS, eNOS was detected in 83.1% and 85.9% of HCC respectively. INOS and eNOS were not detected in normal hepatic tissue. MVD was 34.3±1.5/HP and 38.6±1.6/HP in HCC with positive staining for iNOS and VEGF while it was 31.2± 2.8/HP, and 22.4± 2.0/HP in HCC with negative staining for iNOS and VEGF (P<0.01). A correlation between NOS expression and VEGF in HCC was not observed. Conclusion: iNOS and eNOS may play a role in malignant transformation f post-hepatic cirrhosis. The expression of iNOS and VEGF favors angiogenesis of HCC.

  8. Perlecan and vascular endothelial growth factor-encoding DNA-loaded chitosan scaffolds promote angiogenesis and wound healing.

    Science.gov (United States)

    Lord, Megan S; Ellis, April L; Farrugia, Brooke L; Whitelock, John M; Grenett, Hernan; Li, Chuanyu; O'Grady, Robert L; DeCarlo, Arthur A

    2017-03-28

    The repair of dermal wounds, particularly in the diabetic population, poses a significant healthcare burden. The impaired wound healing of diabetic wounds is attributed to low levels of endogenous growth factors, including vascular endothelial growth factor (VEGF), that normally stimulate multiple phases of wound healing. In this study, chitosan scaffolds were prepared via freeze drying and loaded with plasmid DNA encoding perlecan domain I and VEGF189 and analyzed in vivo for their ability to promote dermal wound healing. The plasmid DNA encoding perlecan domain I and VEGF189 loaded scaffolds promoted dermal wound healing in normal and diabetic rats. This treatment resulted in an increase in the number of blood vessels and sub-epithelial connective tissue matrix components within the wound beds compared to wounds treated with chitosan scaffolds containing control DNA or wounded controls. These results suggest that chitosan scaffolds containing plasmid DNA encoding VEGF189 and perlecan domain I have the potential to induce angiogenesis and wound healing.

  9. PLVAP in diabetic retinopathy: A gatekeeper of angiogenesis and vascular permeability

    NARCIS (Netherlands)

    Wiśniewska-Kruk, J.

    2014-01-01

    Nowadays, approximately 4 million people worldwide experience blindness or severe vision loss caused by diabetic retinopathy. Diabetic retinopathy is a multifactorial disease that can progress from minor changes in vascular permeability, into a proliferative retinal disorder. The increasing incidenc

  10. A 3D Poly(ethylene glycol)-based Tumor Angiogenesis Model to Study the Influence of Vascular Cells on Lung Tumor Cell Behavior

    Science.gov (United States)

    Roudsari, Laila C.; Jeffs, Sydney E.; Witt, Amber S.; Gill, Bartley J.; West, Jennifer L.

    2016-09-01

    Tumor angiogenesis is critical to tumor growth and metastasis, yet much is unknown about the role vascular cells play in the tumor microenvironment. In vitro models that mimic in vivo tumor neovascularization facilitate exploration of this role. Here we investigated lung adenocarcinoma cancer cells (344SQ) and endothelial and pericyte vascular cells encapsulated in cell-adhesive, proteolytically-degradable poly(ethylene) glycol-based hydrogels. 344SQ in hydrogels formed spheroids and secreted proangiogenic growth factors that significantly increased with exposure to transforming growth factor beta 1 (TGF-β1), a potent tumor progression-promoting factor. Vascular cells in hydrogels formed tubule networks with localized activated TGF-β1. To study cancer cell-vascular cell interactions, we engineered a 2-layer hydrogel with 344SQ and vascular cell layers. Large, invasive 344SQ clusters (area > 5,000 μm2, circularity culture system as a platform for studying tumor vascularization.

  11. Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy

    DEFF Research Database (Denmark)

    Olsen, M H; Christensen, M K; Wachtell, K

    2005-01-01

    Cardiac fibrosis and high levels of circulating collagen markers has been associated with left ventricular (LV) hypertrophy. However, the relationship to vascular hypertrophy and blood pressure (BP) load is unclear. In 204 patients with essential hypertension and electrocardiographic LV hypertrophy...

  12. Effect of high glucose and anoxia on Amot expression in vascular endothelial cells with regard to its function in promoting angiogenesis

    Institute of Scientific and Technical Information of China (English)

    禇月颉

    2014-01-01

    Objective To observe the effects of high glucose and anoxia on Amot expression in vascular endothelial cells(VECs),and explore its role in angiogenesis.Methods VECs were incubated with different glucose concentrations for 48 h,and then cultured at normal oxygen concentration or anaerobic condition for 24 h.The protein expressions of p130-Amot and p80-Amot were detected by Western blot.After Amot expression was downregulated in VECs by siRNA,wound healing experiments and angiogenesis experiments were performed to test the effect

  13. Expression of vascular cell adhesion molecule-1 facilitates angiogenesis in gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Yongbin Ding; Tianson Xia; Guoyu Chen; Jianguo Xia

    2006-01-01

    Objective: To investigate the relationship between the expression of VCAM-1 and oncogenesis, tumor angiogenesis and metastasis in gastric carcinoma. Methods: Using RT-PCR and immunohistochemistry technique, the expression of VCAM-1 were detected in specimens from 44 patients with gastric cancer, 8 with ulcer. Microvessel density (MVD) was also counted by endothelial cells immunostained with monoclonal antibodies CD34. In addition, Circulating sVCAM-1 concentrations were measured by an enzyme linked immunosorbent assay. Results:Of 44 gastric cancer tumor tissues, 36were detected the ex pressions of VCAM-1 mRNA. The rates of VCAM-1 mRNA in the primary gastric cancer tissues were significantly higher than those in the para-cancerous tissues and benign ulcer tissues (P < 0.05). The VCAM-1 posithoseive isolates had more lymph node metastases than that of VCAM-l-negative ones (P < 0.05). MVD of positive VCAM-1 expression tissues were higher than those of negative VCAM-1 (P < 0.05). Circulating sVCAM-1 levels decreased significantly after operation (P < 0.05). Furthermore, the levels of sVCAM-1 were positively correlated with the expressions of VCAM-1 in the tumor tissues (r = 0.64, P <0.05). Conclusion: Expressions of VCAM-1 mRNA was closely related to oncogenesis, tumor angiogenesis and metastasis in gastric carcinoma. The concentration of sVCAM-1 may be considered as an effective mark of tumor burden of gastric cancer.

  14. The soluble guanylyl cyclase inhibitor NS-2028 reduces vascular endothelial growth factor-induced angiogenesis and permeability.

    Science.gov (United States)

    Morbidelli, Lucia; Pyriochou, Anastasia; Filippi, Sandra; Vasileiadis, Ioannis; Roussos, Charis; Zhou, Zongmin; Loutrari, Heleni; Waltenberger, Johannes; Stössel, Anne; Giannis, Athanassios; Ziche, Marina; Papapetropoulos, Andreas

    2010-03-01

    Nitric oxide (NO) is known to promote vascular endothelial growth factor (VEGF)-stimulated permeability and angiogenesis. However, effector molecules that operate downstream of NO in this pathway remain poorly characterized. Herein, we determined the effect of soluble guanylyl cyclase (sGC) inhibition on VEGF responses in vitro and in vivo. Treatment of endothelial cells (EC) with VEGF stimulated eNOS phosphorylation and cGMP accumulation; pretreatment with the sGC inhibitor 4H-8-bromo-1,2,4-oxadiazolo(3,4-d)benz(b)(1,4)oxazin-1-one (NS-2028) blunted cGMP levels without affecting VEGF-receptor phosphorylation. Incubation of cells with NS-2028 blocked the mitogenic effects of VEGF. In addition, cells in which sGC was inhibited exhibited no migration and sprouting in response to VEGF. To study the mechanisms through which NS-2028 inhibits EC migration, we determined the effects of alterations in cGMP levels on p38 MAPK. Initially, we observed that inhibition of sGC attenuated VEGF-stimulated activation of p38. In contrast, the addition of 8-Br-cGMP to EC stimulated p38 phosphorylation. The addition of cGMP elevating agents (BAY 41-2272, DETA NO and YC-1) enhanced EC migration. To test whether sGC also mediated the angiogenic effects of VEGF in vivo, we used the rabbit cornea assay. Animals receiving NS-2028 orally displayed a reduced angiogenic response to VEGF. As increased vascular permeability occurs prior to new blood vessel formation, we determined the effect of NS-2028 in vascular leakage. Using a modified Miles assay, we observed that NS-2028 attenuated VEGF-induced permeability. Overall, we provide evidence that sGC mediates the angiogenic and permeability-promoting activities of VEGF, indicating the significance of sGC as a downstream effector of VEGF-triggered responses.

  15. Inhibition of cell proliferation and in vitro markers of angiogenesis by indole-3-carbinol, a major indole metabolite present in cruciferous vegetables.

    Science.gov (United States)

    Wu, Hsiao-Ting; Lin, Shyh-Hsiang; Chen, Yue-Hwa

    2005-06-29

    A variety of studies have suggested a cancer protective role of cruciferous vegetables. In the present study, we investigated the effect of indole-3-carbinol (I3C), a major indole metabolite in cruciferous vegetables, on cell proliferation and in vitro markers of angiogenesis in phorbol myristate acetate (PMA)-stimulated endothelial EA hy926 cells. The results showed that I3C inhibited the growth of EA hy926 cells in a concentration-dependent manner. The capillary-like tube formation by PMA-activated endothelial cells was significantly suppressed by I3C, and such inhibition was associated with decreased vascular endothelial growth factor (VEGF) and increased interleukin-8 (IL-8) secretion, but not with the expression of VEGF receptor-2 protein. Additionally, gelatin zymography analysis indicated that I3C suppressed activities of matrix metalloproteinases-2 (MMP-2) and MMP-9 stimulated by PMA. These results suggest that the dietary I3C may be useful in the treatment of human cancers and angiogenic diseases.

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

    Science.gov (United States)

    2008-04-01

    sufficient for some to drive a car ). In ~90–95% of patients, the disease was arrested, and there was no further loss of sight. By contrast, patients... biopolymer matrices, where functional microvessels were evident 7 to 10 days after implantation into mice.13 Nevertheless, the clinical use of mature ECs...using mature ECs derived from vascular tissue. Both HUVECs and HDMECs, seeded into collagen/ fibronectin gels and biopolymer matrices, respectively, were

  17. Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis.

    Directory of Open Access Journals (Sweden)

    Hung-Yu Yang

    Full Text Available Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX, derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L. Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs. BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.

  18. Anti-cancer activity of an osthole derivative, NBM-T-BMX-OS01: targeting vascular endothelial growth factor receptor signaling and angiogenesis.

    Science.gov (United States)

    Yang, Hung-Yu; Hsu, Ya-Fen; Chiu, Pei-Ting; Ho, Shiau-Jing; Wang, Chi-Han; Chi, Chih-Chin; Huang, Yu-Han; Lee, Cheng-Feng; Li, Ying-Shiuan; Ou, George; Hsu, Ming-Jen

    2013-01-01

    Angiogenesis occurs during tissue growth, development and wound healing. It is also required for tumor progression and represents a rational target for therapeutic intervention. NBM-T-BMX-OS01 (BMX), derived from the semisynthesis of osthole, an active ingredient isolated from Chinese herb Cnidium monnieri (L.) Cuss., was recently shown to enhance learning and memory in rats. In this study, we characterized the anti-angiogenic activities of NBM-T-BMX-OS01 (BMX) in an effort to develop novel inhibitors to suppress angiogenesis and tumor growth. BMX inhibited vascular endothelial growth factor (VEGF)-induced proliferation, migration and endothelial tube formation in human umbilical endothelial cells (HUVECs). BMX also attenuated VEGF-induced microvessel sprouting from aortic rings ex vivo and reduced HCT116 colorectal cancer cells-induced angiogenesis in vivo. Moreover, BMX inhibited the phosphorylation of VEGFR2, FAK, Akt and ERK in HUVECs exposed to VEGF. BMX was also shown to inhibit HCT116 cell proliferation and to suppress the growth of subcutaneous xenografts of HCT116 cells in vivo. Taken together, this study provides evidence that BMX modulates vascular endothelial cell remodeling and leads to the inhibition of tumor angiogenesis. These results also support the role of BMX as a potential drug candidate and warrant the clinical development in the treatment of cancer.

  19. Prostaglandin E2 and vascular endothelial growth factor A mediate angiogenesis of human ovarian follicular endothelial cells

    Science.gov (United States)

    Trau, Heidi A.; Brännström, Mats; Curry, Thomas E.; Duffy, Diane M.

    2016-01-01

    STUDY QUESTION Which receptors for prostaglandin E2 (PGE2) and vascular endothelial growth factor A (VEGFA) mediate angiogenesis in the human follicle around the time of ovulation? SUMMARY ANSWER PGE2 and VEGFA act via multiple PGE2 receptors (PTGERs) and VEGF receptors (VEGFRs) to play complementary roles in follicular angiogenesis. WHAT IS KNOWN ALREADY Production of PGE2 and VEGFA by the follicle are prerequisites for ovulation. PGE2 is an emerging regulator of angiogenesis and has not been examined in the context of the human ovulatory follicle. VEGFA is an established regulator of follicular angiogenesis. STUDY DESIGN, SIZE, DURATION Ovarian biopsies containing the ovulatory follicle were obtained from 11 women of reproductive age (30–45 years) undergoing surgery for laparoscopic sterilization. In some cases, women received hCG to substitute for the ovulatory LH surge before ovarian biopsy. In addition, aspirates from four women of reproductive age (18–31 years) undergoing gonadotrophin stimulation for oocyte donation were obtained for isolation of human ovarian microvascular endothelial cells (hOMECs). PARTICIPANTS/MATERIALS, SETTING, METHODS Ovarian biopsies were utilized for immunocytochemical detection of von Willebrand factor to identify endothelial cells. hOMECs were cultured with PGE2, PTGER receptor selective agonists, VEGFA, or VEGFR selective agonists. hOMECs were assessed for proliferation by Ki67 immunocytochemistry. hOMEC migration was determined by counting cells which migrated through a porous membrane in vitro. Sprout formation was quantified by determining sprout number and length from photographs take after culture of hOMECs in a 3-dimensional matrix. MAIN RESULTS AND THE ROLE OF CHANCE Endothelial cells were not observed within the granulosa cell layer of human ovulatory follicles prior to an ovulatory dose of hCG and were first seen amongst granulosa cells 18–34 h after hCG. In vitro, PGE2 enhanced migration and sprout formation but

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

    Directory of Open Access Journals (Sweden)

    Zhou T

    2016-12-01

    Full Text Available Tian Zhou,1 Qinglei Dong,1 Yang Shen,2 Wei Wu,1 Haide Wu,1 Xianglin Luo,3 Xiaoling Liao,4 Guixue Wang1 1Key Laboratory for Biorheological Science and Technology of Ministry of Education, State and Local Joint Engineering Laboratory for Vascular Implants, Bioengineering College of Chongqing University, Chongqing, 2Institute of Biomedical Engineering, School of Preclinical and Forensic Medicine, Sichuan University, 3College of Polymer Science and Engineering, Sichuan University, Chengdu, Sichuan, 4Chongqing Key Laboratory of Nano/Micro Composite Materials and Devices, School of Metallury and Materials Engineering, Chongqing University of Science and Technology, Chongqing, People’s Republic of China Abstract: 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

  1. Targeting Vascular Endothelial Growth Factor Receptor 2 and Protein Kinase D1 Related Pathways by a Multiple Kinase Inhibitor in Angiogenesis and Inflammation Related Processes In Vitro

    OpenAIRE

    Attila Varga; Pál Gyulavári; Zoltán Greff; Krisztina Futosi; Tamás Németh; Laura Simon-Szabó; Krisztina Kerekes; Csaba Szántai-Kis; Diána Brauswetter; Márton Kokas; Gábor Borbély; Anna Erdei; Attila Mócsai; György Kéri; Tibor Vántus

    2015-01-01

    Emerging evidence suggests that the vascular endothelial growth factor receptor 2 (VEGFR2) and protein kinase D1 (PKD1) signaling axis plays a critical role in normal and pathological angiogenesis and inflammation related processes. Despite all efforts, the currently available therapeutic interventions are limited. Prior studies have also proved that a multiple target inhibitor can be more efficient compared to a single target one. Therefore, development of novel inflammatory pathway-specific...

  2. Low-energy extracorporeal shock wave therapy for promotion of vascular endothelial growth factor expression and angiogenesis and improvement of locomotor and sensory functions after spinal cord injury.

    Science.gov (United States)

    Yahata, Kenichiro; Kanno, Haruo; Ozawa, Hiroshi; Yamaya, Seiji; Tateda, Satoshi; Ito, Kenta; Shimokawa, Hiroaki; Itoi, Eiji

    2016-12-01

    OBJECTIVE Extracorporeal shock wave therapy (ESWT) is widely used to treat various human diseases. Low-energy ESWT increases expression of vascular endothelial growth factor (VEGF) in cultured endothelial cells. The VEGF stimulates not only endothelial cells to promote angiogenesis but also neural cells to induce neuroprotective effects. A previous study by these authors demonstrated that low-energy ESWT promoted expression of VEGF in damaged neural tissue and improved locomotor function after spinal cord injury (SCI). However, the neuroprotective mechanisms in the injured spinal cord produced by low-energy ESWT are still unknown. In the present study, the authors investigated the cell specificity of VEGF expression in injured spinal cords and angiogenesis induced by low-energy ESWT. They also examined the neuroprotective effects of low-energy ESWT on cell death, axonal damage, and white matter sparing as well as the therapeutic effect for improvement of sensory function following SCI. METHODS Adult female Sprague-Dawley rats were divided into the SCI group (SCI only) and SCI-SW group (low-energy ESWT applied after SCI). Thoracic SCI was produced using a New York University Impactor. Low-energy ESWT was applied to the injured spinal cord 3 times a week for 3 weeks after SCI. Locomotor function was evaluated using the Basso, Beattie, and Bresnahan open-field locomotor score for 42 days after SCI. Mechanical and thermal allodynia in the hindpaw were evaluated for 42 days. Double staining for VEGF and various cell-type markers (NeuN, GFAP, and Olig2) was performed at Day 7; TUNEL staining was also performed at Day 7. Immunohistochemical staining for CD31, α-SMA, and 5-HT was performed on spinal cord sections taken 42 days after SCI. Luxol fast blue staining was performed at Day 42. RESULTS Low-energy ESWT significantly improved not only locomotion but also mechanical and thermal allodynia following SCI. In the double staining, expression of VEGF was observed in Neu

  3. Cytotoxicity of VEGF121/rGel on vascular endothelial cells resulting in inhibition of angiogenesis is mediated via VEGFR-2

    Directory of Open Access Journals (Sweden)

    Hittelman Walter N

    2011-08-01

    Full Text Available Abstract Background The fusion protein VEGF121/rGel composed of the growth factor VEGF121 and the plant toxin gelonin targets the tumor neovasculature and exerts impressive anti-vascular effects. We have previously shown that VEGF121/rGel is cytotoxic to endothelial cells overexpressing VEGFR-2 but not to endothelial cells overexpressing VEGFR-1. In this study, we examined the basis for the specific toxicity of this construct and assessed its intracellular effects in vitro and in vivo. Methods We investigated the binding, cytotoxicity and internalization profile of VEGF121/rGel on endothelial cells expressing VEGFR-1 or VEGFR-2, identified its effects on angiogenesis models in vitro and ex vivo, and explored its intracellular effects on a number of molecular pathways using microarray analysis. Results Incubation of PAE/VEGFR-2 and PAE/VEGFR-1 cells with 125I-VEGF121/rGel demonstrated binding specificity that was competed with unlabeled VEGF121/rGel but not with unlabeled gelonin. Assessment of the effect of VEGF121/rGel on blocking tube formation in vitro revealed a 100-fold difference in IC50 levels between PAE/VEGFR-2 (1 nM and PAE/VEGFR-1 (100 nM cells. VEGF121/rGel entered PAE/VEGFR-2 cells within one hour of treatment but was not detected in PAE/VEGFR-1 cells up to 24 hours after treatment. In vascularization studies using chicken chorioallantoic membranes, 1 nM VEGF121/rGel completely inhibited bFGF-stimulated neovascular growth. The cytotoxic effects of VEGF121/rGel were not apoptotic since treated cells were TUNEL-negative with no evidence of PARP cleavage or alteration in the protein levels of select apoptotic markers. Microarray analysis of VEGF121/rGel-treated HUVECs revealed the upregulation of a unique "fingerprint" profile of 22 genes that control cell adhesion, apoptosis, transcription regulation, chemotaxis, and inflammatory response. Conclusions Taken together, these data confirm the selectivity of VEGF121/rGel for VEGFR-2

  4. Eukaryotic Initiation Factor 4E (eIF4E and angiogenesis: prognostic markers for breast cancer

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    Zhou Muxiang

    2006-09-01

    Full Text Available Abstract Background The overexpression of eukaryotic translation initiation factor 4E (eIF4E, a key regulator of protein synthesis, is involved in the malignant progression of human breast cancer. This study investigates the relationship between eIF4E and angiogenesis, as well as their prognostic impact in patients with human breast cancer. Methods Immunohistochemical staining was used to determine protein expression of eIF4E, vascular endothelial growth factor (VEGF, interleukin-8 (IL-8, and CD105 in a set of 122 formalin-fixed, paraffin-embedded primary breast cancer tissues. Expression of eIF4E in positive cells was characterized by cytoplasmic staining. Evaluation of VEGF and IL-8 in the same tissue established the angiogenic profiles, while CD105 was used as an indicator of microvessel density (MVD. Results A significant relationship was found between the level of eIF4E expression and histological grade (P = 0.016. VEGF, IL-8, and MVD were closely related to tumor grade (P = 0.003, P = 0.022, and P P = 0.007, P = 0.048, and P P = 0.007, IL-8 (P = 0.007, and MVD (P = 0.006. Patients overexpressing eIF4E had significantly worse overall (P = 0.01 and disease-free survival (P = 0.006. When eIF4E, histological grade, tumor stage, ER, PR, Her-2 status and the levels of VEGF, IL-8, MVD were included in a multivariate Cox regression analysis, eIF4E emerged as an independent prognostic factor for breast cancer (P = 0.001, along with stage (P = 0.005, node status (P = 0.046, and MVD (P = 0.004. Conclusion These results suggest that higher eIF4E expression correlates with both angiogenesis and vascular invasion of cancer cells, and could therefore serve as a useful histological predictor for less favorable outcome in breast cancer patients, as well as represent a potential therapeutic target.

  5. Body mass and white matter integrity: the influence of vascular and inflammatory markers.

    Directory of Open Access Journals (Sweden)

    Brianne Magouirk Bettcher

    Full Text Available High adiposity is deleteriously associated with brain health, and may disproportionately affect white matter integrity; however, limited information exists regarding the mechanisms underlying the association between body mass (BMI and white matter integrity. The present study evaluated whether vascular and inflammatory markers influence the relationship between BMI and white matter in healthy aging. We conducted a cross-sectional evaluation of white matter integrity, BMI, and vascular/inflammatory factors in a cohort of 138 healthy older adults (mean age: 71.3 years. Participants underwent diffusion tensor imaging, provided blood samples, and participated in a health evaluation. Vascular risk factors and vascular/inflammatory blood markers were assessed. The primary outcome measure was fractional anisotropy (FA of the genu, body, and splenium (corpus callosum; exploratory measures included additional white matter regions, based on significant associations with BMI. Regression analyses indicated that higher BMI was associated with lower FA in the corpus callosum, cingulate, and fornix (p<.001. Vascular and inflammatory factors influenced the association between BMI and FA. Specifically, BMI was independently associated with the genu [β=-.21; B=-.0024; 95% CI, -.0048 to -.0000; p=.05] and cingulate fibers [β=-.39; B=-.0035; 95% CI,-.0056 to -.0015; p<.001], even after controlling for vascular/inflammatory risk factors and blood markers. In contrast, BMI was no longer significantly associated with the fornix and middle/posterior regions of the corpus callosum after controlling for these markers. Results partially support a vascular/inflammatory hypothesis, but also suggest a more complex relationship between BMI and white matter characterized by potentially different neuroanatomic vulnerability.

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

    Directory of Open Access Journals (Sweden)

    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.

  7. The vascular delta-like ligand-4 (DLL4)-Notch4 signaling correlates with angiogenesis in primary glioblastoma: an immunohistochemical study.

    Science.gov (United States)

    Zhang, Jin-Feng; Chen, Yao; Qiu, Xian-Xin; Tang, Wen-Long; Zhang, Jian-Dong; Huang, Jian-Huang; Lin, Guo-Shi; Wang, Xing-Fu; Lin, Zhi-Xiong

    2016-03-01

    Delta-like ligand-4 (DLL4)-Notch signaling is known to play a pivotal role in the regulation of tumor angiogenesis. We had previously found that DLL4 was overexpressed, while Notch1 receptor, which binds to DLL4 during angiogenesis, was absent in the majority of human primary glioblastomas. Thus, DLL4-Notch signaling pathway in the regulation of tumor angiogenesis in primary glioblastoma remains unknown. Tumor tissues from 70 patients with primary glioblastoma were analyzed by immunohistochemistry for expression of components of DLL4-Notch signaling, vascular endothelial growth factor (VEGF), and microvessel density (MVD). Immunohistochemistry results showed that the positive staining of DLL4 and Notch4 was primarily distributed in tumor vascular endothelial cells but rarely detected in tumor cells. However, VEGF, hairy/enhancer of split-1 (HES1; a target gene of Notch signaling), and Notch1-3 expression was seen in both tumor vascular endothelial cells and tumor cells. Univariate analysis showed that the expression levels of VEGF and DLL4, HES1, and Notch4 in tumor endothelial cells were significantly associated with MVD in primary glioblastoma (P glioblastoma, while MVD increased with elevated VEGF expression in contrast. In addition, DLL4, Notch4, and HES1 expression were positively correlated in tumor vascular endothelial cells (P glioblastoma. Graphical abstract A, positive staining of DLL4 in human kidney; B, positive staining of VEGF in human breast cancer; C, positive staining of CD34 in human lung cancer; D, positive staining of HES1 in human breast cancer; E-H, positive staining of Notch1-4: E-F in human lung cancer; G-H in human kidney.

  8. Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells

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    Xing-Cheng Zhao

    2013-07-01

    Full Text Available 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 of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD motif targeting endothelial cells (ECs. We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2+ perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

  9. The expression of osteopontin and vascular endothelial growth factor in correlation with angiogenesis in monoclonal gammopathy of undetermined significance and multiple myeloma.

    Science.gov (United States)

    Babarović, Emina; Valković, Toni; Budisavljević, Ivana; Balen, Ivan; Štifter, Sanja; Duletić-Načinović, Antica; Lučin, Ksenija; Jonjić, Nives

    2016-06-01

    Several studies have shown a gradual increase in the extent of bone marrow angiogenesis in various stages of proliferative plasma cell disorders, from monoclonal gammopathy of undetermined significance (MGUS) to active multiple myeloma (MM). The main aim of this study was to evaluate tumor angiogenesis parameters in detail and to correlate them with the expression of osteopontin (OPN) and vascular endothelial growth factor (VEGF) in the bone marrow of patients with MGUS and MM. In addition, we wanted to determine their prognostic significance in active MM. Ninety-five patients were enrolled in the study: 14 diagnosed with MGUS, 13 with asymptomatic myeloma (AMM) and 68 with active MM. Computer assisted image analysis was used to determine the angiogenesis parameters, the quantity of microvessels per 1mm(2) (MVD), the area occupied by microvessels per 1mm(2) and the percentage of microvessel area in total section area (TVA). Double immunohistochemical methods CD138+VEGF and CD138+OPN were used to evaluate expression of these proteins in plasma cells, and OPN was also analyzed for its interstitial expression (iOPN). A significant positive correlation was determined between VEGF and iOPN with angiogenic parameters in the MGUS stage of the disease. In advanced stages of the disease, a significant negative correlation was recorded between OPN and iOPN with parameters of angiogenesis. Overall survival was significantly shorter for patients with negative iOPN (p=0.002) and higher angiogenic parameters, MVD (p=0.009), TVA (p=0.008) and area of microvessels per 1mm(2) (p=0.02). Positive VEGF expression in our model predicted a better three-year survival of patients with active MM (OR: 5.25, p=0.03; HR: 0.44, p=0.04). The results of our study suggested a possible key role of VEGF and OPN in the induction of angiogenesis in early-stage disease.

  10. Amphetamine and environmentally induced hyperthermia differentially alter the expression of genes regulating vascular tone and angiogenesis in the meninges and associated vasculature.

    Science.gov (United States)

    Thomas, Monzy; George, Nysia I; Patterson, Tucker A; Bowyer, John F

    2009-10-01

    An amphetamine (AMPH) regimen that does not produce a prominent blood-brain barrier breakdown was shown to significantly alter the expression of genes regulating vascular tone, immune function, and angiogenesis in vasculature associated with arachnoid and pia membranes of the forebrain. Adult-male Sprague-Dawley rats were given either saline injections during environmentally-induced hyperthermia (EIH) or four doses of AMPH with 2 h between each dose (5, 7.5, 10, and 10 mg/kg d-AMPH, s.c.) that produced hyperthermia. Rats were sacrificed either 3 h or 1 day after dosing, and total RNA and protein was isolated from the meninges, arachnoid and pia membranes, and associated vasculature (MAV) that surround the forebrain. Vip, eNos, Drd1a, and Edn1 (genes regulating vascular tone) were increased by either EIH or AMPH to varying degrees in MAV, indicating that EIH and AMPH produce differential responses to enhance vasodilatation. AMPH, and EIH to a lesser extent, elicited a significant inflammatory response at 3 h as indicated by an increased MAV expression of cytokines Il1b, Il6, Ccl-2, Cxcl1, and Cxcl2. Also, genes related to heat shock/stress and disruption of vascular homeostasis such as Icam1 and Hsp72 were also observed. The increased expression of Ctgf and Timp1 and the decreased expression of Akt1, Anpep, and Mmp2 and Tek (genes involved in stimulating angiogenesis) from AMPH exposure suggest that angiogenesis was arrested or disrupted in MAV to a greater extent by AMPH compared to EIH. Alterations in vascular-related gene expression in the parietal cortex and striatum after AMPH were less in magnitude than in MAV, indicating less of a disruption of vascular homeostasis in these two regions. Changes in the levels of insulin-like growth factor binding proteins Igfbp1, 2, and 5 in MAV, compared to those in striatum and parietal cortex, imply an interaction between these regions to regulate the levels of insulin-like growth factor after AMPH damage. Thus, the

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

    Directory of Open Access Journals (Sweden)

    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.

  12. Dickkopf‑related protein 1 induces angiogenesis by upregulating vascular endothelial growth factor in the synovial fibroblasts of patients with temporomandibular joint disorders.

    Science.gov (United States)

    Jiang, Sheng-Jun; Li, Wei; Li, Ying-Jie; Fang, Wei; Long, Xing

    2015-10-01

    Angiogenesis has an important role in the progression of temporomandibular joint disorders (TMD). The aim of the present study was to explore the association between dickkopf‑related protein 1 (DKK‑1) and angiogenesis in TMD. The expression levels of DKK‑1 and vascular endothelial growth factor (VEGF) were quantified by an ELISA assay of the synovial fluid from patients with TMD. The correlation between DKK‑1 and VEGF was analyzed by Pearson correlation test. Synovial fibroblasts were isolated from patients with TMD and were subsequently treated with recombinant human DKK‑1, anti‑DKK‑1 antibody, hypoxia inducible factor‑1α (HIF‑1α), or small interfering RNA (siRNA). The expression levels of DKK‑1, HIF‑1α, and VEGF were subsequently quantified. The present study also investigated the effects of DKK‑1 on the migration of human umbilical vein endothelial cells (HUVEC). Increased expression levels of DKK‑1 were concordant with increased expression levels of VEGF in the synovial fluid from patients with TMD. In the synovial fibroblasts, DKK‑1 increased the expression levels of VEGF, and promoted HIF‑1α nuclear localization. In addition, DKK‑1 induced HUVEC migration, and HIF‑1α siRNA inhibited DKK‑1‑induced cell migration. The results of the present study indicate that DKK‑1 is associated with angiogenesis in the synovial fluid of patients with TMD. Furthermore, HIF‑1α may be associated with DKK‑1‑induced HUVEC activation.

  13. A vascular endothelial growth factor activating transcription factor increases the endothelial progenitor cells population and induces therapeutic angiogenesis in a type 1 diabetic mouse with hindlimb ischemia

    Institute of Scientific and Technical Information of China (English)

    Diao Yongpeng; Lian Lishan; Guo Lilong; Chen Houzao; Chen Yuexin; Song Xiaojun; Li Yongjun

    2014-01-01

    Background Therapeutic angiogenesis has been shown to promote blood vessel growth and improve tissue perfusion.Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis.However,it has side effects that limit its therapeutic utility in vivo,especially at high concentrations.This study aimed to investigate whether an intramuscular injection of a genetically engineered zinc finger VEGF-activating transcription factor modulates the endothelial progenitor cells (EPC) and promotes therapeutic angiogenesis in a hindlimb ischemia model with type 1 diabetes.Methods Alloxan (intravenous injection) was used to induce type Ⅰ diabetes in C57BL/6 mice (n=58).The ischemic limb received ZFP-VEGF (125 μg ZFP-VEGF plasmid in 1% poloxamer) or placebo (1% poloxamer) intramuscularly.Mice were sacrificed 3,5,10,or 20 days post-injection.Limb blood flow was monitored using laser Doppler perfusion imaging.VEGF mRNA and protein expression were examined using real-time PCR and ELISA,respectively.Capillary density,proliferation,and apoptosis were examined using immunohistochemistry techniques.Flow cytometry was used to detect the EPC population in bone marrow.Two-tailed Student's paired t test and repeated-measures analysis of variance were used for statistical analysis.Results ZFP-VEGF increased VEGF mRNA and protein expression at 3 and 10 days post-injection,and increased EPC in bone marrow at day 5 and 20 post-injection compared with controls (P<0.05).ZFP-VEGF treatment resulted in better perfusion recovery,a higher capillary density and proliferation,and less apoptosis compared with controls (P<0.05).Conclusions Intramuscular ZFP-VEGF injection promotes therapeutic angiogenesis in an ischemic hindlimb model with type 1 diabetes.This might be due to the effects of VEGF on cell survival and EPC recruitment.

  14. Suppressing Akt phosphorylation and activating Fas by safrole oxide inhibited angiogenesis and induced vascular endothelial cell apoptosis in the presence of fibroblast growth factor-2 and serum.

    Science.gov (United States)

    Zhao, Jing; Miao, Junying; Zhao, Baoxiang; Zhang, Shangli; Yin, Deling

    2006-01-01

    At present, vascular endothelial cell (VEC) apoptosis induced by deprivation of fibroblast growth factor-2 (FGF-2) and serum has been well studied. But how to trigger VEC apoptosis in the presence of FGF-2 and serum is not well known. To address this question, in this study, the effects of safrole oxide on angiogenesis and VEC growth stimulated by FGF-2 were investigated. The results showed that safrole oxide inhibited angiogenesis and induced VEC apoptosis in the presence of FGF-2 and serum. To understand the possible mechanism of safrole oxide acting, we first examined the phosphorylation of Akt and the activity of nitric oxide synthase (NOS); secondly, we analyzed the expressions and distributions of Fas and P53; then we measured the activity of phosphatidylcholine specific phospholipase C (PC-PLC) in the VECs treated with and without safrole oxide. The results showed that this small molecule obviously suppressed Akt phosphorylation and the activity of NOS, and promoted the expressions of Fas and P53 markedly. Simultaneously, Fas protein clumped on cell membrane, instead of homogenously distributed. The activity of PC-PLC was not changed obviously. The data suggested that safrole oxide effectively inhibited angiogenesis and triggered VEC apoptosis in the presence of FGF-2 and serum, and it might perform its functions by suppressing Akt/NOS signal pathway, upregulating the expressions of Fas and P53 and modifying the distributing pattern of Fas in VEC. This finding provided a powerful chemical probe for promoting VEC apoptosis during angiogenesis stimulated by FGF-2.

  15. Improved scar in postburn patients following interferon-alpha2b treatment is associated with decreased angiogenesis mediated by vascular endothelial cell growth factor.

    Science.gov (United States)

    Wang, Jianfei; Chen, Hong; Shankowsky, Heather A; Scott, Paul G; Tredget, Edward E

    2008-07-01

    Hypertrophic scar (HTS) after thermal injury is a dermal fibroproliferative disorder, which leads to considerable morbidity. Previous clinical studies from our laboratory have suggested that interferon-alpha2b (IFN-alpha2b) improves scar quality as a result of the suppression of fibroblast function. More recently, our work has demonstrated that the improvement of scar in patients with HTS after IFN-alpha2b treatment may be associated with a decreased number of fibrocytes and/or altered fibrocyte function. In this study, we report that the improvement of HTS after IFNalpha-2b treatment may be associated with a decrease in angiogenesis. Using immunohistochemistry, we demonstrate an increase in angiogenesis in HTS compared to normal skin, and also show an increase in the expression of vascular endothelial cell growth factor (VEGF) in HTS. Subsequently, we demonstrate a significant reduction in angiogenesis in HTS tissue from patients after treatment with systemic IFN-alpha2b. By using a [3H] thymidine incorporation assay, we demonstrate that IFN-alpha2b suppresses the proliferation of human umbilical vein endothelial cells (HUVECs) in a dose-dependent manner. In addition, IFN-alpha2b inhibits VEGF-induced proliferation and tube formation by using HUVECs. All these effects may be a result of the blocking of VEGF receptor expression on endothelial cells by IFN-alpha2b. Taken together with previous results, the present study suggests that the improvement of scar quality in HTS patients after IFN-alpha2b treatment may also be associated with decreased angiogenesis in HTS. The current in vitro results may provide some insights into the scar improvement that is seen with systemic IFN-alpha2b treatment.

  16. 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.)

  17. Key role of microRNA-15a in the KLF4 suppressions of proliferation and angiogenesis in endothelial and vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Zheng, Xuemei; Li, Aiqin; Zhao, Liang; Zhou, Tengfei; Shen, Qiang [Institute of Cardiovascular Science, Peking University Health Science Center, Beijing 100191 (China); Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing 100191 (China); Cui, Qinghua [Department of Biomedical Informatics, Peking University Health Science Center, Beijing 100191 (China); Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing 100191 (China); Qin, Xiaomei, E-mail: xmqin@bjmu.edu.cn [Institute of Cardiovascular Science, Peking University Health Science Center, Beijing 100191 (China); Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Peking University Health Science Center, Beijing 100191 (China)

    2013-08-09

    Highlights: •This is the first demonstration that miR-15a is a novel target gene of KLF4. •A novel finding that KLF4 increases the expression of miR-15a in ECs and VSMCs. •The novel mechanism is that KLF4 inhibits the proliferation of ECs via miR-15a. •The novel mechanism is that KLF4 inhibits the proliferation of VSMCs via miR-15. •miR-15a mediates the anti-angiogenic activity of KLF4. -- Abstract: While recent insights indicate that the transcription factor Krüppel-like factor 4 (KLF4) is indispensable for vascular homeostasis, its exact role in proliferation and angiogenesis and how it functions remain unresolved. Thus, the aim of the present study was to evaluate the role of KLF4 in the proliferations of endothelial and vascular smooth muscle cells, as well as the angiogenesis. The overexpression of KLF4 in endothelial cells significantly impaired tube formation. KLF4 inhibited the formation of a vascular network in implanted Matrigel plugs in nude mice. Importantly, we found that KLF4 significantly upregulated the miR-15a expression in endothelial cells and vascular smooth muscle cells, and conversely, KLF4 depletion reduced the amount of miR-15a. Furthermore, KLF4 blocked cell cycle progression and decreased cyclin D1 expression in endothelial cells and vascular smooth muscle cells through the induction of miR-15a. Intriguingly, the delivery of a miR-15a antagomir to nude mice resulted in marked attenuation of the anti-angiogenic effect of KLF4. Collectively, our present study provide the first evidence that miR-15a as a direct transcriptional target of KLF4 that mediates the anti-proliferative and anti-angiogenic actions of KLF4, which indicates that KLF4 upregulation of miR-15a may represent a therapeutic option to suppress proliferative vascular disorders.

  18. The hypoxia-inducible factor-responsive proteins semaphorin 4D and vascular endothelial growth factor promote tumor growth and angiogenesis in oral squamous cell carcinoma

    Energy Technology Data Exchange (ETDEWEB)

    Zhou, Hua; Yang, Ying-Hua [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Binmadi, Nada O. [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Department of Oral Basic and Clinical Sciences, King Abdulaziz University, Jeddah 21589 (Saudi Arabia); Proia, Patrizia [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Department of Sports Science (DISMOT), University of Palermo, Via Eleonora Duse 2 90146, Palermo (Italy); Basile, John R., E-mail: jbasile@umaryland.edu [Department of Oncology and Diagnostic Sciences, University of Maryland Dental School, 650W. Baltimore Street, 7-North, Baltimore, MD 21201 (United States); Greenebaum Cancer Center, 22S. Greene Street, Baltimore, MD 21201 (United States)

    2012-08-15

    Growth and metastasis of solid tumors requires induction of angiogenesis to ensure the delivery of oxygen, nutrients and growth factors to rapidly dividing transformed cells. Through either mutations, hypoxia generated by cytoreductive therapies, or when a malignancy outgrows its blood supply, tumor cells undergo a change from an avascular to a neovascular phenotype, a transition mediated by the hypoxia-inducible factor (HIF) family of transcriptional regulators. Vascular endothelial growth factor (VEGF) is one example of a gene whose transcription is stimulated by HIF. VEGF plays a crucial role in promoting tumor growth and survival by stimulating new blood vessel growth in response to such stresses as chemotherapy or radiotherapy-induced hypoxia, and it therefore has become a tempting target for neutralizing antibodies in the treatment of advanced neoplasms. Emerging evidence has shown that the semaphorins, proteins originally associated with control of axonal growth and immunity, are regulated by changes in oxygen tension as well and may play a role in tumor-induced angiogenesis. Through the use of RNA interference, in vitro and in vivo angiogenesis assays and tumor xenograft experiments, we demonstrate that expression of semaphorin 4D (SEMA4D), which is under the control of the HIF-family of transcription factors, cooperates with VEGF to promote tumor growth and vascularity in oral squamous cell carcinoma (OSCC). We use blocking antibodies to show that targeting SEMA4D function along with VEGF could represent a novel anti-angiogenic therapeutic strategy for the treatment of OSCC and other solid tumors. -- Highlights: Black-Right-Pointing-Pointer Similar to VEGF, SEMA4D promotes angiogenesis in vitro and in vivo. Black-Right-Pointing-Pointer Both VEGF and SEMA4D are produced by OSCC cells in a HIF-dependent manner. Black-Right-Pointing-Pointer These factors combine to elicit a robust pro-angiogenic phenotype in OSCC. Black-Right-Pointing-Pointer Anti-SEMA4D

  19. Markers of collagen synthesis is related to blood pressure and vascular hypertrophy: a LIFE substudy

    DEFF Research Database (Denmark)

    Olsen, M H; Christensen, M K; Wachtell, K;

    2005-01-01

    , we measured sitting BP, serum collagen type I carboxy-terminal telopeptide (ICTP) reflecting degradation, procollagen type I carboxy-terminal propeptide (PICP) reflecting synthesis and LV mass by echocardiography after 2 weeks of placebo treatment and after 1 year of antihypertensive treatment......Cardiac fibrosis and high levels of circulating collagen markers has been associated with left ventricular (LV) hypertrophy. However, the relationship to vascular hypertrophy and blood pressure (BP) load is unclear. In 204 patients with essential hypertension and electrocardiographic LV hypertrophy...

  20. Priming Dental Pulp Stem Cells With Fibroblast Growth Factor-2 Increases Angiogenesis of Implanted Tissue-Engineered Constructs Through Hepatocyte Growth Factor and Vascular Endothelial Growth Factor Secretion.

    Science.gov (United States)

    Gorin, Caroline; Rochefort, Gael Y; Bascetin, Rumeyza; Ying, Hanru; Lesieur, Julie; Sadoine, Jérémy; Beckouche, Nathan; Berndt, Sarah; Novais, Anita; Lesage, Matthieu; Hosten, Benoit; Vercellino, Laetitia; Merlet, Pascal; Le-Denmat, Dominique; Marchiol, Carmen; Letourneur, Didier; Nicoletti, Antonino; Vital, Sibylle Opsahl; Poliard, Anne; Salmon, Benjamin; Muller, Laurent; Chaussain, Catherine; Germain, Stéphane

    2016-03-01

    Tissue engineering strategies based on implanting cellularized biomaterials are promising therapeutic approaches for the reconstruction of large tissue defects. A major hurdle for the reliable establishment of such therapeutic approaches is the lack of rapid blood perfusion of the tissue construct to provide oxygen and nutrients. Numerous sources of mesenchymal stem cells (MSCs) displaying angiogenic potential have been characterized in the past years, including the adult dental pulp. Establishment of efficient strategies for improving angiogenesis in tissue constructs is nevertheless still an important challenge. Hypoxia was proposed as a priming treatment owing to its capacity to enhance the angiogenic potential of stem cells through vascular endothelial growth factor (VEGF) release. The present study aimed to characterize additional key factors regulating the angiogenic capacity of such MSCs, namely, dental pulp stem cells derived from deciduous teeth (SHED). We identified fibroblast growth factor-2 (FGF-2) as a potent inducer of the release of VEGF and hepatocyte growth factor (HGF) by SHED. We found that FGF-2 limited hypoxia-induced downregulation of HGF release. Using three-dimensional culture models of angiogenesis, we demonstrated that VEGF and HGF were both responsible for the high angiogenic potential of SHED through direct targeting of endothelial cells. In addition, FGF-2 treatment increased the fraction of Stro-1+/CD146+ progenitor cells. We then applied in vitro FGF-2 priming to SHED before encapsulation in hydrogels and in vivo subcutaneous implantation. Our results showed that FGF-2 priming is more efficient than hypoxia at increasing SHED-induced vascularization compared with nonprimed controls. Altogether, these data demonstrate that FGF-2 priming enhances the angiogenic potential of SHED through the secretion of both HGF and VEGF.

  1. Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum

    Science.gov (United States)

    Azmitia, E. C.; Saccomano, Z. T.; Alzoobaee, M. F.; Boldrini, M.; Whitaker-Azmitia, P. M.

    2016-01-01

    In the current work, we conducted an immunocytochemical search for markers of ongoing neurogenesis (e.g. nestin) in auditory cortex from postmortem sections of autism spectrum disorder (ASD) and age-matched control donors. We found nestin labeling in cells of the vascular system, indicating blood vessels plasticity. Evidence of angiogenesis was…

  2. Longitudinal Changes in Vascular Risk Markers and Mortality Rates among a Latino Population with Hypertension.

    Science.gov (United States)

    Pflederer, Matthew C; Long, Carlin S; Beaty, Brenda; Havranek, Edward P; Mehler, Philip S; Keniston, Angela; Krantz, Mori J

    2016-04-01

    Vascular markers such as pulse-wave velocity and carotid intima-media thickness (CIMT) might improve the prediction of incident cardiovascular disease beyond traditional risk factors. These vascular markers have not been well characterized in minority populations and might be more useful than inflammatory biomarkers. We conducted a prospective, longitudinal cohort study among hypertensive patients in an urban safety-net hospital. We evaluated inflammatory biomarkers, arterial pulse-wave velocity, and carotid intima-media thickness at baseline, 1 year, and 2 years. The primary outcome variable was CIMT. Generalized linear mixed-effects models were used to evaluate associations between CIMT and predictive variables accounting for the correlation of multiple measurements within subjects over time. For our secondary outcome, we used administrative and National Death Index data to determine all-cause death, and univariate relationships were evaluated. Among 175 subjects, 117 were Latino (67%) and 117 were female (67%). Pulse-wave velocity and CIMT regressed over time (both P <0.001) and were highly correlated (P <0.001). Only pulse-wave velocity (P=0.002) and total cholesterol (P=0.03) were associated with CIMT in time-varying covariate analysis. At a median follow-up period of 80 months, 17 of 175 subjects had died (10%). Higher baseline CIMT and pulse-wave velocity were associated with increased mortality rates (both P <0.01). No serum inflammatory marker was significantly correlated with longitudinal changes in CIMT or death. In conclusion, both arterial stiffness and preclinical carotid atherosclerosis were associated with increased mortality rates and might be useful risk-stratification markers among this minority population.

  3. Angiogenic synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in an in vitro quantitative microcarrier-based three-dimensional fibrin angiogenesis system

    Institute of Scientific and Technical Information of China (English)

    Xi-Tai Sun; Yi-Tao Ding; Xiao-Gui Yan; Ling-Yun Wu; Qiang Li; Ni Cheng; Yu-Dong Qiu; Min-Yue Zhang

    2004-01-01

    AIM: To develop an in vitro three-dimensional (3-D)angiogenesis system to analyse the capillary sprouts induced in response to the concentration ranges of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) and to quantify their synergistic activity.METHODS: Microcarriers (MCs) coated with human microvascular endothelial cells (HMVECs) were embedded in fibrin gel and cultured in 24-well plates with assay media. The growth factors bFGF, or VEGF, or both were added to the system. The wells (n = 8/group) were digitally photographed and the average length of capillary-like sprouts (ALS) from each microcarrier was quantitated.RESULTS: In aprotinin-stabilized fibrin matrix, human microvascular endothelial cells on the MCs invaded fibrin,forming sprouts and capillary networks with lumina. The angiogenic effects of bFGF or VEGF were dose-dependent in the range from 10 to 40 ng/mL. At d 1, 10 ng/mL of bFGF and VEGF induced angiogenesis with an ALS of 32.13±16.6 μm and 43.75±27.92 μm, respectively, which were significantly higher than that of the control (5.88±4.45 μm, P<0.01),and the differences became more significant as the time increased. In addition, the combination of 10 ng/mL of bFGF and VEGF each induced a more significant effect than the summed effects of bFGF (10 ng/mL) alone and VEGF (10 ng/mL) alone when analyzed using SPSS system for general linear model (GLM) (P= 0.011), and that also exceeded the effects by 20 ng/mL of either bFGF or VEGF.CONCLUSION: A microcarrier-based in vitro threedimensional angiogenesis model can be developed in fibrin.It offers a unique system for quantitative analysis of angiogenesis. Both bFGF and VEGF exert their angiogenic effects on HMVECs synergistically and in a dose-dependent manner.

  4. Quantitative EEG Markers in Mild Cognitive Impairment: Degenerative versus Vascular Brain Impairment

    Directory of Open Access Journals (Sweden)

    D. V. Moretti

    2012-01-01

    Full Text Available We evaluated the relationship between brain rhythmicity and both the cerebrovascular damage (CVD and amygdalohippocampal complex (AHC atrophy, as revealed by scalp electroencephalography (EEG in a cohort of subjects with mild cognitive impairment (MCI. All MCI subjects underwent EEG recording and magnetic resonance imaging. EEGs were recorded at rest. Relative power was separately computed for delta, theta, alpha1, alpha2, and alpha3 frequency bands. In the spectral band power the severity of CVD was associated with increased delta power and decreased alpha2 power. No association of vascular damage was observed with alpha3 power. Moreover, the theta/alpha1 ratio could be a reliable index for the estimation of the individual extent of CV damage. On the other side, the group with moderate hippocampal atrophy showed the highest increase of alpha2 and alpha3 power. Moreover, when the amygdalar and hippocampal volumes are separately considered, within amygdalohippocampal complex (AHC, the increase of theta/gamma ratio is best associated with amygdalar atrophy whereas alpha3/alpha2 ratio is best associated with hippocampal atrophy. CVD and AHC damages are associated with specific EEG markers. So far, these EEG markers could have a prospective value in differential diagnosis between vascular and degenerative MCI.

  5. The Association between Fibroblast Growth Factor-23 and Vascular Calcification Is Mitigated by Inflammation Markers

    Directory of Open Access Journals (Sweden)

    Mohamed M. NasrAllah

    2013-11-01

    Full Text Available Background: Fibroblast growth factor-23 (FGF-23 has been linked to vascular calcification, ventricular hypertrophy and mortality in chronic kidney disease (CKD, although these links may not be direct and independent. Similar grave outcomes are associated with inflammation and oxidative stress in CKD. Recently, accumulating evidence has linked components of phosphate homeostasis to inflammation and oxidative stress. The interaction between the triad of inflammation, FGF-23 and cardiovascular outcomes is underinvestigated. Methods: We studied 65 patients with stage 5 CKD on hemodialysis. Serum levels of FGF-23, high-sensitivity C-reactive protein (hsCRP, endogenous soluble receptor of advanced glycation end products (esRAGE, advanced oxidation protein products (AOPP, parathormone, lipids, calcium and phosphorous were measured. The aortic calcification index (ACI was determined using non-contrast CT scans of the abdominal aorta. Results: FGF-23 was elevated (mean: 4,681 pg/ml, SD: 3,906 and correlated with hsCRP, esRAGE, AOPP, dialysis vintage and phosphorus in univariate analysis. In multiple regression analysis, hsCRP, AOPP and phosphorus but not esRAGE were all significantly correlated to FGF-23 (R2 = 0.7, p 2 = 0.65, p Conclusion: FGF-23 is strongly correlated to various markers of inflammation and oxidative stress in hemodialysis patients. The association between FGF-23 and vascular calcification was mitigated when corrected for inflammation markers.

  6. ER Stress and Angiogenesis.

    Science.gov (United States)

    Binet, François; Sapieha, Przemyslaw

    2015-10-01

    Proper tissue vascularization is vital for cellular function as it delivers oxygen, nutrients, hormones, and immune cells and helps to clear cellular debris and metabolic waste products. Tissue angiogenesis occurs to satisfy energy requirements and cellular sensors of metabolic imbalance coordinate vessel growth. In this regard, the classical pathways of the unfolded protein response activated under conditions of ER stress have recently been described to generate angiomodulatory or angiostatic signals. This review elaborates on the link between angiogenesis and ER stress and discusses the implications for diseases characterized by altered vascular homeostasis, such as cancer, retinopathies, and atherosclerosis.

  7. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

    Directory of Open Access Journals (Sweden)

    Naveed Sattar

    2009-06-01

    Full Text Available BACKGROUND: Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD events, but robust prospective evidence is lacking. We tested whether interleukin (IL-6, C-reactive protein (CRP, and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI and stroke. METHODS AND FINDINGS: In the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER, baseline inflammatory markers in up to 5,680 men and women aged 70-82 y were related to risk for endpoints; nonfatal CVD (i.e., nonfatal MI and nonfatal stroke [n = 672], fatal CVD (n = 190, death from other CV causes (n = 38, and non-CVD mortality (n = 300, over 3.2-y follow-up. Elevations in baseline IL-6 levels were significantly (p = 0.0009; competing risks model analysis more strongly associated with fatal CVD (hazard ratio [HR] for 1 log unit increase in IL-6 1.75, 95% confidence interval [CI] 1.44-2.12 than with risk of nonfatal CVD (1.17, 95% CI 1.04-1.31, in analyses adjusted for treatment allocation. The findings were consistent in a fully adjusted model. These broad trends were similar for CRP and, to a lesser extent, for fibrinogen. The results were also similar in placebo and statin recipients (i.e., no interaction. The C-statistic for fatal CVD using traditional risk factors was significantly (+0.017; p<0.0001 improved by inclusion of IL-6 but not so for nonfatal CVD events (p = 0.20. CONCLUSIONS: In PROSPER, inflammatory markers, in particular IL-6 and CRP, are more strongly associated with risk of fatal vascular events than nonfatal vascular events. These novel observations may have important implications for better understanding aetiology of CVD mortality, and have potential clinical relevance.

  8. Effect of Vascular Endothelial Growth Factor on Regulation of Angiogenesis during Early Luteal Development in Livestock%VEGF在家畜黄体早期发育过程中对血管生成的调控作用

    Institute of Scientific and Technical Information of China (English)

    罗倩萍; 张正红; 陈佳洁; 黄晓红; 成勇; 王正朝

    2011-01-01

    对黄体时期VEGF依赖性血管生成的分子机制研究,将有助于我们开发新的策略用于治疗黄体相关的不孕症,以及改善动物的繁殖性能.论文对VEGF在家畜黄体血管生成过程中的调控作用进行综述,旨在为临床研究及畜牧生产提供理论依据及参考资料.%Angiogenesis is a process of vascular growth which is mainly limited to the reproductive system in healthy adult animals. In mammalian, the corpus luteum is a site of intense angiogenesis. Within a short period of the corpus luteum, the angiogenesis is followed either by controlled regression of the micro-vascular tree in the non-fertile cycle, or maintenance and stabilisation of the new vasculature in a conceptual cycle. Therefore, the corpus luteum is a unique model system in which the cellular and molecular regulation of angiogenesis can be studied. The development of new blood vessels in the ovarian corpus luteum is essential for corpus luteum formation to guarantee the necessary supply of nutrients and hormones. At present, the study of the molecular mechanism indicated vascular endothelial growth factor has a major role in the corpus luteum, since significantly inhibitory effects on luteal angiogenesis and function are observed when its action was blocked by antagonists at specific stages of the luteal phase in vivo. Investigations of the mechanisms of vascular endothelial growth factor-dependent angiogenesis in mammalian corpus luteum will provide insights into new strategies in treatment of luteal-based infertility and methods of improving animal reproduction. Based on our previous researches, we reviewed the effect of vascular endothelial growth factor on luteal angiogenesis in livestock, in order to provide some important references for clinic researches and animal husbandry production.

  9. von Hippel-Lindau tumor suppressor mutants faithfully model pathological hypoxia-driven angiogenesis and vascular retinopathies in zebrafish

    NARCIS (Netherlands)

    van Rooijen, E.; Voest, E.E.; Logister, I.; Bussmann, J.; Korving, J.; van Eeden, F.J.; Giles, R.H.; Schulte-Merker, S.

    2010-01-01

    Biallelic inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene predisposes human patients to the development of highly vascularized neoplasms in multiple organ systems. We show that zebrafish vhl mutants display a marked increase in blood vessel formation throughout the embryo, starting

  10. Anti-angiogenesis effect of generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide on breast cancer in vitro

    Institute of Scientific and Technical Information of China (English)

    Shan-zhi GU; Xin-han ZHAO; Ling-xiao ZHANG; Li LI; Zhi-yu WANG; Min MENG; Gai-li AN

    2009-01-01

    Objective: To study the effects of the generation 4 polyamidoamine/vascular endothelial growth factor antisense oligodeoxynucleotide (G4PAMAMNEGFASODN) compound on the expressions of vascular endothelial growth factor (VEGF) and its mRNA of breast cancer cells and on the inhibition of vascular endothelial cells. Methods: We examined the morphology of G4PAMAM/VEGFASODN compound and its pH stability, in vitro transfection efficiency and toxicity, and the expressions of VEGF and its mRNA. Methyl thiazolyl tetrazolium assay was used to detect the inhibitory function of the compound on vascular endothelial cells. Results: The compound was about 10 nm in diameter and was homogeneously netlike. From pH 5 to 10, it showed quite a buffered ability. The 48-h transfection rate in the charge ratio of 1:40 was 98.76%, significantly higher than that of the liposome group (P<0.05). None of the transfection products showed obvious toxicity on the cells. The expressions of both VEGF protein and its mRNA after G4PAMAM/VEGFASODN transfection decreased markedly. Conclusion: With a low toxicity, high safety, and high transfection rate, G4PAMAMNEGFASODN could be a promising gene vector. Specifically, it inhibits VEGF gene expression efficiently, laying a basis for further in vivo animal studies.

  11. An easily accessible sulfated saccharide mimetic inhibits in vitro human tumor cell adhesion and angiogenesis of vascular endothelial cells

    Directory of Open Access Journals (Sweden)

    Grazia Marano

    2012-05-01

    Full Text Available Oligosaccharides aberrantly expressed on tumor cells influence processes such as cell adhesion and modulation of the cell’s microenvironment resulting in an increased malignancy. Schmidt’s imidate strategy offers an effective method to synthesize libraries of various oligosaccharide mimetics. With the aim to perturb interactions of tumor cells with extracellular matrix proteins and host cells, molecules with 3,4-bis(hydroxymethylfuran as core structure were synthesized and screened in biological assays for their abilities to interfere in cell adhesion and other steps of the metastatic cascade, such as tumor-induced angiogenesis.The most active compound, (4-{[(β-D-galactopyranosyloxy]methyl}furan-3-ylmethyl hydrogen sulfate (GSF, inhibited the activation of matrix-metalloproteinase-2 (MMP-2 as well as migration of the human melanoma cells of the lines WM-115 and WM-266-4 in a two-dimensional migration assay. GSF inhibited completely the adhesion of WM-115 cells to the extracellular matrix (ECM proteins, fibrinogen and fibronectin.In an in vitro angiogenesis assay with human endothelial cells, GSF very effectively inhibited endothelial tubule formation and sprouting of blood vessels, as well as the adhesion of endothelial cells to ECM proteins. GSF was not cytotoxic at biologically active concentrations; neither were 3,4-bis{[(β-D-galactopyranosyloxy]methyl}furan (BGF nor methyl β-D-galactopyranoside nor 3,4-bis(hydroxymethylfuran, which were used as controls, eliciting comparable biological activity. In silico modeling experiments, in which binding of GSF to the extracellular domain of the integrin αvβ3 was determined, revealed specific docking of GSF to the same binding site as the natural peptidic ligands of this integrin. The sulfate in the molecule coordinated with one manganese ion in the binding site.These studies show that this chemically easily accessible molecule GSF, synthesized in three steps from 3,4-bis

  12. Effect of exercise on markers of vascular health in renal transplant recipients.

    Science.gov (United States)

    Piťha, J; Králová Lesná, I; Stávek, P; Mahrová, A; Racek, J; Sekerková, A; Teplan, V; Štollová, M

    2015-01-01

    The cornerstone of cardiovascular risk management is lifestyle intervention including exercise which could exert favorable impact also in renal transplant recipients. Nevertheless, reliable assessment of the effect of lifestyle interventions is complicated and the available data in this population are not consistent. The aim of the study was to evaluate the effect of physical activity on selected laboratory markers of vascular health including circulating stem cells, endothelial progenitor cells, microparticles, and plasma asymmetric dimethyl arginine in renal transplant recipients. Nineteen men and 7 women were recruited in 6-month program of standardized and supervised exercise. Control group consisted of 23 men and 13 women of similar age and body mass index not included into the program. One year after the transplantation, the main difference between intervention and control group was found in the change of endothelial progenitor cells (p=0.006). Surprisingly, more favorable change was seen in the control group in which endothelial progenitor cells significantly increased compared to the intervention group. The explanation of this finding might be a chronic activation of reparative mechanisms of vascular system in the population exposed to multiple risk factors which is expressed as relatively increased number of endothelial progenitor cells. Therefore, their decrease induced by exercise might reflect stabilization of these processes.

  13. ''Occult'' post-contrast signal enhancement in pediatric diffuse intrinsic pontine glioma is the MRI marker of angiogenesis?

    Energy Technology Data Exchange (ETDEWEB)

    Conway, Ashley E.; Reddick, Wilburn E.; Li, Yimei; Yuan, Ying; Glass, John O.; Baker, Justin N.; Kun, Larry E.; Broniscer, Alberto; Patay, Zoltan [St. Jude Children' s Research Hospital, Department of Radiological Sciences, Memphis, TN (United States)

    2014-05-15

    In diffuse intrinsic pontine gliomas (DIPG), subtracting pre-contrast from post-contrast T1-weighted images (T1WI) occasionally reveals subtle, ''occult'' enhancement. We hypothesized that this represents intravascular enhancement related to angiogenesis and hence that these tumors should have greater blood volume fractions than do non-enhancing tumors. We retrospectively screened MR images of 66 patients initially diagnosed with DIPG and analyzed pretreatment conventional and dynamic susceptibility contrast (DSC) perfusion MRI studies of 61 patients. To determine the incidence of occult enhancement, cerebral blood volume (CBV) values were compared in areas of occult enhancement (OcE), no enhancement (NE), and normal-appearing deep cerebellar white matter (DCWM). Tumors of 10 patients (16.4 %) had occult enhancement; those of 6 patients (9.8 %) had no enhancement at all. The average CBV in areas of occult enhancement was significantly higher than that in non-enhancing areas of the same tumor (P =.03), within DCWM in the same patient (P =.03), and when compared to anatomically paired/similar regions of interest (ROI) in patients with non-enhancing tumors (P =.005). Areas of OcE correspond to areas of higher CBV in DIPG, which may be an MRI marker for angiogenesis, but larger scale studies may be needed to determine its potential relevance to grading by imaging, treatment stratification, biopsy guidance, and evaluation of response to targeted therapy. (orig.)

  14. Predictive value of tumor markers in patients with recurrent hepatocellular carcinoma in different vascular invasion pattern

    Institute of Scientific and Technical Information of China (English)

    Feng Gao; Shu-Sen Zheng; Heng-Kai Zhu; Yang-Bo Zhu; Qiao-Nan Shan; Qi Ling; Xu-Yong Wei; Hai-Yang Xie; Lin Zhou; Xiao Xu

    2016-01-01

    BACKGROUND: Four tumor markers for hepatocellular car-cinoma (HCC), alpha-fetoprotein (AFP), glypican-3 (GPC3), vascular endothelial growth factor (VEGF) and des-gamma-carboxy prothrombin (DCP), are closely associated with tumor invasion and patient’s survival. This study estimated the predict-ability of preoperative tumor marker levels along with patho-logical parameters on HCC recurrence after hepatectomy. METHODS: A total of 140 patients with HCC who underwent hepatectomy between January 2012 and August 2012 were enrolled. The demographics, clinical and follow-up data were collected and analyzed. The patients were divided into two groups: patients with macroscopic vascular invasion (MaVI +) and those without MaVI (MaVI-). The predictive value of tumor markers and clinical parameters were evaluated by uni-variate and multivariate analysis. RESULTS: In all patients, tumor size (>8 cm) and MaVI were closely related to HCC recurrence after hepatectomy. For MaVI+ patients, VEGF (>900 pg/mL) was a signiifcant predic-tor for recurrence (RR=2.421; 95% CI: 1.272-4.606;P=0.007). The 1- and 2-year tumor-free survival rates for MaVI+ pa-tients with VEGF≤900 pg/mL versus for those with VEGF>900 pg/mL were 51.5% and 17.6% versus 19.0% and 4.8%(P445 mAu/mL and tumor size >8 cm were two independent risk factors for tumor recur-rence (RR=2.307, 95% CI: 1.132-4.703,P=0.021; RR=3.150, 95% CI: 1.392-7.127,P=0.006; respectively). The 1- and 2-year tumor-free survival rates for the patients with DCP≤445 mAu/mL and those with DCP >445 mAu/mL were 90.4% and 70.7% versus 73.2% and 50.5% respectively (P=0.048). The 1-and 2-year tumor-free survival rates for the patients with tu-mor size≤8 cm and >8 cm were 83.2% and 62.1% versus 50.0%and 30.0%, respectively (P=0.003). CONCLUSIONS: The MaVI+ patients with VEGF≤900 pg/mL had a relatively high tumor-free survival than those with VEGF >900 pg/mL. In the MaVI- patients, DCP >445 mAu/mL and tumor size >8 cm were predictive factors

  15. Circulating vascular endothelial growth factor six months after primary surgery as a prognostic marker in patients with colorectal cancer

    DEFF Research Database (Denmark)

    Werther, Kim; Sørensen, Steen; Christensen, Ib Jarle;

    2003-01-01

    High preoperative circulating vascular endothelial growth factor (VEGF) is predictive of poor prognosis in patients with colorectal cancer (CRC). However, postoperative circulating VEGF has not yet been evaluated as a prognostic marker in CRC patients. In 318 consecutive patients who had undergone...

  16. In vitro and in vivo imaging of prostate cancer angiogenesis using anti-vascular endothelial growth factor receptor 2 antibody-conjugated quantum dot

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Haejin; Lee, Jiyeon; Song, Rita; Lee, Jung Han [Medicinal Chemistry Laboratory, Institute Pasteur Korea (IP-K), Seongnam (Korea, Republic of); Hwang, Sung Il; Lee, Hak Jong [Seoul National University Bundang Hospital, Institute of Radiation Medicine, Seoul National University Medical Research Center, Clinical Research Institute, Seongnam (Korea, Republic of); Kim, Young Hwa [Cancer Research Institute, Seoul National University College of Medicine, Seoul (Korea, Republic of)

    2013-01-15

    Authors aimed to determine the targeting ability of vascular endothelial growth factor receptor 2 (VEGFR2)-conjugated quantum dots (QDs) in vitro, and apply it for a xenograft prostate cancer mouse model. Conjugation reaction of QDs was performed by using the N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDC) and sulfo-(N-hydroxysulfosuccinimide) (Sulfo-NHS). The human umbilical vein cord endothelial cells (HUVECs) were incubated with QDs, conjugated with antiVGFR2, to see a specific binding in vitro. Fluorescent cell images were taken by a confocal microscope. The human prostate cancer cells (PC3) were injected to five nude mice on hind limbs to make the xenograft tumor model. QD-antiVEGFR2 antibody complex was injected into the tumor model and fluorescence measurements were performed at 1, 4, 9, 12, 15, and 24 hours after the injection. The specific interaction between HUVECs and QD-antiVEGFR2 antibody was clearly shown in vitro. The in vivo fluorescence image disclosed that there was an increased signal of tumor, 12 hours after the injection of QDs. By showing endothelial cells binding with QDs-antiVEGFR2 antibodyand an experimental application of the antibody for VEGFR2 imaging in the prostate cancer xenograft mouse model, we suggests that the antibody-conjugated QDs can be a potential imaging tool for angiogenesis of the cancer.

  17. Fcγ receptor-induced soluble vascular endothelial growth factor receptor-1 (VEGFR-1) production inhibits angiogenesis and enhances efficacy of anti-tumor antibodies.

    Science.gov (United States)

    Justiniano, Steven E; Elavazhagan, Saranya; Fatehchand, Kavin; Shah, Prexy; Mehta, Payal; Roda, Julie M; Mo, Xiaokui; Cheney, Carolyn; Hertlein, Erin; Eubank, Timothy D; Marsh, Clay; Muthusamy, Natarajan; Butchar, Jonathan P; Byrd, John C; Tridandapani, Susheela

    2013-09-13

    Monocytes/macrophages are potent mediators of antitumor antibody therapy, where they engage target cells via Fcγ receptors (FcγR). Binding of these cells to opsonized tumor targets elicits cytokine production, phagocytosis, and antibody-mediated cellular cytotoxicity. Here we show for the first time that activation of monocyte FcγR results in the secretion of soluble vascular endothelial growth factor receptor-1 (VEGFR-1/sFlt-1), which serves to antagonize VEGF-mediated angiogenesis and tumor growth. Consistent with this, using a murine solid tumor model of antibody therapy, we show that sFlt-1 is involved in restricting tumor growth. Analyzing the mechanism of induction of sFlt-1, we found that the Erk and PI3K pathways were required for transcription, and NF-κB was required for translation. Upon closer examination of the role of NF-κB, we found that a microRNA, miR181a, negatively regulates FcγR-mediated sFlt-1 production and that NF-κB serves to antagonize this microRNA. Taken together, these results demonstrate a novel and biologically important function of monocytes and macrophages during antibody therapy.

  18. Fcγ Receptor-induced Soluble Vascular Endothelial Growth Factor Receptor-1 (VEGFR-1) Production Inhibits Angiogenesis and Enhances Efficacy of Anti-tumor Antibodies*

    Science.gov (United States)

    Justiniano, Steven E.; Elavazhagan, Saranya; Fatehchand, Kavin; Shah, Prexy; Mehta, Payal; Roda, Julie M.; Mo, Xiaokui; Cheney, Carolyn; Hertlein, Erin; Eubank, Timothy D.; Marsh, Clay; Muthusamy, Natarajan; Butchar, Jonathan P.; Byrd, John C.; Tridandapani, Susheela

    2013-01-01

    Monocytes/macrophages are potent mediators of antitumor antibody therapy, where they engage target cells via Fcγ receptors (FcγR). Binding of these cells to opsonized tumor targets elicits cytokine production, phagocytosis, and antibody-mediated cellular cytotoxicity. Here we show for the first time that activation of monocyte FcγR results in the secretion of soluble vascular endothelial growth factor receptor-1 (VEGFR-1/sFlt-1), which serves to antagonize VEGF-mediated angiogenesis and tumor growth. Consistent with this, using a murine solid tumor model of antibody therapy, we show that sFlt-1 is involved in restricting tumor growth. Analyzing the mechanism of induction of sFlt-1, we found that the Erk and PI3K pathways were required for transcription, and NF-κB was required for translation. Upon closer examination of the role of NF-κB, we found that a microRNA, miR181a, negatively regulates FcγR-mediated sFlt-1 production and that NF-κB serves to antagonize this microRNA. Taken together, these results demonstrate a novel and biologically important function of monocytes and macrophages during antibody therapy. PMID:23902770

  19. 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.

  20. The role of the vascular endothelial growth factor/vascular endothelial growth factor receptors axis mediated angiogenesis in curcumin-loaded nanostructured lipid carriers induced human HepG2 cells apoptosis

    Directory of Open Access Journals (Sweden)

    Fengling Wang

    2015-01-01

    Full Text Available Background: Curcumin (diferuloylmethane, the active constituent of turmeric extract has potent anti-cancer properties have been demonstrated in hepatocellular carcinoma (HCC. However, its underlying molecular mechanism of therapeutic effects remains unclear. Vascular endothelial growth factor (VEGF and its receptors (VEGFRs have crucial roles in tumor angiogenesis. Purpose: The goal of this study was to investigate the role of the VEGF/VEGFRs mediated angiogenesis during the proliferation and apoptosis of human HepG2 hepatoma cell line and the effect of curcumin-loaded nanostructured lipid carriers (Cur-NLC. Materials and Methods: The proliferation of HepG2 cells was determined by methyl thiazolyl tetrazolium after exposure to Cur-NLC and native curcumin. Apoptosis was quantified by flow cytometry with annexin V-fluorescein isothiocyanate and propidium iodide staining. Cellular internalization of Cur-NLC was observed by fluorescent microscope. The level of VEGF was detected by enzyme-linked immunosorbent assay kits. The expression of VEGFRs was quantified by Western blotting. Results: Cur-NLC was more effective in inhibiting the proliferation and enhancing the apoptosis of HepG2 cells than native curcumin. Fluorescent microscope analysis showed that HepG2 cells internalized Cur-NLC more effectively than native curcumin. Furthermore, Cur-NLC down-regulated the level of VEGF and the expression of VEGFR-2, but had a slight effect on VEGFR-1. Conclusion: These results clearly demonstrated that Cur-NLC was more effective in anti-cancer activity than the free form of curcumin. These studies demonstrate for the 1 st time that Cur-NLC exerts an antitumor effect on HepG2 cells by modulating VEGF/VEGFRs signaling pathway.

  1. Effect of non-anticoagulant N-desulfated heparin on expression of vascular endothelial growth factor, angiogenesis and metastasis of orthotopic implantation of human gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Jin-Lian Chen; Jing Hong; Jin-Lai Lu; Ming-Xiang Chen; Wei-Xiong Chen; Jin-Shui Zhu; Ni-Wei Chen; Guo-Qiang Chen; Jian-Guo Geng

    2007-01-01

    AIM: To investigate the effect of N-desulfated heparin on tumor metastasis and angiogenesis, and expression of vascular endothelial growth factor (VEGF) of orthotopic implantation of human gastric carcinoma in male severe combined immune deficiency (SCID) mice.METHODS: Human gastric cancer SGC-7901 cells were orthotopically implanted into the stomach of SCID mice.The mice were randomly divided into normal saline group and N-desulfated heparin group. One week after operation, the mice in N-desulfated heparin group received i.v. injections of N-desulfated heparin (Shanghai Institute of Cell Biology, Chinese Academy of Sciences,10 mg/kg.d) twice weekly for 3 wk. The mice in normal saline group received i.v. injections of normal saline (100pL) twice weekly for 3 wk. The mice were sacrificed six weeks after implantation. Tumor metastasis was evaluated histologically for metastasis under microscope. Intratumoral microvessel density (MVD) and VEGF expression were evaluated immuohistochemically. VEGF mRNA expression in gastric tissue of SCID mice was detected by real time PCR.RESULTS: The tumor metastasis rate was 80% in normal saline group and 20% in N-desulfated heparin group(P < 0.05). MVD was 8.0±3.1 in normal saline group and 4.3±1.8 in N-desulfated heparin group (P < 0.05).VEGF positive immunostaining was found in cytoplasm of cancer cells. The rate of VEGF positive expression was higher in normal saline group than in N-desulfated heparin treated group (90% VS 20%, P < 0.05). VEGF mRNA expression was significantly inhibited by N-desulfated heparin and was higher in normal saline group than in N-desulfated heparin group (Ct value 19.51±1.01 vs22.55±1.36, P < 0.05). N-desulfated heparin significantly inhibited the expression of VEGF mRNA in cancer cells. No bleeding occurred in N-desulfated heparin group.CONCLUSION: N-desulfated heparin can inhibit metastasis of gastric cancer by suppressing tumor VEGF expression and tumor angiogenesis, but has no obvious

  2. Ischemia-driven angiogenesis.

    Science.gov (United States)

    Dor, Y; Keshet, E

    1997-11-01

    New blood vessels usually develop in places where they are most needed. A prime example of neovascularization representing a positive feedback response to insufficient perfusion is the development of collateral blood vessels in the ischemic myocardium and leg. The recent discoveries of hypoxia-inducible transcription and angiogenic factors have provided important mechanistic links between the metabolic consequences of ischemia and compensatory angiogenesis. Vascular endothelial growth factor (VEGF) has emerged as the key mediator of ischemia-driven angiogenesis. Environmental stresses, including hypoxia, hypoglycemia, and hypoferremia, upregulate VEGF expression at both the transcriptional and posttranscriptional levels. VEGF acts in turn on adjacent vascular beds expressing cognate receptors and induces sprouting and capillary growth toward the ischemic tissue. In addition to expanding the vasculature at sites where existing vessels have been occluded or obliterated, VEGF also functions to match the vascular density according to development and physiologic increases in oxygen consumption. Fine adjustment of the vasculature includes a step of oxygen-regulated vascular pruning mediated by VEGF in its capacity as a survival factor for newly formed vessels. Pathologic settings of ischemia-driven angiogenesis include a major component of stress-induced angiogenesis during tumor neovascularization and abnormal vessel growth associated with retinopathies. The latter represents an excessive angiogenic response to conditions of severe retinal ischemia. Further insights into the mechanism of stress-induced angiogenesis are likely to suggest new ways to augment growth of collateral vessels and to restrain unwarranted neovascularization in tumors and retinopathies. (Trends Cardiovasc Med 1997;7:289-294). © 1997, Elsevier Science Inc.

  3. Increased proliferation of explanted vascular smooth muscle cells: a marker presaging atherogenesis.

    Science.gov (United States)

    Absher, P M; Schneider, D J; Baldor, L C; Russell, J C; Sobel, B E

    1997-06-01

    The JCR:LA-cp homozygous cp/cp corpulent rat is genetically predisposed to develop atherosclerosis evident after 9 and 18 months of age in males and females and to manifest metabolic derangements resembling those seen in type II diabetes in humans (hyperinsulinemia, insulin resistance, hyperglycemia and hypertriglyceridemia). The present study was undertaken to determine whether vascular smooth muscle cells (SMCs) explanted from vessels destined to become atherosclerotic later in life exhibit intrinsic properties ex vivo that presage atherogenesis to provide a means for evaluating promptly intervention designed to modify it. SMCs were cultured from aortic explants of JCR:LA-cp corpulent (cp/cp) and lean control (+/+) rats of 4, 5, 6, and 9 months of age. Compared with SMCs from controls, SMCs from cp/cp rats exhibited increased proliferation, higher saturation density, increased augmentation of proliferation in response to selected mitogens and greater adherence to extracellular matrix proteins. The increased proliferative activity ex vivo anteceded by several months the development of atherosclerotic lesions in vivo. Thus, it is a promising marker in assessments of the efficacy of interventions designed to retard or prevent atherosclerosis.

  4. Citicoline induces angiogenesis improving survival of vascular/human brain microvessel endothelial cells through pathways involving ERK1/2 and insulin receptor substrate-1

    Directory of Open Access Journals (Sweden)

    Krupinski Jerzy

    2012-12-01

    Full Text Available Abstract Background Citicoline is one of the neuroprotective agents that have been used as a therapy in stroke patients. There is limited published data describing the mechanisms through which it acts. Methods We used in vitro angiogenesis assays: migration, proliferation, differentiation into tube-like structures in Matrigel™ and spheroid development assays in human brain microvessel endothelial cells (hCMEC/D3. Western blotting was performed on protein extraction from hCMEC/D3 stimulated with citicoline. An analysis of citicoline signalling pathways was previously studied using a Kinexus phospho-protein screening array. A staurosporin/calcium ionophore-induced apoptosis assay was performed by seeding hCMEC/D3 on to glass coverslips in serum poor medium. In a pilot in vivo study, transient MCAO in rats was carried out with and without citicoline treatment (1000 mg/Kg applied at the time of occlusion and subsequently every 3 days until euthanasia (21 days. Vascularity of the stroke-affected regions was examined by immunohistochemistry. Results Citicoline presented no mitogenic and chemotactic effects on hCMEC/D3; however, it significantly increased wound recovery, the formation of tube-like structures in Matrigel™ and enhanced spheroid development and sprouting. Citicoline induced the expression of phospho-extracellular-signal regulated kinase (ERK-1/2. Kinexus assays showed an over-expression of insulin receptor substrate-1 (IRS-1. Knock-down of IRS-1 with targeted siRNA in our hCMEC/D3 inhibited the pro-angiogenic effects of citicoline. The percentage of surviving cells was higher in the presence of citicoline. Citicoline treatment significantly increased the numbers of new, active CD105-positive microvessels following MCAO. Conclusions The findings demonstrate both a pro-angiogenic and protective effect of citicoline on hCMEC/D3 in vitro and following middle cerebral artery occlusion (MCAO in vivo.

  5. Tumor angiogenesis: A potential marker of the ongoing process of malignant transformation in leukoplakia patients, removing the veil

    Directory of Open Access Journals (Sweden)

    Mubeen Khan

    2012-01-01

    Full Text Available Context: The diagnosis of malignant and potentially malignant epithelial lesions of the oral mucosa is based on a careful histologic evaluation of a representative biopsy specimen. The site for the biopsy, however, is always a subjective choice that raises doubts about its representativeness. So far, no simple and reliable method is available for selecting the most appropriate area for biopsy. Colposcopy, a well-known gynecological diagnostic procedure, is helpful in the selection of these sites of epithelial dysplasia depending upon the vascular patterns. Aims: The present study aimed at assessing the vascular patterns by colposcopic findings and selecting the biopsy site in leukoplakia patients and compared the two methods, clinical criteria, and colposcopic examination, for selecting the biopsy site. Settings and Design: Sixty patients between the ages of 30-60 years clinically diagnosed with leukoplakia were included in the study. Materials and Methods: For each of the subject, a thorough clinical examination was carried out followed by colpospopic examination for the selection of biopsy site. The histopathological findings were then compared in the two cases. Statistical Analysis Used: The statistical analysis was done using paired t-test. Results: Based on clinical criteria, a sensitivity of 0.5714 (57% and a specificity of 0.5000 (50% and that guided by colposcopic examination to be 0.8571 (85% and 0.6667 (66%, respectively, was found. Conclusions: From the study, it was concluded that colposcopic examination could prove to be a valuable diagnostic adjunct in the selection of biopsy site for leukoplakia patients.

  6. Association between noninvasive fibrosis markers and cardio-vascular organ damage among adults with hepatic steatosis.

    Directory of Open Access Journals (Sweden)

    Giorgio Sesti

    Full Text Available Evidence suggests that advanced fibrosis, as determined by the noninvasive NAFLD fibrosis score (NFS, is a predictor of cardiovascular mortality in individuals with ultrasonography-diagnosed NAFLD. Whether the severity of histology (i.e., fibrosis stage is associated with more pronounced cardiovascular organ damage is unsettled. In this study, we analyzed the clinical utility of NFS in assessing increased carotid intima-media thickness (cIMT, and left ventricular mass index (LVMI. In this cross-sectional study NFS, cIMT and LVMI were assessed in 400 individuals with ultrasonography-diagnosed steatosis. As compared with individuals at low probability of liver fibrosis, individuals both at high and at intermediate probability of fibrosis showed an unfavorable cardio-metabolic risk profile having significantly higher values of waist circumference, insulin resistance, high sensitivity C-reactive protein (hsCRP, fibrinogen, cIMT, and LVMI, and lower insulin-like growth factor-1 (IGF-1 levels. The differences in cIMT and LVMI remained significant after adjustment for smoking and metabolic syndrome. In a logistic regression model adjusted for age, gender, smoking, and diagnosis of metabolic syndrome, individuals at high probability of fibrosis had a 3.9-fold increased risk of vascular atherosclerosis, defined as cIMT>0.9 mm, (OR 3.95, 95% CI 1.12-13.87 as compared with individuals at low probability of fibrosis. Individuals at high probability of fibrosis had a 3.5-fold increased risk of left ventricular hypertrophy (LVH (OR 3.55, 95% CI 1.22-10.34 as compared with individuals at low probability of fibrosis. In conclusion, advanced fibrosis, determined by noninvasive fibrosis markers, is associated with cardiovascular organ damage independent of other known factors.

  7. 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 t...... targets the angiogenic process by investigation of tumor expression of MMP-2, MMP-9, and tissue inhibitors of metalloproteinase (TIMP)-1. A possible correlation with gender, patient age, symptom duration, tumor size, and the absolute and relative growth rate is explored....

  8. Use of tritiated thymidine as a marker to compare the effects of matrix proteins on adult human vascular endothelial cell attachment: implications for seeding of vascular prostheses

    Energy Technology Data Exchange (ETDEWEB)

    Hasson, J.E.; Wiebe, D.H.; Sharefkin, J.B.; D' Amore, P.A.; Abbott, W.M.

    1986-11-01

    We have developed a technique to measure attachment of adult human vascular endothelial cells to test surfaces with tritiated thymidine used as a marker. With this technique, we measured attachment of adult human vascular endothelial cells to a series of extracellular matrix proteins, including fibronectin-coated (10 micrograms/cm/sup 2/), laminin-coated (10 micrograms/cm/sup 2/), and collagen-coated (1% gelatin) surfaces because of the role of these proteins in promoting cell attachment and growth. For a typical experiment, in the presence of serum, initial attachment (at 1 hour) was greatest on fibronectin-coated (63%) and gelatin-coated (60%) tissue culture plastic (polystyrene) and was least on laminin-coated (28%) or untreated polystyrene (18%). The data suggest that fibronectin, either alone, or with a more complex combination of extracellular components may need to be present on prosthetic surfaces to produce maximal cell attachment and subsequent growth to confluence in vivo. The described method of measuring attachment is independent of surface properties, ensures complete recovery of cells, and will allow systematic exploration of those properties that best support human endothelial cell attachment to vascular prosthetic surfaces.

  9. Phosphocalcic Markers and Calcification Propensity for Assessment of Interstitial Fibrosis and Vascular Lesions in Kidney Allograft Recipients

    Science.gov (United States)

    Berchtold, Lena; Ponte, Belen; Moll, Solange; Hadaya, Karine; Seyde, Olivia; Bachtler, Matthias; Vallée, Jean-Paul; Martin, Pierre-Yves; Pasch, Andreas; de Seigneux, Sophie

    2016-01-01

    Renal interstitial fibrosis and arterial lesions predict loss of function in chronic kidney disease. Noninvasive estimation of interstitial fibrosis and vascular lesions is currently not available. The aim of the study was to determine whether phosphocalcic markers are associated with, and can predict, renal chronic histological changes. We included 129 kidney allograft recipients with an available transplant biopsy in a retrospective study. We analyzed the associations and predictive values of phosphocalcic markers and serum calcification propensity (T50) for chronic histological changes (interstitial fibrosis and vascular lesions). PTH, T50 and vitamin D levels were independently associated to interstitial fibrosis. PTH elevation was associated with increasing interstitial fibrosis severity (r = 0.29, p = 0.001), while T50 and vitamin D were protective (r = -0.20, p = 0.025 and r = -0.23, p = 0.009 respectively). On the contrary, fibroblast growth factor 23 (FGF23) and Klotho correlated only modestly with interstitial fibrosis (p = 0.045) whereas calcium and phosphate did not. PTH, vitamin D and T50 were predictors of extensive fibrosis (AUC: 0.73, 0.72 and 0.68 respectively), but did not add to renal function prediction. PTH, FGF23 and T50 were modestly predictive of low fibrosis (AUC: 0.63, 0.63 and 0.61) but did not add to renal function prediction. T50 decreased with increasing arterial lesions (r = -0.21, p = 0.038). The discriminative performance of T50 in predicting significant vascular lesions was modest (AUC 0.61). In summary, we demonstrated that PTH, vitamin D and T50 are associated to interstitial fibrosis and vascular lesions in kidney allograft recipients independently of renal function. Despite these associations, mineral metabolism indices do not show superiority or additive value to fibrosis prediction by eGFR and proteinuria in kidney allograft recipients, except for vascular lesions where T50 could be of relevance. PMID:28036331

  10. The activation of RhoC in vascular endothelial cells is required for the S1P receptor type 2-induced inhibition of angiogenesis.

    Science.gov (United States)

    Del Galdo, Sabrina; Vettel, Christiane; Heringdorf, Dagmar Meyer Zu; Wieland, Thomas

    2013-12-01

    Sphingosine-1-phosphate (S1P) is a multifunctional phospholipid inducing a variety of cellular responses in endothelial cells (EC). S1P responses are mediated by five G protein coupled receptors of which three types (S1P1R-S1P3R) have been described to be of importance in vascular endothelial cells (EC). Whereas the S1P1R regulates endothelial barrier function by coupling to Gαi and the monomeric GTPase Rac1, the signaling pathways involved in the S1P-induced regulation of angiogenesis are ill defined. We therefore studied the sprouting of human umbilical vein EC (HUVEC) in vitro and analyzed the activation of the RhoGTPases RhoA and RhoC. Physiological relevant concentrations of S1P (100-300nM) induce a moderate activation of RhoA and RhoC. Inhibition or siRNA-mediated depletion of the S1P2R preferentially decreased the activation of RhoC. Both manipulations caused an increase of sprouting in a spheroid based in vitro sprouting assay. Interestingly, a similar increase in sprouting was detected after effective siRNA-mediated knockdown of RhoC. In contrast, the depletion of RhoA had no influence on sprouting. Furthermore, suppression of the activity of G proteins of the Gα12/13 subfamily by adenoviral overexpression of the regulator of G protein signaling domain of LSC as well as siRNA-mediated knockdown of the Rho specific guanine nucleotide exchange factor leukemia associated RhoGEF (LARG) inhibited the S1P-induced activation of RhoC and concomitantly increased sprouting of HUVEC with similar efficacy. We conclude that the angiogenic sprouting of EC is suppressed via the S1P2R subtype. Thus, the increase in basal sprouting can be attributed to blocking of the inhibitory action of autocrine S1P stimulating the S1P2R. This inhibitory pathway involves the activation of RhoC via Gα12/13 and LARG, while the simultaneously occurring activation of RhoA is apparently dispensable here.

  11. No effect of unfractioned or low molecular weight heparin treatment on markers of vascular wall and hemostatic function in incipient diabetic nephropathy

    NARCIS (Netherlands)

    Myrup, B.; Jensen, T.; Gram, J.; Kluft, C.; Jespersen, J.; Deckert, T.

    1997-01-01

    OBJECTIVE - The high risk for cardiovascular disease in IDDM patients with nephropathy may be mediated by abnormal function of the vascular wall. We investigated whether heparin was able to modulate markers of vascular wall and hemostatic function in patients with incipient nephropathy. RESEARCH DES

  12. Regulation of Vascular Tone, Angiogenesis and Cellular Bioenergetics by the 3-Mercaptopyruvate Sulfurtransferase/H2S Pathway: Functional Impairment by Hyperglycemia and Restoration by DL-α-Lipoic Acid.

    Science.gov (United States)

    Coletta, Ciro; Módis, Katalin; Szczesny, Bartosz; Brunyánszki, Attila; Oláh, Gábor; Rios, Ester C S; Yanagi, Kazunori; Ahmad, Akbar; Papapetropoulos, Andreas; Szabo, Csaba

    2015-02-18

    Hydrogen sulfide (H2S), as a reducing agent and an antioxidant molecule, exerts protective effects against hyperglycemic stress in the vascular endothelium. The mitochondrial enzyme 3-mercaptopyruvate sulfurtransferase (3-MST) is an important biological source of H2S. We have recently demonstrated that 3-MST activity is inhibited by oxidative stress in vitro and speculated that this may have an adverse effect on cellular homeostasis. In the current study, given the importance of H2S as a vasorelaxant, angiogenesis stimulator and cellular bioenergetic mediator, we first determined whether the 3-MST/H2S system plays a physiological regulatory role in endothelial cells. Next, we tested whether a dysfunction of this pathway develops during the development of hyperglycemia and μmol/L to diabetes-associated vascular complications. Intraperitoneal (IP) 3-MP (1 mg/kg) raised plasma H2S levels in rats. 3-MP (10 1 mmol/L) promoted angiogenesis in vitro in bEnd3 microvascular endothelial cells and in vivo in a Matrigel assay in mice (0.3-1 mg/kg). In vitro studies with bEnd3 cell homogenates demonstrated that the 3-MP-induced increases in H2S production depended on enzymatic activity, although at higher concentrations (1-3 mmol/L) there was also evidence for an additional nonenzymatic H2S production by 3-MP. In vivo, 3-MP facilitated wound healing in rats, induced the relaxation of dermal microvessels and increased mitochondrial bioenergetic function. In vitro hyperglycemia or in vivo streptozotocin diabetes impaired angiogenesis, attenuated mitochondrial function and delayed wound healing; all of these responses were associated with an impairment of the proangiogenic and bioenergetic effects of 3-MP. The antioxidants DL-α-lipoic acid (LA) in vivo, or dihydrolipoic acid (DHLA) in vitro restored the ability of 3-MP to stimulate angiogenesis, cellular bioenergetics and wound healing in hyperglycemia and diabetes. We conclude that diabetes leads to an impairment of the 3-MST

  13. The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model.

    Directory of Open Access Journals (Sweden)

    Eric C Woolf

    Full Text Available The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.

  14. Angiogenesis in female reproductive system

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    @@Neovascularization, i.e. new blood vessels formation, can be divided into two different processes: vasculogenesis, whereby a primitive vascular network is established during embryogenesis from multipotential mesenchymal progenitors; and angiogenesis, which refers to the new blood vessels formation from pre-existing vessels[1,2]. Angiogenesis contributes to the most process throughout the whole life span from embryonic development to adult growth[2]. In this meaning, neovascularization is usually used to imply angiogenesis. Under physiological condi-tions, angiogenesis is a strictly regulated event and rarely happens in most adult tissues except for fracture or heal-ing of wounds[2,3]. However, a notable phenomenon is that the tissues of ovary and uterine endometrium are unique in the cycle-specific changes in vascularity that occur in each estrous/menstrual cycle. Active angiogenesis occurs in placenta to satisfy the needs of embryonic implantation and development. Defects in angiogenesis are associated with some gynecopathies including luteal phase defect, endometriosis, pregnancy loss and preeclampsia[4].

  15. Targeting Angiogenesis in Biliary Tract Cancers: An Open Option

    Directory of Open Access Journals (Sweden)

    Valeria Simone

    2017-02-01

    Full Text Available Biliary tract cancers (BTCs are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF and fibroblast growth factor (FGF, are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2, are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.

  16. Angiogenesis in male breast cancer

    Directory of Open Access Journals (Sweden)

    Kanthan Rani

    2005-03-01

    Full Text Available Abstract Background Male breast cancer is a rare but aggressive and devastating disease. This disease presents at a later stage and in a more advanced fashion than its female counterpart. The immunophenotype also appears to be distinct when compared to female breast cancer. Angiogenesis plays a permissive role in the development of a solid tumor and provides an avenue for nutrient exchange and waste removal. Recent scrutiny of angiogenesis in female breast cancer has shown it to be of significant prognostic value. It was hypothesized that this holds true in invasive ductal carcinoma of the male breast. In the context of male breast cancer, we investigated the relationship of survival and other clinico-pathological variables to the microvascular density of the tumor tissue. Methods Seventy-five cases of primary male breast cancer were identified using the records of the Saskatchewan Cancer Agency over a period of 26 years. Forty-seven cases of invasive ductal carcinoma of the male breast had formalin-fixed paraffin-embedded tissue blocks that were suitable for this study. All cases were reviewed. Immunohistochemical staining was performed for the angiogenic markers (cluster designations 31 (CD31, 34 (CD34 and 105 (CD105, von Willebrand factor (VWF, and vascular endothelial growth factor (VEGF. Microvascular density (MVD was determined using average, centre, and highest microvessel counts (AMC, CMC, and HMC, respectively. Statistical analyses compared differences in the distribution of survival times and times to relapse between levels of MVD, tumor size, node status and age at diagnosis. In addition, MVD values were compared within each marker, between each marker, and were also compared to clinico-pathological data. Results Advanced age and tumor size were related to shorter survival times. There were no statistically significant differences in distributions of survival times and times to relapse between levels of MVD variables. There was no

  17. Erythropoietin and vascular endothelial growth factor as risk markers for severe hypoglycaemia in type 1 diabetes

    DEFF Research Database (Denmark)

    Kristensen, P L; Pedersen-Bjergaard, U; Schalkwijk, C

    2010-01-01

    OBJECTIVE: Circulating erythropoietin (EPO) and vascular endothelial growth factor (VEGF) increase during hypoglycaemia and may represent protective hormonal counter-regulatory responses. We tested the hypothesis that low levels of EPO and VEGF are associated with a higher frequency of severe...... levels to determine future risk of severe hypoglycaemia in people with type 1 diabetes....

  18. Comparison of mesenchymal stem cell surface markers from bone marrow aspirates and adipose stromal vascular fraction sites

    Directory of Open Access Journals (Sweden)

    Meghan eSullivan

    2016-01-01

    Full Text Available AbstractThe objective of this study was to subjectively evaluate the harvest of 2 areas of adipose collection and 3 areas of bone marrow collection as potential sites for clinical harvest of adipose stromal vascular fraction and bone marrow concentrate for clinical use by quantifying the amount of tissue harvested, subjective ease of harvest, the variation of each site, and determining the cell surface marker characteristics using commercially available antibodies. Bone marrow and adipose tissue samples were collected from 10 adult mixed breed dogs. Adipose tissue was collected from the caudal scapular region and falciform fat ligament. Bone marrow aspirates were collected from the ilium, humerus, and tibia. Tissues were weighed (adipose or measured by volume (bone marrow, processed to isolate the stromal vascular fraction or bone marrow concentrate, and flow cytometry was performed to quantitate the percentage of cells that were CD90, CD44 positive and CD45 negative. Sites and tissue types were compared using matched pairs t-test. Subjectively subcutaneous fat collection was the most difficult and large amounts of tissue dissection were necessary. Additionally the subcutaneous area yielded less than the goal amount of tissue. The bone marrow harvest ranged from 10-27.5 ml. Adipose tissue had the highest concentration of cells with CD90+, CD44+, and CD45- markers (p<0.05, and bone marrow had the highest total number of these cells at harvest (p<0.05. Variation was high for all sites but the adipose collection yielded more consistent results. These results describe the relative cellular components in the stromal vascular fraction of adipose tissue and bone marrow as defined by the biomarkers chosen. Although bone marrow yielded higher absolute cell numbers on average, adipose tissue yielded more consistent results. Fat from the falciform ligament was easily obtained with less dissection and therefore created less perceived relative patient trauma.

  19. Markers of T cell infiltration and function associate with favorable outcome in vascularized high-grade serous ovarian carcinoma.

    Directory of Open Access Journals (Sweden)

    Katelin N Townsend

    Full Text Available BACKGROUND: When T cells infiltrate the tumor environment they encounter a myriad of metabolic stressors including hypoxia. Overcoming the limitations imposed by an inadequate tumor vasculature that contributes to these stressors may be a crucial step to immune cells mounting an effective anti-tumor response. We sought to determine whether the functional capacity of tumor infiltrating lymphocytes (TIL could be influenced by the tumor vasculature and correlated this with survival in patients with ovarian cancer. METHODOLOGY AND PRINCIPAL FINDINGS: In 196 high-grade serous ovarian tumors, we confirmed that the tumor vascularity as measured by the marker CD31 was associated with improved patient disease-specific survival. We also found that tumors positive for markers of TIL (CD8, CD4 and forkhead box P3 (FoxP3 and T cell function (granzyme B and T-cell restricted intracellular antigen-1 (TIA-1 correlated significantly with elevated vascularity. In vitro, hypoxic CD8 T cells showed reduced cytolytic activity, secreted less effector cytokines and upregulated autophagy. Survival analysis revealed that patients had a significant improvement in disease-specific survival when FoxP3 expressing cells were present in CD31-high tumors compared to patients with FoxP3 expressing cells in CD31-low tumors [HR: 2.314 (95% CI 1.049-5.106; p = 0.0377]. Patients with high vascular endothelial growth factor (VEGF expressing tumors containing granzyme B positive cells had improved survival compared to patients with granzyme B positive cells in VEGF-low tumors [HR: 2.522 (95% CI 1.097-5.799; p = 0.0294]. SIGNIFICANCE: Overall, this data provides a rationale for developing strategies aimed at improving the adaptability and function of TIL to hypoxic tumor conditions.

  20. Are markers of inflammation more strongly associated with risk for fatal than for nonfatal vascular events?

    LENUS (Irish Health Repository)

    Sattar, Naveed

    2009-06-23

    Circulating inflammatory markers may more strongly relate to risk of fatal versus nonfatal cardiovascular disease (CVD) events, but robust prospective evidence is lacking. We tested whether interleukin (IL)-6, C-reactive protein (CRP), and fibrinogen more strongly associate with fatal compared to nonfatal myocardial infarction (MI) and stroke.

  1. 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.

  2. Role of angiogenesis in chronic lymphocytic leukemia.

    Science.gov (United States)

    Letilovic, Tomislav; Vrhovac, Radovan; Verstovsek, Srdan; Jaksic, Branimir; Ferrajoli, Alessandra

    2006-09-01

    Angiogenesis is a physiologic process of new blood vessels formation mediated by various cytokines called angiogenic and angiostatic factors. Although its potential pathophysiologic role in solid tumors has been extensively studied for more than 3 decades, enhancement of angiogenesis in chronic lymphocytic leukemia (CLL) and other malignant hematological disorders has been recognized more recently. An increased level of angiogenesis has been documented by various experimental methods both in bone marrow and lymph nodes of patients with CLL. Although the role of angiogenesis in the pathophysiology of this disease remains to be fully elucidated, experimental data suggest that several angiogenic factors play a role in the disease progression. Biologic markers of angiogenesis were also shown to be of prognostic relevance in CLL. The current findings provide the rationale for investigating antiangiogenic agents in CLL. In the current review angiogenesis in CLL is discussed and its potential diagnostic and therapeutic applications.

  3. Cardiovascular, renal and thyroid toxicity during angiogenesis inhibition: A translational approach

    NARCIS (Netherlands)

    M.H.W. Kappers (Mariette)

    2011-01-01

    textabstractInhibition of angiogenesis with humanized monoclonal antibodies to vascular endothelial growth factor (VEGF) or with tyrosine kinase inhibitors targeting VEGF receptors has become an established treatment for various tumor types. Contrary to expectations, angiogenesis inhibition by block

  4. Analyzing the Correlation between the Level of Serum Markers and Ischemic Cerebral Vascular Disease by Multiple Parameters

    Directory of Open Access Journals (Sweden)

    Laibin Dong

    2015-01-01

    Full Text Available Objective. To explore the serum markers associated with ischemic cerebral vascular disease (ICVD and discuss their diagnostic value. Methods. Two hundred and eighty-eight patients with ICVD and one hundred and eighty healthy persons were enrolled as the case group and the control group, respectively. This paper then carried out the univariate and multivariate logistic regression analyses of their respective levels of serum markers, made combined analysis of related factors, and detected the diagnostic value. Results. Meta-analysis results showed that for ICVD patients the levels of CRP, S-100, TNF-α, HCY, NSE, and IL-6 were higher than those of the healthy persons, while the level of HDL was obviously lower than that of the healthy persons. The multivariate regression analysis indicated that the association between the level of HDL and TNF-α and the occurrence of ICVD was statistically significant (P<0.05. The area under the curves (AUC of receiver operating characteristic (ROC curve of HDL and TNF-α was 0.916, with sensitivity of 90.91% and specificity of 76.47%. Conclusion. HDL has negative correlation with the occurrence of ICVD, while TNF-α was positively correlated with it. The combination test of HDL and TNF-α could raise the accuracy of ICVD diagnosis.

  5. Angiogenesis in the corpus luteum

    Directory of Open Access Journals (Sweden)

    Wulff Christine

    2003-11-01

    Full Text Available Abstract The corpus luteum (CL is a site of intense angiogenesis. Within a short period, this is followed either by controlled regression of the microvascular tree in the non-fertile cycle, or maintenance and stabilisation of the new vasculature a conceptual cycle. The molecular regulation of these diverse aspects is examined. The CL provides a unique model system in which to study the cellular and molecular regulation of angiogenesis. Vascular endothelial growth factor (VEGF has been found to have a major role in the CL. By targeting its action at specific stages of the luteal phase in vivo by antagonists, profound inhibitory effects on luteal angiogenesis and function are observed.

  6. The Role of Capillaries in the Lesser Ailments of Old Age and in Alzheimer's Disease and Vascular Dementia: The Potential of Pro-Therapeutic Angiogenesis.

    Science.gov (United States)

    Ambrose, Charles T

    2016-07-01

    Apart from chronic diseases (arthritis, diabetes, etc.), old age is generally characterized by three lesser ailments: muscle weakness, minor memory lapses, and cold intolerance. This trio of complaints may have a common, underlying cause, namely, the age-associated reduced microcirculation in muscles, brain, skin, and elsewhere in the body. The Angiogenesis Hypothesis proposes that old age is in part a deficiency disease due to the decline in angiogenic (AG) factors, resulting in a reduced capillary density (CD) throughout the body. Over fifty published papers document waning levels of AG factors and/or decreased CD in various organ systems of aged animals and people, including those with Alzheimer's disease. The deficiency of AG factors is analogous to that of certain hormones (e.g., testosterone) whose blood levels also decline with age. In theory, therapeutic angiogenesis employing recombinant AG factors is a tenable treatment for the lesser ailments of old age and may improve the later years of human life. An optimal administration route may be intranasal.

  7. Relationship between arterial vascular calcifications seen on screening mammograms and biochemical markers of endothelial injury

    Energy Technology Data Exchange (ETDEWEB)

    Pidal, Diego [Unidad de Investigacion del, Hospital de Jove, Gijon (Spain)], E-mail: dpidal@hotmail.com; Sanchez Vidal, M Teresa [Servicio de Medicina Interna, Hospital de Jove (Spain)], E-mail: medicinainterna@hospitaldejove.com; Rodriguez, Juan Carlos [Unidad de Investigacion del, Hospital de Jove, Gijon (Spain); Servicio de Cirugia General, Hospital de Jove (Spain); Instituto Universitario de Oncologia del Principado de Asturias, Oviedo (Spain)], E-mail: investigacion@hospitaldejove.com; Corte, M Daniela [Unidad de Investigacion del, Hospital de Jove, Gijon (Spain); Instituto Universitario de Oncologia del Principado de Asturias, Oviedo (Spain)], E-mail: mdanielac@hotmail.com; Pravia, Paz [Servicio de Radiodiagnostico, Hospital de Jove (Spain)], E-mail: radiologia@hospitaldejove.com; Guinea, Oscar [Servicio de Radiodiagnostico, Hospital de Jove (Spain)], E-mail: oscarfguinea@seram.org; Pidal, Ivan [Unidad de Investigacion del, Hospital de Jove, Gijon (Spain)], E-mail: ivanpida@hotmail.com; Bongera, Miguel [Unidad de Investigacion del, Hospital de Jove, Gijon (Spain)], E-mail: mbchoppy@hotmail.com; Escribano, Damaso [Servicio de Medicina Interna, Hospital de Jove (Spain)], E-mail: medicinainterna@hospitaldejove.com; Gonzalez, Luis O. [Unidad de Investigacion del, Hospital de Jove, Gijon (Spain)], E-mail: lovidiog@telefonica.net; Diez, M Cruz [Servicio de Cirugia General, Hospital de Jove (Spain)], E-mail: cirugiageneral@hospitaldejove.com; Venta, Rafael [Servicio de Analisis Clinicos, Hospital de San Agustin, Aviles (Spain); Departamento de Bioquimica y Biologia Molecular, Universidad de Oviedo (Spain)], E-mail: rafael.venta@sespa.princast.es; Vizoso, Francisco J. [Unidad de Investigacion del, Hospital de Jove, Gijon (Spain); Servicio de Cirugia General, Hospital de Jove (Spain); Instituto Universitario de Oncologia del Principado de Asturias, Oviedo (Spain)], E-mail: fjvizoso@telefonica.net

    2009-01-15

    To assess whether breast arterial calcifications (BAC) are associated with altered serum markers of cardiovascular risk, mammograms and records from 1759 women (age range: 45-65 years) screened for breast cancer were revised. One hundred and forty seven (8.36%) women showed BAC. A total of 136 women with BAC and controls (mean age: 57 and 55 years, respectively) accepted entering the study. There were no significant differences in serum levels of urea, glucose, uric acid, creatinine, total cholesterol, HDL-C, LDL-C, folic acid, vitamin B{sub 12}, TSH or cysteine, between both groups of patients. However, women with BAC showed higher serum levels of triglycerides (p = 0.006), homocysteine (p = 0.002) and hs-CRP (p = 0.003) than women without BAC. Likewise, we found a significantly higher percentage of cases with an elevated LDL-C/HDL-C ratio (coronary risk index >2) amongst women with BAC than in women without BAC (56.7 and 38.2%, respectively; p = 0.04). Our results indicate that the finding of BAC identify women showing altered serum markers of cardiovascular risk.

  8. Role of endogenous angiogenesis inhibitors in Down syndrome.

    Science.gov (United States)

    Ryeom, Sandra; Folkman, Judah

    2009-03-01

    New blood vessel growth via angiogenesis is a fundamental process in both physiological and pathological conditions. Physiological angiogenesis is critical during embryogenesis and placental development, whereas pathological angiogenesis plays an important role in the progression of many diseases, most notably tumor growth. Tumor angiogenesis is well accepted to be regulated by a balance of proangiogenic and antiangiogenic factors produced both by tumor cells and surrounding stromal cells. For many years, investigation of antiangiogenic therapies for cancer has focused on the proangiogenic cytokine, vascular endothelial growth factor; its receptors; or downstream signaling pathways. However, more recently with the identification of endogenous angiogenesis inhibitors, studies have turned toward understanding the role of endogenous antiangiogenic proteins in preventing disease progression. Clinical clues have suggested that specific populations may have dysregulated angiogenesis due to differential expression of endogenous angiogenesis regulators. For example, individuals with Down syndrome may possess a systemic antiangiogenic state with a significantly decreased incidence of angiogenesis-dependent diseases. Our work suggests that endogenous angiogenesis inhibitors may be the master regulators controlling progression of angiogenesis-dependent diseases such as vascular anomalies and cancer. The molecular regulation of angiogenesis is not yet fully understood; however, the Down syndrome population may give us insights toward novel therapies for controlling angiogenesis in disease.

  9. Slit-Robo signaling in ocular angiogenesis.

    Science.gov (United States)

    Chen, Haoyu; Zhang, Mingzhi; Tang, Shibo; London, Nyall R; Li, Dean Y; Zhang, Kang

    2010-01-01

    Slit-Robo signaling was firstly discovered as a major repellent pathway at the midline of the central nervous system. Intense investigation found that this pathway also plays an important role in other biological process including angiogenesis. Robo4 is the vascular endothelial cell specific member of Robo family. It was found that Slit-Robo signaling can inhibit endothelial cell migration, tube formation and vascular permeability. Slit-Robo signaling also plays an important role in embryonic and tumor angiogenesis. In animal model of ocular angiogenesis, addition of Slit inhibited laser induced choroidal neovascularization, oxygen induced retinopathy and VEGF induced retinal permeability in a Robo4 dependent manner. Recent data demonstrates that Robo1 and Robo4 form a heterodimer in endothelial cells, The role of this heterodimer in counteracting VEGF signaling is unknown. Further investigation is required to better understand Slit-Robo signaling and develop novel therapy for angiogenesis.

  10. Aberrant angiogenesis: The gateway to diabetic complications

    Directory of Open Access Journals (Sweden)

    Sunil K Kota

    2012-01-01

    Full Text Available Diabetes Mellitus is a metabolic cum vascular syndrome with resultant abnormalities in both micro- and macrovasculature. The adverse long-term effects of diabetes mellitus have been described to involve many organ systems. Apart from hyperglycemia, abnormalities of angiogenesis may cause or contribute toward many of the clinical manifestations of diabetes. These are implicated in the pathogenesis of vascular abnormalities of the retina, kidneys, and fetus, impaired wound healing, increased risk of rejection of transplanted organs, and impaired formation of coronary collaterals. A perplexing feature of the aberrant angiogenesis is that excessive and insufficient angiogenesis can occur in different organs in the same individual. The current article hereby reviews the molecular mechanisms including abnormalities in growth factors, cytokines, and metabolic derangements, clinical implications, and therapeutic options of dealing with abnormal angiogenesis in diabetes.

  11. Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer

    Institute of Scientific and Technical Information of China (English)

    Atsuko Sakurai; Colleen Doci; J Silvio Gutkind

    2012-01-01

    Angiogenesis,the formation of new blood vessels from preexisting vasculature,is essential for many physiological processes,and aberrant angiogenesis contributes to some of the most prevalent human diseases,including cancer.Angiogenesis is controlled by delicate balance between pro- and anti-angiogenic signals.While pro-angiogenic signaling has been extensively investigated,how developmentally regulated,naturally occurring anti-angiogenic molecules prevent the excessive growth of vascular and lymphatic vessels is still poorly understood.In this review,we summarize the current knowledge on how semaphorins and their receptors,plexins and neuropilins,control normal and pathological angiogenesis,with an emphasis on semaphorin-regulated anti-angiogenic signaling circuitries in vascular and lymphatic endothelial cells.This emerging body of information may afford the opportunity to develop novel anti-angiogenic therapeutic strategies.

  12. Immunotherapy of tumor by targeting angiogenesis

    Institute of Scientific and Technical Information of China (English)

    HOU Jianmei; TIAN Ling; WEI Yuquan

    2004-01-01

    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy represents a new strategy for the development of anti-cancer therapies. In recent years, there has been made great progress in anti-angiogenic therapy. As far as the passive immunotherapy is concerned, a recombinant humanized antibody to vascular endothelial growth factor (VEGF)-Avastin has been approved by FDA as the first angiogenesis inhibitor to treat colorectal cancer. For active specific immunotherapy, various strategies for cancer vaccines, including whole endothelial cell vaccines, dendritic cell vaccines, DNA vaccines, and peptides or protein vaccines, have been developed to break immune tolerance against important molecules associated with tumor angiogenesis and induce angiogenesis-specific immune responses. This article reviews the angiogenesis-targeted immunotherapy of tumor from the above two aspects.

  13. Vascular and Alzheimer's disease markers independently predict brain atrophy rate in Alzheimer's Disease Neuroimaging Initiative controls.

    Science.gov (United States)

    Barnes, Josephine; Carmichael, Owen T; Leung, Kelvin K; Schwarz, Christopher; Ridgway, Gerard R; Bartlett, Jonathan W; Malone, Ian B; Schott, Jonathan M; Rossor, Martin N; Biessels, Geert Jan; DeCarli, Charlie; Fox, Nick C

    2013-08-01

    This study assessed relationships among white matter hyperintensities (WMH), cerebrospinal fluid (CSF), Alzheimer's disease (AD) pathology markers, and brain volume loss. Subjects included 197 controls, 331 individuals with mild cognitive impairment (MCI), and 146 individuals with AD with serial volumetric 1.5-T MRI. CSF Aβ1-42 (n = 351) and tau (n = 346) were measured. Brain volume change was quantified using the boundary shift integral (BSI). We assessed the association between baseline WMH volume and annualized BSI, adjusting for intracranial volume. We also performed multiple regression analyses in the CSF subset, assessing the relationships of WMH and Aβ1-42 and/or tau with BSI. WMH burden was positively associated with BSI in controls (p = 0.02) but not MCI or AD. In multivariable models, WMH (p = 0.003) and Aβ1-42 (p = 0.001) were independently associated with BSI in controls; in MCI Aβ1-42 (p brain atrophy in the context of AD pathology in pre-dementia stages.

  14. Comparison of Mesenchymal Stem Cell Surface Markers from Bone Marrow Aspirates and Adipose Stromal Vascular Fraction Sites.

    Science.gov (United States)

    Sullivan, Meghan O; Gordon-Evans, Wanda J; Fredericks, Lisa Page; Kiefer, Kristina; Conzemius, Michael G; Griffon, Dominique J

    2015-01-01

    The objective of this study was to subjectively evaluate the harvest of two areas of adipose collection and three areas of bone marrow collection as potential sites for clinical harvest of adipose stromal vascular fraction (SVF) and bone marrow concentrate for clinical use by quantifying the amount of tissue harvested, subjective ease of harvest, the variation of each site, and determining the cell surface marker characteristics using commercially available antibodies. Bone marrow and adipose tissue samples were collected from 10 adult mixed breed dogs. Adipose tissue was collected from the caudal scapular region and falciform fat ligament. Bone marrow aspirates were collected from the ilium, humerus, and tibia. Tissues were weighed (adipose) or measured by volume (bone marrow), processed to isolate the SVF or bone marrow concentrate, and flow cytometry was performed to quantitate the percentage of cells that were CD90, CD44 positive, and CD45 negative. Sites and tissue types were compared using matched pairs t-test. Subjectively subcutaneous fat collection was the most difficult and large amounts of tissue dissection were necessary. Additionally the subcutaneous area yielded less than the goal amount of tissue. The bone marrow harvest ranged from 10 to 27.5 ml. Adipose tissue had the highest concentration of cells with CD90(+), CD44(+), and CD45(-) markers (P adipose collection yielded more consistent results. These results describe the relative cellular components in the SVF of adipose tissue and bone marrow as defined by the biomarkers chosen. Although bone marrow yielded higher absolute cell numbers on average, adipose tissue yielded more consistent results. Fat from the falciform ligament was easily obtained with less dissection and therefore created less perceived relative patient trauma.

  15. The LIPT-Study: On Risk Markers of Vascular Thrombosis in Polycystic Ovary Syndrome. A Randomized, Double-Blind, Placebo-Controlled Study of the Effect of Liraglutide

    DEFF Research Database (Denmark)

    Frøssing, Signe; Nylander, Malin; Kistorp, Caroline Michaela;

    2015-01-01

    arterial stiffness, all regarded as risk factors or markers for the development of cardiovascular disease. These factors are not taken into account in the definition of the syndrome, which is based on the 3 Rotterdam criteria. An uncertainty of the clinical risk of cardiovascular disease (CVD......) in these relatively young women has led to many studies on surrogate markers of CVD in PCOS, including the search for new markers with additional information of the arteriosclerotic burden in PCOS. GLP-1 analogues, originally developed for the treatment of diabetes, induce weight loss also in non-diabetic people. We...... therefore questioned whether treatment with the GLP-1 analogue Liraglutide to women with PCOS in doses used for diabetes could induce weight loss and improve IR and through this action, or independently, improve markers of vascular thrombosis in women with PCOS. Thus, 70 overweight and/or insulin resistant...

  16. Expression of angiopoietin-2 and vascular endothelial growth factor receptor-3 correlates with lymphangiogenesis and angiogenesis and affects survival of oral squamous cell carcinoma.

    Directory of Open Access Journals (Sweden)

    Chao Li

    Full Text Available BACKGROUND: Both Ang-2 and VEGFR-3 are major regulators of angiogenesis and lymphangiogenesis, respectively, and thus may affect prognosis of OSCC. We sought to determine the associations between Ang-2 and VEGFR-3 expression and survival of OSCC. METHODS: Ang-2 and VEGFR-3 expression was determined immunohistochemically in tumor tissues from 112 patients with OSCC; OSCC-adjacent noncancerous oral tissue from 85 OSCC patients; and normal oral mucosa from 37 cancer-free individuals. A log-rank test and Cox proportional hazard models were used to compare survival among different groups with expression of Ang-2 and VEGFR-3. RESULTS: Ang-2 and VEGFR-3 expression was upregulated in OSCC compared to nontumor tissue (all P<0.05. High Ang-2 expression positively correlated with microvessel density (MVD (P<0.01, and high VEGFR-3 expression positively correlated with lymph node metastasis (P<0.01 and lymphatic vessel density (LVD (P<0.01. The patients with high expression of Ang-2 alone or in combination with VEGFR-3 had a significantly worse survival than in patients with low expression of Ang-2 or any other co-expression status (all P<0.05, respectively. Furthermore, multivariable analysis showed that patients with high expression of Ang-2 alone or in combination with VEGFR-3 had a significantly increased risk of death compared with those with low expression of Ang-2 or any other co-expression status (HR, 2.7, 95% CI, 1.1-6.2 and 5.0, 1.3-15.4, respectively. CONCLUSIONS: These results suggest that increased expression in tumors of Ang-2 may individually, or in combination with VEGFR-3, predict poor prognosis of OSCC.

  17. The effect of short-term withdrawal from continuous positive airway pressure therapy on sympathetic activity and markers of vascular inflammation in subjects with obstructive sleep apnoea.

    Science.gov (United States)

    Phillips, Craig L; Yang, Qiao; Williams, Andrew; Roth, Michael; Yee, Brendon J; Hedner, Jan A; Berend, Norbert; Grunstein, Ronald R

    2007-06-01

    Obstructive sleep apnoea (OSA) is commonly associated with cardiovascular disease and sympathetic activation. However, it is unclear whether this association is independent of obesity and to what extent treatment with nasal continuous positive airway pressure (CPAP) alleviates the vascular inflammation that underpins cardiovascular disease. We therefore evaluated whether short-term withdrawal from CPAP therapy in subjects with moderate-severe OSA would result in increased levels of sympathetic activity and circulating inflammatory cytokines independent of weight. Vascular inflammatory markers (hsCRP, hsIL-6 and hsTNF-alpha) were assessed in 20 subjects after one and seven nights of withdrawal from CPAP together with the hypoxia-responsive angiogenic marker VEGF and urinary catecholamines. Compared with baseline on CPAP, withdrawal from therapy resulted in an immediate return of OSA with an increase in RDI to 26.7 +/- 5.2 and 39.0 +/- 5.9 events per hour after one and seven nights without CPAP, respectively (both P 0.1). In conclusion, 1 week of CPAP withdrawal was associated with a return of OSA and a marked increase in sympathetic activity without a concomitant elevation of vascular inflammatory markers.

  18. In situ vascular regeneration using substance P-immobilised poly(L-lactide-co-ε-caprolactone) scaffolds: stem cell recruitment, angiogenesis, and tissue regeneration.

    Science.gov (United States)

    Shafiq, M; Jung, Y; Kim, S H

    2015-11-27

    In situ tissue regeneration holds great promise for regenerative medicine and tissue engineering applications. However, to achieve control over long-term and localised presence of biomolecules, certain barriers must be overcome. The aim of this study was to develop electrospun scaffolds for the fabrication of artificial vascular grafts that can be remodelled within a host by endogenous cell recruitment. We fabricated scaffolds by mixing appropriate proportions of linear poly (l-lactide-co-ε-caprolactone) (PLCL) and substance P (SP)-immobilised PLCL, using electrospinning to develop vascular grafts. Substance P was released in a sustained fashion from electrospun membranes for up to 30 d, as revealed by enzyme-linked immunosorbent assay. Immobilised SP remained bioactive and recruited human bone marrow-derived mesenchymal stem cells (hMSCs) in an in vitro Trans-well migration assay. The biocompatibility and biological performance of the scaffolds were evaluated by in vivo experiments involving subcutaneous scaffold implantations in Sprague-Dawley rats for up to 28 d followed by histological and immunohistochemical studies. Histological analysis revealed a greater extent of accumulative host cell infiltration and collagen deposition in scaffolds containing higher contents of SP than observed in the control group at both time points. We also observed the presence of a large number of laminin-positive blood vessels and Von Willebrand factor (vWF+) cells in the explants containing SP. Additionally, scaffolds containing SP showed the existence of CD90+ and CD105+ MSCs. Collectively, these findings suggest that the methodology presented here may have broad applications in regenerative medicine, and the novel scaffolding materials can be used for in situ tissue regeneration of soft tissues.

  19. Role of EC-SOD overexpression in preserving pulmonary angiogenesis inhibited by oxidative stress.

    Directory of Open Access Journals (Sweden)

    Shahana Perveen

    Full Text Available UNLABELLED: Angiogenesis is one of the most important processes for normal lung development. Oxidative stress can impair the pulmonary angiogenesis, leading to chronic lung disease or Bronchopulmonary dysplasia (BPD. OBJECTIVE: To investigate the protective effects of EC-SOD overexpression on pulmonary angiogenesis on neonates following exposure to acute hyperoxia. DESIGN/METHODS: Transgenic (TG and wild-type (WT neonatal mice (10 mice per group were exposed either to air (control group or 95% O(2 for 7 days starting at birth. After exposure, all animals were sacrificed. ROS concentration was measured in lung homogenates using OxiSelect ROS assay kit. Mean vascular density (MVD was measured using anti CD34 staining. RNA was extracted and the angiogenesis markers, VEGF, VEGFR1 and VEGFR2 and PECAM-1 were analyzed by RT-q PCR. VGEF protein was measured using Western blots. Endothelial progenitor cells (EPCs was assayed by flow cytometer. RESULTS: There was a significant reduction of ROS in TG hyperoxic neonate group (156±14.2 compared to WT hyperoxic animals (255±35.1. Evaluation of MVD, using anti-CD34, showed marked significant increase of MVD in the TG group following hyperoxic exposure (85±12 in comparison to the WT hyperoxic group (62±8.4, (P0.05. PECAM expression was significantly reduced in both hyperoxic compared to normoxic groups (P0.05. CONCLUSIONS: EC-SOD plays a key role in preserving angiogenesis by scavenging free radicals which has an inhibitory effect on angiogenesis process in neonatal mice lung following exposure to hyperoxia.

  20. Role of EC-SOD Overexpression in Preserving Pulmonary Angiogenesis Inhibited by Oxidative Stress

    Science.gov (United States)

    Perveen, Shahana; Patel, Hardik; Arif, Arslan; Younis, Sharif; Codipilly, Champa N.; Ahmed, Mohamed

    2012-01-01

    Angiogenesis is one of the most important processes for normal lung development. Oxidative stress can impair the pulmonary angiogenesis, leading to chronic lung disease or Bronchopulmonary dysplasia (BPD). Objective To investigate the protective effects of EC-SOD overexpression on pulmonary angiogenesis on neonates following exposure to acute hyperoxia. Design/Methods Transgenic (TG) and wild-type (WT) neonatal mice (10 mice per group) were exposed either to air (control group) or 95% O2 for 7 days starting at birth. After exposure, all animals were sacrificed. ROS concentration was measured in lung homogenates using OxiSelect ROS assay kit. Mean vascular density (MVD) was measured using anti CD34 staining. RNA was extracted and the angiogenesis markers, VEGF, VEGFR1 and VEGFR2 and PECAM-1 were analyzed by RT-q PCR. VGEF protein was measured using Western blots. Endothelial progenitor cells (EPCs) was assayed by flow cytometer. Results There was a significant reduction of ROS in TG hyperoxic neonate group (156±14.2) compared to WT hyperoxic animals (255±35.1). Evaluation of MVD, using anti-CD34, showed marked significant increase of MVD in the TG group following hyperoxic exposure (85±12) in comparison to the WT hyperoxic group (62±8.4), (P0.05). PECAM expression was significantly reduced in both hyperoxic compared to normoxic groups (P0.05). Conclusions EC-SOD plays a key role in preserving angiogenesis by scavenging free radicals which has an inhibitory effect on angiogenesis process in neonatal mice lung following exposure to hyperoxia. PMID:23284826

  1. Dietary proteins and angiogenesis.

    Science.gov (United States)

    Medina, Miguel Ángel; Quesada, Ana R

    2014-01-17

    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.

  2. Targeting the Tumor Microenvironment: Focus on Angiogenesis

    Directory of Open Access Journals (Sweden)

    Fengjuan Fan

    2012-01-01

    Full Text Available Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.

  3. Targeting the tumor microenvironment: focus on angiogenesis.

    Science.gov (United States)

    Fan, Fengjuan; Schimming, Alexander; Jaeger, Dirk; Podar, Klaus

    2012-01-01

    Tumorigenesis is a complex multistep process involving not only genetic and epigenetic changes in the tumor cell but also selective supportive conditions of the deregulated tumor microenvironment. One key compartment of the microenvironment is the vascular niche. The role of angiogenesis in solid tumors but also in hematologic malignancies is now well established. Research on angiogenesis in general, and vascular endothelial growth factor in particular, is a major focus in biomedicine and has led to the clinical approval of several antiangiogenic agents including thalidomide, bevacizumab, sorafenib, sunitinib, pazopanib, temesirolimus, and everolimus. Indeed, antiangiogenic agents have significantly changed treatment strategies in solid tumors (colorectal cancer, renal cell carcinoma, and breast cancer) and multiple myeloma. Here we illustrate important aspects in the interrelationship between tumor cells and the microenvironment leading to tumor progression, with focus on angiogenesis, and summarize derived targeted therapies.

  4. LGALS3BP, lectin galactoside-binding soluble 3 binding protein, induces vascular endothelial growth factor in human breast cancer cells and promotes angiogenesis.

    Science.gov (United States)

    Piccolo, Enza; Tinari, Nicola; Semeraro, Daniela; Traini, Sara; Fichera, Imma; Cumashi, Albana; La Sorda, Rossana; Spinella, Francesca; Bagnato, Anna; Lattanzio, Rossano; D'Egidio, Maurizia; Di Risio, Annalisa; Stampolidis, Pavlos; Piantelli, Mauro; Natoli, Clara; Ullrich, Axel; Iacobelli, Stefano

    2013-01-01

    Elevated serum or tissue levels of lectin galactoside-binding soluble 3 binding protein (LGALS3BP) have been associated with short survival and development of metastasis in a variety of human cancers. However, the role of LGALS3BP, particularly in the context of tumor-host relationships, is still missing. Here, we show that LGALS3BP knockdown in MDA-MB-231 human breast cancer cells leads to a decreased adhesion to fibronectin, a reduced transendothelial migration and, more importantly, a reduced expression of vascular endothelial growth factor (VEGF). Production of VEGF, that was restored by exposure of silenced cells to recombinant LGALS3BP, required an intact PI3k/Akt signaling. Furthermore, we show that LGALS3BP was able to directly stimulate HUVEC tubulogenesis in a VEGF-independent, galectin-3-dependent manner. Immunohistochemical analysis of human breast cancer tissues revealed a correlation among LGALS3BP expression, VEGF expression, and blood vessel density. We propose that in addition to its prometastatic role, LGALS3BP secreted by breast cancer cells functions critically as a pro-angiogenic factor through a dual mechanism, i.e by induction of tumor VEGF and stimulation of endothelial cell tubulogenesis.

  5. 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.

  6. Angiogenesis and the inception of pregnancy

    NARCIS (Netherlands)

    Kapiteijn, Kitty

    2006-01-01

    Vascular maladaptation prior and during implantation may lead to serious complications during pregnancy, perinatally, but also later in life (Barker hypothesis). The consequences later in life often appear to be related to endothelial dysfunction. Angiogenesis, the formation of new blood vessels fro

  7. miR-21 Is Linked to Glioma Angiogenesis

    DEFF Research Database (Denmark)

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

    2016-01-01

    (Sox2) and CD133. We developed an image analysis-based co-localization approach allowing global alignment and quantitation of the individual markers, and measured the miR-21 in situ hybridization signal against the immunohistochemical staining of the six different markers. miR-21 significantly co......-positive tumor cells, we systematically stained consecutive serial sections from ten astrocytomas for miR-21, hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), phosphatase and tensin homolog (PTEN), octamer-binding transcription factor 4 (Oct4), sex-determining region Y box 2......-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...

  8. Impaired Arterial Elasticity Identified by Pulse Waveform Analysis as a Marker for Vascular Wall Damage in Humans With Aging and Hypertension

    Institute of Scientific and Technical Information of China (English)

    Wang Yan; Tao Jun; Tu Chang; Yang Zhen; Xu Mingguo; Wang Jiemei; Jin Yafei; Ma Hong

    2005-01-01

    Objectives Cardiovascular risk factors lead to pathogenesis of atherosclerosis and its clinical events by impairing vascular wall. Endothelial dysfunction is the earliest marker for vascular wall injuries. Development of new method to detect early vascular wall damage has an important clinical implication for the prevention and treatment of cardiovascular diseases. Therefore, the present study was performed to evaluate effect of aging and hypertension, two independent risk factors for cardiovascular diseases, on arterial elasticity by using pulse waveform analysis and investigate whether the changes in arterial elasticity can be used as a risk marker for vascular structural and functional abnormalities. Methods Using modified Windkessel model of the circulation and pulse waveform analysis,C 1 large artery and C2 small artery elasticity indices of 204 Chinese normal healthy subjects ( age 15-80years) and 46 Chinese essential hypertensive patients (age 35-70 years) were measured. Age- and hypertension-related arterial elasticity changes were examined. Results C1 large artery and C2 small artery elasticity indices were reduced with advancing age in healthy subjects. C1 large artery and C2 small artery elasticity indices were negatively correlated with age (r=-0.628, P<0.001; r=-0.595, P<0.001). C1 large artery and C2 small artery elasticity indices in patients with essential hypertension compared with the agematched healthy subjects were (9.31±3.85 ml/mm Hg x 10 versus 15.13±4.14 ml/mmHg x 10, P<0.001) and (3.57± 1.62 ml/mm Hg x 100 versus 7.89±2.91 ml/mmHg ×100 P <0.001), respectively, and were significantly lower than the corresponding healthy subjects. There were negative association between C1large artery and C2 small artery elasticity indices and systolic blood pressure (r=-0.37, P<0.05; r=-0.39,P<0.05) and pulse pressure (r=-0.39, P<0.05; r=0.43,P<0.05) in patients with essential hypertension.Conclusions Advancing age and essential

  9. Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited

    OpenAIRE

    Plate, Karl H.; Scholz, Alexander; Dumont, Daniel J.

    2012-01-01

    The cellular and molecular mechanisms of tumor angiogenesis and its prospects for anti-angiogenic cancer therapy are major issues in almost all current concepts of both cancer biology and targeted cancer therapy. Currently, (1) sprouting angiogenesis, (2) vascular co-option, (3) vascular intussusception, (4) vasculogenic mimicry, (5) bone marrow-derived vasculogenesis, (6) cancer stem-like cell-derived vasculogenesis and (7) myeloid cell-driven angiogenesis are all considered to contribute to...

  10. Endothelial markers in malignant vascular tumours of the liver: superiority of QB-END/10 over von Willebrand factor and Ulex europaeus agglutinin 1.

    Science.gov (United States)

    Anthony, P P; Ramani, P

    1991-01-01

    A new monoclonal antibody, QB-END/10, raised against the CD34 antigen in human endothelial cell membranes and haemopoietic progenitor cells, was studied for its usefulness as a marker of neoplastic vascular cells in 21 angiosarcomas and seven malignant haemangioendotheliomas of the liver. QB-END/10 was both more sensitive and more specific than Von Willebrand factor (VWF) and Ulex europaeus 1 agglutinin (UEA-1) in labelling endothelial cells and it did not cross react with epithelia as UEA-1 often does. Staining was uniformly strong and clear in all histological variants of these two tumours. QB-END/10 should prove particularly useful in the differential diagnosis of malignant vascular tumours of the liver. Images PMID:1705261

  11. VEGF165 Stimulates Vessel Density and Vessel Diameter Differently in Angiogenesis and Lymphangiogenesis

    Science.gov (United States)

    Parsons-Wingerter, Patricia; Radhakrishnan, Krishnan; DiCorleto, Paul E.; Leontiev, Dmitry; Anand-Apte, Bela; Albarran, Brian; Farr, Andrew G.

    2005-01-01

    Vascular endothelial growth factor-165 (VEGF(sub 165)) stimulated angiogenesis in the quail chorioallantoic membrane (CAM) by vessel expansion from the capillary network. However, lymphangiogenesis was stimulated by the filopodial guidance of tip cells located on blind-ended lymphatic sprouts. As quantified by fractal/generational branching analysis using the computer code VESGEN, vascular density increased maximally at low VEGF concentrations, and vascular diameter increased most at high VEGF concentrations. Increased vascular density and diameter were statistically independent events (r(sub s), -0.06). By fluorescence immunohistochemistry of VEGF receptors VEGFR-1 and VEGFR-2, alpha smooth muscle actin ((alpha) SMA) and a vascular/lymphatic marker, VEGF(sub 165) increased the density and diameter of sprouting lymphatic vessels guided by tip cells (accompanied by the dissociation of lymphatics from blood vessels). Isolated migratory cells expressing (alpha)SMA were recruited to blood vessels, whereas isolated cells expressing VEGFR-2 were recruited primarily to lymphatics. In conclusion, VEGF(sub 165) increased lymphatic vessel density by lymphatic sprouting, but increased blood vessel density by vascular expansion from the capillary network.

  12. Monitoring angiogenesis using magnetic resonance methods

    DEFF Research Database (Denmark)

    Holm, David Alberg

    2008-01-01

    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......-angiogenic treatment is presented in the first manuscript. In the second and third manuscript, two separate methods of quantifying perfusion, blood volume and vessel permeability are presented. The methods are used to show that drug delivery to a xenografted tumor is plausible and to show possible vascular maturation...

  13. Metabolomic and Genomic Markers of Atherosclerosis as Related to Oxidative Stress, Inflammation, and Vascular Function in Twin Astronauts

    Science.gov (United States)

    Lee, Stuart M. C.; Rana, Brinda K.; Stenger, Michael B.; Sears, Dorothy D.; Smith, Scott M.; Zwart, Sara R.; Macias, Brandon R.; Hargans, Alan R.; Sharma, Kumar; De Vivo, Immaculata

    2017-01-01

    that is associated with elevated atherosclerosis risk factors. METHODS: In the space-flown twin, a panel of biomarkers of oxidative and inflammatory stress were measured in venous blood samples and in 24-h (in-flight) and 48-h (pre- and post-flight) urine pools collected twice before flight, six times during the mission (FD15, 75, 180, 240, 300, 335), and early in the post-flight recovery phase (3-5 days after landing). We also measured metabolomic (targeted and untargeted approaches) and genomic markers (DNA methylation, mRNA gene expression, telomere length) in these samples. Arterial structure, assessed from measures of intima-media thickness, also were measured using standard clinical ultrasound at the same time points. Arterial function was assessed using brachial flow-mediated dilation, a well-validated measure used to assess endothelium-dependent vasodilation and a sensitive predictor of atherosclerotic risk, only before and after spaceflight. All of the same measures were obtained in the ground-based twin, but less frequently. DISCUSSION: All data collection has been completed for both the space-flown twin and the ground-based twin. Vascular structure and function measures have been analyzed, blood and urine samples have been batch-processed. Results from these individuals will be compared to each other, to data from other Twin Study investigations, and to the larger complement of subjects participating in the companion study currently ongoing in ISS astronauts.

  14. Mediators of ocular angiogenesis

    Indian Academy of Sciences (India)

    Yureeda Qazi; Surekha Maddula; Balamurali K. Ambati

    2009-12-01

    Angiogenesis is the formation of new blood vessels from pre-existing vasculature. Pathologic angiogenesis in the eye can lead to severe visual impairment. In our review, we discuss the roles of both pro-angiogenic and anti-angiogenic molecular players in corneal angiogenesis, proliferative diabetic retinopathy, exudative macular degeneration and retinopathy of prematurity, highlighting novel targets that have emerged over the past decade.

  15. Long non-coding RNA MALAT1 promotes gastric cancer tumorigenicity and metastasis by regulating vasculogenic mimicry and angiogenesis.

    Science.gov (United States)

    Li, Yue; Wu, Zhenzhen; Yuan, Jia; Sun, Li; Lin, Li; Huang, Na; Bin, Jianping; Liao, Yulin; Liao, Wangjun

    2017-06-01

    MALAT1 is an oncogenic long non-coding RNA that has been found to promote the proliferation of many malignant cell types and non-malignant human umbilical vein endothelial cells (HUVECs). However, the functions of MALAT1 in vasculogenic mimicry (VM) and angiogenesis and the potential mechanisms responsible have not yet been investigated in any malignancy. Here, in situ hybridization and CD31/periodic acid-Schiff double staining of 150 gastric cancer (GC) clinical specimens revealed that MALAT1 expression was tightly associated with densities of VM and endothelial vessels. MALAT1 knockdown markedly reduced GC cell migration, invasion, tumorigenicity, metastasis, and VM, while restricting HUVEC angiogenesis and increasing vascular permeability. Moreover, MALAT1 was found to regulate expression of VE-cadherin, β-catenin, MMPs 2 and 9, MT1-MMP, p-ERK, p-FAK, and p-paxillin, which have been established as classical markers of VM and angiogenesis and components of associated signaling pathways. Consistent with this, the p-ERK inhibitors U0126 and PD98059 both effectively blocked GC cell VM. In conclusion, MALAT1 can promote tumorigenicity and metastasis in GC by facilitating VM and angiogenesis via the VE-cadherin/β-catenin complex and ERK/MMP and FAK/paxillin signaling pathways.

  16. VEGF/VEGFR2 Axis in Periodontal Disease Progression and Angiogenesis: Basic Approach for a New Therapeutic Strategy.

    Science.gov (United States)

    Vladau, Mircea; Cimpean, Anca Maria; Balica, Raluca Amalia; Jitariu, Andreea Adriana; Popovici, Ramona Amina; Raica, Marius

    2016-01-01

    Periodontal lesions are associated with activation of pathological angiogenesis and a high number of newly-formed blood vessels. Most angiogenic growth factors have been studied in the crevicular fluid or serum, but tissue correlations with vascular density or endothelial proliferation, are very rare, even inexistent. We assessed the VEGF/VEGFR2 axis expression in a multimodal fashion, in both epithelial and stromal compartments, with emphasis to endothelial proliferation and severity of periodontal lesions. Compared to normal gingiva, negative for VEGF/VEGFR2, periodontal lesions had a progressive increase for these markers from low to severe periodontal lesions. The transition from low to moderate periodontal lesions represents the milestone in disease progression and implies an active angiogenesis based on the highest angiogenic parameter variability observed for these lesions. Epithelial vascularization was firstly observed in moderate periodontal lesions and persists during severe periodontal disease. All the parameters used to quantify angiogenesis in periodontal lesions, were significantly increased in severe periodontal lesions dependent on VEGF expression in both the epithelial and stromal compartment. Our results support the use of anti-VEGF/VEGFR2-targeted therapy as adjuvant treatment for severe periodontal lesions.

  17. The relationship between factor inhibiting HIF-1-alpha (HIF1AN( expression and vascular invasion in colon cancer

    Directory of Open Access Journals (Sweden)

    Reza Najafipour

    2016-10-01

    Full Text Available Background: Hypoxia is a common phenomenon in human solid tumors which by increasing in angiogenesis induction cause tumor growth survival and metastasis. Inhibitory factor hypoxia regulatory factor (HIF1AN by binding to transcription co activators CBP/P300(, inhibits hypoxia inducible factor (HIF1α. Objective: The relationship between HIF1AN expression and vascular invasion in colon tumors. Methods: The study included 101 patients with colon adenocarcinoma which were divided to vascular invasion and non-vascular invasion groups. Tumor paraffin blocks were immunohistochemistry stained for HIF1AN and were assessed for intensity and extent of positivity. Statistical relation of marker expression and clinic pathologic findings were assessed. Data were analyzed by SPSS 21 software and logistic regression and chi-square test. Findings: Nuclear immunoreactivity of HIF1AN was different between two groups. Statistical relation between low HIF1AN expression and tumor vascular invasion were seen (P=0.01. No relation was found between tumor differentiation, depth and HIF1AN. Conclusion: Evidence showed that the low expression or incorrect position of HIF1AN in nucleus of tumor cells was effective on HIF1α inhibition failure and factors associated angiogenesis increased. The HIF1AN played an tumor suppressor gene (TSG( role in colon tumors and decreased protein in the nucleus of colon cancer cells increased the expression of angiogenesis factors and vascular invasion.

  18. Angiogenesis is inhibitory for mammalian digit regeneration.

    Science.gov (United States)

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

    2014-06-01

    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.

  19. Soliton driven angiogenesis

    Science.gov (United States)

    Bonilla, L. L.; Carretero, M.; Terragni, F.; Birnir, B.

    2016-08-01

    Angiogenesis is a multiscale process by which blood vessels grow from existing ones and carry oxygen to distant organs. Angiogenesis is essential for normal organ growth and wounded tissue repair but it may also be induced by tumours to amplify their own growth. Mathematical and computational models contribute to understanding angiogenesis and developing anti-angiogenic drugs, but most work only involves numerical simulations and analysis has lagged. A recent stochastic model of tumour-induced angiogenesis including blood vessel branching, elongation, and anastomosis captures some of its intrinsic multiscale structures, yet allows one to extract a deterministic integropartial differential description of the vessel tip density. Here we find that the latter advances chemotactically towards the tumour driven by a soliton (similar to the famous Korteweg-de Vries soliton) whose shape and velocity change slowly. Analysing these collective coordinates paves the way for controlling angiogenesis through the soliton, the engine that drives this process.

  20. Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells.

    Science.gov (United States)

    Chu, Shu-Chen; Yu, Cheng-Chia; Hsu, Li-Sung; Chen, Kuo-Shuen; Su, Mei-Yu; Chen, Pei-Ni

    2014-12-01

    Metastasis is the most common cause of cancer-related death in patients, and epithelial-to-mesenchymal transition (EMT) is essential for cancer metastasis, which is a multistep complicated process that includes local invasion, intravasation, extravasation, and proliferation at distant sites. When cancer cells metastasize, angiogenesis is also required for metastatic dissemination, given that an increase in vascular density will allow easier access of tumor cells to circulation, and represents a rational target for therapeutic intervention. Berberine has several anti-inflammation and anticancer biologic effects. In this study, we provided molecular evidence that is associated with the antimetastatic effect of berberine by showing a nearly complete inhibition on invasion (P metalloproteinase-2 and urokinase-type plasminogen activator. Berberine reversed transforming growth factor-β1-induced EMT and caused upregulation of epithelial markers such as E-cadherin and inhibited mesenchymal markers such as N-cadherin and snail-1. Selective snail-1 inhibition by snail-1-specific small interfering RNA also showed increased E-cadherin expression in SiHa cells. Berberine also reduced tumor-induced angiogenesis in vitro and in vivo. Importantly, an in vivo BALB/c nude mice xenograft model and tail vein injection model showed that berberine treatment reduced tumor growth and lung metastasis by oral gavage, respectively. Taken together, these findings suggested that berberine could reduce metastasis and angiogenesis of cervical cancer cells, thereby constituting an adjuvant treatment of metastasis control.

  1. Pathophysiological mechanisms of angiogenesis in atherogenesis

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    Vučević Danijela

    2013-01-01

    Full Text Available Introduction. Atherosclerosis is a progressive, multifactorial, diffuse, multisystemic, chronic, inflammatory disease, which is manifested by disorders of vascular, immune and metabolic system. Pathogenesis of this disease is not fully understood. Accordingly, angiogenesis represents a special field of research due to its role in atherogenesis. Steps of Angiogenesis. Angiogenesis is a complex biological process, which requires the precise coordination of its four steps (vasodilatation and permeability, vessel destabilization and matrix degradation, endothelial cell proliferation and migration, and lumen formation and vessel stabilization. Mediators of Angiogenic Process. The process of forming new blood vessels is regulated by a delicate balance between proangiogenic and antiangiogenic molecules. Numerous soluble growth factors and inhibitors, cytokines, proteases, extracellular matrix proteins and adhesion molecules, as well as hypoxia, inflammatory process, shear stress, hypertension and interaction between cells and extracellular matrix strictly control the angiogenic process. Neovascularization is halted due to the downregulation of angiogenic factors or the increase of inhibitors of this process. Tumor Vascularization. In the asymptomatic phase of cancerogenesis, cancer rarely exceeds the diameter of 1-2 millimeters. However, when the metabolic demand increases, it leads to tumor vascularization. In this way, tumor switches to an angiogenic phenotype. The molecular basis of angiogenic switch refers to increased production of angiogenic factors and/or loss of angiogenic inhibitors. Conclusion. The contribution of angiogenic process has become increasingly meaningful in understanding the pathogenesis of atherosclerosis. [Projekat Ministarstva nauke Republike Srbije, br. 175015

  2. The role of vascular disorders in the genesis and maintenance of infammation in the pathogenesis of rosacea

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    Slesarenko N.S.

    2012-06-01

    Full Text Available

    Aims. The study was aimed to identify relationships of immune disorders and angiogenesis in patients at different stages of rosacea. Materials and methods. We examined 110 patients with rosacea. The diagnosis was based on diagnostic criteria. We summarized the role of predictors in the development of rosacea. We investigated pro- and anti-infammatory cytokines, vascular endothelial growth actor (VEGF, fbroblast growth factor (FGF for the detection of immune disorders and angiogenesis. Results. The immune response in patients with rosacea was of mixed Th-1 and Th-2 type which can be markers of chronic autoimmune infammation. Simultaneously with the change in cytokine profle we revealed activation of angiogenesis (high levels of VEGF, FGF.

  3. “Decoding” angiogenesis: new facets controlling endothelial cell behavior

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    Massimo Mattia Santoro

    2016-07-01

    Full Text Available Angiogenesis, the formation of new blood vessels, is a unique and crucial biological process occurring during both development and adulthood. A better understanding of the mechanisms that regulates such process is mandatory to intervene in pathophysiological conditions. Here we highlight some recent argument on new players that are critical in endothelial cells, by summarizing novel discoveries that regulate notorious vascular pathways such as Vascular Endothelial Growth Factor (VEGF, Notch and Planar Cell Polarity, and by discussing more recent findings that put metabolism, redox signaling and hemodynamic forces as novel unforeseen facets in angiogenesis. These new aspects, that critically regulate angiogenesis and vascular homeostasis in health and diseased, represent unforeseen new ground to develop anti-angiogenic therapies.

  4. Angiogenesis and liver fibrosis

    Institute of Scientific and Technical Information of China (English)

    Gülsüm ?zlem Elpek

    2015-01-01

    Recent data indicate that hepatic angiogenesis,regardless of the etiology, takes place in chronic liverdiseases (CLDs) that are characterized by inflammationand progressive fibrosis. Because antiangiogenictherapy has been found to be efficient inthe prevention of fibrosis in experimental models ofCLDs, it is suggested that blocking angiogenesis couldbe a promising therapeutic option in patients withadvanced fibrosis. Consequently, efforts are beingdirected to revealing the mechanisms involved inangiogenesis during the progression of liver fibrosis.Literature evidences indicate that hepatic angiogenesisand fibrosis are closely related in both clinical andexperimental conditions. Hypoxia is a major inducer ofangiogenesis together with inflammation and hepaticstellate cells. These profibrogenic cells stand at theintersection between inflammation, angiogenesis andfibrosis and play also a pivotal role in angiogenesis.This review mainly focuses to give a clear view on therelevant features that communicate angiogenesis withprogression of fibrosis in CLDs towards the-end point ofcirrhosis that may be translated into future therapies.The pathogenesis of hepatic angiogenesis associatedwith portal hypertension, viral hepatitis, non-alcoholicfatty liver disease and alcoholic liver disease are alsodiscussed to emphasize the various mechanisms involvedin angiogenesis during liver fibrogenesis.

  5. Hydrogels for therapeutic cardiovascular angiogenesis.

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    Rufaihah, Abdul Jalil; Seliktar, Dror

    2016-01-15

    Acute myocardial infarction (MI) caused by ischemia is the most common cause of cardiac dysfunction. While growth factor or cell therapy is promising, the retention of bioactive agents in the highly vascularized myocardium is limited and prevents sustained activation needed for adequate cellular responses. Various types of biomaterials with different physical and chemical properties have been developed to improve the localized delivery of growth factor and/or cells for therapeutic angiogenesis in ischemic tissues. Hydrogels are particularly advantageous as carrier systems because they are structurally similar to the tissue extracellular matrix (ECM), they can be processed under relatively mild conditions and can be delivered in a minimally invasive manner. Moreover, hydrogels can be designed to degrade in a timely fashion that coincides with the angiogenic process. For these reasons, hydrogels have shown great potential as pro-angiogenic matrices. This paper reviews a few of the hydrogel systems currently being applied together with growth factor delivery and/or cell therapy to promote therapeutic angiogenesis in ischemic tissues, with emphasis on myocardial applications.

  6. Monocyte Subpopulations in Angiogenesis

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    Dalton, Heather J.; Armaiz-Pena, Guillermo; Gonzalez-Villasana, Vianey; Lopez-Berestein, Gabriel; Bar-Eli, Menashe; Sood, Anil K.

    2014-01-01

    Growing understanding of the role of the tumor microenvironment in angiogenesis has brought monocyte-derived cells into focus. Monocyte subpopulations are an increasingly attractive therapeutic target in many pathologic states, including cancer. Before monocyte-directed therapies can be fully harnessed for clinical use, understanding of monocyte-driven angiogenesis in tissue development and homeostasis, as well as malignancy, is required. Here, we provide an overview of the mechanisms by which monocytic subpopulations contribute to angiogenesis in tissue and tumor development, highlight gaps in our existing knowledge, and discuss opportunities to exploit these cells for clinical benefit. PMID:24556724

  7. Serum human chorionic gonadotropin is associated with angiogenesis in germ cell testicular tumors

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    Avilés-Salas Alejandro

    2009-08-01

    Full Text Available Abstract Background Germ cell testicular tumors have survival rate that diminishes with high tumor marker levels, such as human chorionic gonadotropin (hCG. hCG may regulate vascular neoformation through vascular endothelial growth factor (VEGF. Our purpose was to determine the relationship between hCG serum levels, angiogenesis, and VEGF expression in germ cell testicular tumors. Methods We conducted a retrospective study of 101 patients. Serum levels of hCG, alpha-fetoprotein (AFP, and lactate dehydrogenase were measured prior to surgery. Vascular density (VD and VEGF tissue expression were determined by immunohistochemistry and underwent double-blind analysis. Results Histologically, 46% were seminomas and 54%, non-seminomas. Median follow-up was 43 ± 27 months. Relapse was present in 7.5% and mortality in 11.5%. Factors associated with high VD included non-seminoma type (p = 0.016, AFP ≥ 14.7 ng/mL (p = 0.0001, and hCG ≥ 25 mIU/mL (p = 0.0001. In multivariate analysis, the only significant VD-associated factor was hCG level (p = 0.04. When hCG levels were stratified, concentrations ≥ 25 mIU/mL were related with increased neovascularization (p Conclusion This is the first study that relates increased serum hCG levels with vascularization in testicular germ cell tumors. Hence, its expression might play a role in tumor angiogenesis, independent of VEGF expression, and may explain its association with poor prognosis. hCG might represent a molecular target for therapy.

  8. Hypoxia,angiogenesis and liver fibrogenesis in the progression of chronic liver diseases

    Institute of Scientific and Technical Information of China (English)

    Claudia; Paternostro; Ezio; David; Erica; Novo; Maurizio; Parola

    2010-01-01

    Angiogenesis is a dynamic,hypoxia-stimulated and growth factor-dependent process,and is currently referred to as the formation of new vessels from preexisting blood vessels.Experimental and clinical studies have unequivocally reported that hepatic angiogenesis,irrespective of aetiology,occurs in conditions of chronic liver diseases(CLDs) characterized by perpetuation of cell injury and death,inflammatory response and progressive fibrogenesis.Angiogenesis and related changes in liver vascular architecture,th...

  9. Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma.

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    Wang, Jian; Svendsen, Agnete; Kmiecik, Justyna; Immervoll, Heike; Skaftnesmo, Kai Ove; Planagumà, Jesús; Reed, Rolf Kåre; Bjerkvig, Rolf; Miletic, Hrvoje; Enger, Per Øyvind; Rygh, Cecilie Brekke; Chekenya, Martha

    2011-01-01

    Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4) or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM) and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy.

  10. Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma.

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    Jian Wang

    Full Text Available Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4 or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy.

  11. KSHV-Mediated Angiogenesis in Tumor Progression

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    Pravinkumar Purushothaman

    2016-07-01

    Full Text Available Human herpesvirus 8 (HHV-8, also known as Kaposi’s sarcoma-associated herpesvirus (KSHV, is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL and a plasmablastic variant of multicentric Castleman’s disease (MCD. KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders.

  12. KSHV-Mediated Angiogenesis in Tumor Progression

    Science.gov (United States)

    Purushothaman, Pravinkumar; Uppal, Timsy; Sarkar, Roni; Verma, Subhash C.

    2016-01-01

    Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma-associated herpesvirus (KSHV), is a malignant human oncovirus belonging to the gamma herpesvirus family. HHV-8 is closely linked to the pathogenesis of Kaposi’s sarcoma (KS) and two other B-cell lymphoproliferative diseases: primary effusion lymphoma (PEL) and a plasmablastic variant of multicentric Castleman’s disease (MCD). KS is an invasive tumor of endothelial cells most commonly found in untreated HIV-AIDS or immuno-compromised individuals. KS tumors are highly vascularized and have abnormal, excessive neo-angiogenesis, inflammation, and proliferation of infected endothelial cells. KSHV directly induces angiogenesis in an autocrine and paracrine fashion through a complex interplay of various viral and cellular pro-angiogenic and inflammatory factors. KS is believed to originate due to a combination of KSHV’s efficient strategies for evading host immune systems and several pro-angiogenic and pro-inflammatory stimuli. In addition, KSHV infection of endothelial cells produces a wide array of viral oncoproteins with transforming capabilities that regulate multiple host-signaling pathways involved in the activation of angiogenesis. It is likely that the cellular-signaling pathways of angiogenesis and lymph-angiogenesis modulate the rate of tumorigenesis induction by KSHV. This review summarizes the current knowledge on regulating KSHV-mediated angiogenesis by integrating the findings reported thus far on the roles of host and viral genes in oncogenesis, recent developments in cell-culture/animal-model systems, and various anti-angiogenic therapies for treating KSHV-related lymphoproliferative disorders. PMID:27447661

  13. Expression of HIF-1α and Markers of Angiogenesis Are Not Significantly Different in Triple Negative Breast Cancer Compared to Other Breast Cancer Molecular Subtypes: Implications for Future Therapy.

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    Lamis Yehia

    Full Text Available Triple negative breast cancer lacks estrogen, progesterone and epidermal growth factor receptors rendering it refractory to available targetedtherapies. TNBC is associated with central fibrosis and necrosis, both indicators of tumor hypoxia. Hypoxia inducible factor 1α is up-regulated under hypoxia and its expression is associated with induction of angiogenesis resulting in proliferation, aggressive tumor phenotype and metastasis. In this study we evaluate the potential use of HIF-1α as aTNBC-specific marker.62 TNBC, 64 HER2+, and 64 hormone-receptors positive breast cancer cases were evaluated for central fibrosis and necrosis, HIF-1α, HIF-1β, VEGFR3, CD31 expression and microvessel density. RNA extraction from paraffin-embedded samples, followed by quantitative real-time polymerase chain reaction (qRT-PCR evaluation of HIF-1α and VEGF transcripts was performed on 54 cases (18 from each subtype.HIF-1α protein was expressed in 35.5% TNBC, 45.3% HER2+and 25.0% ER+/PR+ (p = 0.055; χ2 test. PCRanalysis of subgroup of breast cancers, 84.2% expressed HIF-1α protein and its transcripts, while only 66.7% expressed VEGF transcripts simultaneously with the HIF-1α protein and its transcripts. Central fibrosis and necrosis was highest in TNBC (p = 0.015; χ2 test, while MVD was comparable among all groups (p = 0.928; χ2 test. VEGFR3 was highest in TNBC expressing HIF-1α. HIF-1β protein was expressed in 32.0% of HIF-1α(+, and in (44.3% of HIF-1α(- breast cancer cases (p = 0.033; χ2 test. Moreover, HIF-1α expression in cases with central fibrosis and necrosis was highest in the HER2+ followed by the TNBC (p = 0.156; χ2 test.A proportion of TNBC express HIF-1α but not in a significantly different manner from other breast cancer subtypes. The potential of anti-HIF-1α targeted therapy is therefore not a candidate for exclusive use in TNBC, but should be considered in all breast cancers, especially in the setting of clinically aggressive or

  14. Imbalance of angiogenesis in diabetic complications: The mechanisms

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    Zoya Tahergorabi

    2012-01-01

    Full Text Available Type 2 diabetes mellitus is a complex disease and a chronic health-care problem. Nowadays, because of alteration of lifestyle such as lack of exercise, intake of high fat diet subsequently obesity and aging population, the prevalence of diabetes mellitus is increasing quickly in around the world. The international diabetes federation estimated in 2008, that 246 million adults in worldwide suffered from diabetes mellitus and the prevalence of disease is expected to reach to 380 million by 2025. Although, mainly in management of diabetes focused on hyperglycemia, however, it is documented that abnormalities of angiogenesis may contribute in the pathogenesis of diabetes complications. Angiogenesis is the generation of new blood vessels from pre-existing ones. Normal angiogenesis depends on the intricate balance between angiogenic factors (such as VEGF, FGF 2 , TGF-β, angiopoietins and angiostatic factors (angiostatin, endostatin, thrombospondins. Vascular abnormalities in different tissues including retina and kidney can play a role in pathogenesis of micro-vascular complications of diabetes; also vascular impairment contributes in macrovascular complications e.g., diabetic neuropathy and impaired formation of coronary collaterals. Therefore, identifying of different mechanisms of the diabetic complications can give us an opportunity to prevent and/or treat the following complications and improves quality of life for patients and society. In this review, we studied the mechanisms of angiogenesis in micro-vascular and macro-vascular complications of diabetes mellitus.

  15. Lipocalin-7 is a matricellular regulator of angiogenesis.

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    Leslie J Brown

    Full Text Available BACKGROUND: Matricellular proteins are extracellular regulators of cellular adhesion, signaling and performing a variety of physiological behaviors such as proliferation, migration and differentiation. Within vascular microenvironments, matricellular proteins exert both positive and negative regulatory cues to vascular endothelium. The relative balance of these matricellular cues is believed to be critical for vascular homeostasis, angiogenesis activation or angiogenesis resolution. However, our knowledge of matricellular proteins within vascular microenvironments and the mechanisms by which these proteins impact vascular function remain largely undefined. The matricellular protein lipocalin-7 (LCN7 is found throughout vascular microenvironments, and circumstantial evidence suggests that LCN7 may be an important regulator of angiogenesis. Therefore, we hypothesized that LCN7 may be an important regulator of vascular function. METHODOLOGY AND PRINCIPAL FINDINGS: To test this hypothesis, we examined the effect of LCN7 overexpression, recombinant protein and gene knockdown in a series of in vitro and in vivo models of angiogenesis. We found that overexpression of LCN7 in MB114 and SVEC murine endothelial cell lines or administration of highly purified recombinant LCN7 protein increased endothelial cell invasion. Similarly, LCN7 increased angiogenic sprouting from quiescent endothelial cell monolayers and ex vivo aortic rings. Moreover, LCN7 increased endothelial cell sensitivity to TGF-β but did not affect sensitivity to other pro-angiogenic growth factors including bFGF and VEGF. Finally, morpholino based knockdown of LCN7 in zebrafish embryos specifically inhibited angiogenic sprouting but did not affect vasculogenesis within injected embryos. CONCLUSIONS AND SIGNIFICANCE: No functional analysis has previously been performed to elucidate the function of LCN7 in vascular or other cellular processes. Collectively, our results show for the first

  16. The effect of blocking angiogenesis on anterior cruciate ligament healing following stem cell transplantation.

    Science.gov (United States)

    Takayama, Koji; Kawakami, Yohei; Mifune, Yutaka; Matsumoto, Tomoyuki; Tang, Ying; Cummins, James H; Greco, Nick; Kuroda, Ryosuke; Kurosaka, Masahiro; Wang, Bing; Fu, Freddie H; Huard, Johnny

    2015-08-01

    Ruptured human anterior cruciate ligaments (ACL) contain vascular stem cells capable of enhancing the healing of tendon grafts. In the current study we explored the role that neo-angiogenesis plays in ACL healing. ACL-derived CD34+ cells were isolated via Fluorescence Activated Cell Sorting (FACS) from the rupture sites of human ACLs. The cells were then virally transduced to express either vascular endothelial growth factor (VEGF) or soluble FLT-1 (sFLT-1), which is an antagonist of VEGF. We established five groups: CD34+VEGF(100%), where 100% of the cells were transduced with VEGF, CD34+VEGF(25%), where only 25% of the cells were transduced with VEGF, CD34+, CD34+sFLT-1, and a No cells group. The CD34+sFLT1 group had a significant reduction in biomechanical strength compared to the CD34+ group at 4 and 8 weeks; whereas the biomechanical strength of the CD34+VEGF(25%) group was significantly greater than the CD34+ group at week 4; however, no difference was observed by week 8. Immunohistochemical staining demonstrated a significantly lower number of isolectin B4 and hCD31 positive cells, markers associated with angiogenesis, in the CD34+sFLT1 group, and a higher number of isolectin B4 and hCD31 positive cells in the CD34+VEGF(100%) and CD34+VEGF(25%) groups compared to the CD34+ group. Graft maturation was significantly delayed in the CD34+sFLT1 group and accelerated in the CD34+VEGF(25%) group compared to the CD34+ group. In conclusion, blocking VEGF reduced angiogenesis, graft maturation and biomechanical strength following ACL reconstruction. Native expression of VEGF by the CD34+ cells improved tendon graft maturation and biomechanical strength; however, over-expression of VEGF impeded improvements in biomechanical strength.

  17. 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

  18. Effects of Ivabradine and Metoprolol on Cardiac Angiogenesis and Endothelial Dysfunction in Rats With Heart Failure

    NARCIS (Netherlands)

    Ulu, Nadir; Henning, Rob H.; Goris, Maaike; Schoeinaker, Regien G.; van Gilst, Wiek H.

    2009-01-01

    Myocardial infarction (MI)-induced remodeling is associated with disturbed myocardial perfusion through vascular changes, such as reduced capillary density and endothelial dysfunction. Heart rate reduction (HRR) initiated immediately after MI stimulates angiogenesis and attenuates left ventricular d

  19. Toll-like receptor 2/6-dependent stimulation of mesenchymal stem cells promotes angiogenesis by paracrine factors

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    H Kokemüller

    2013-09-01

    Full Text Available Reconstruction of critical size bone defects represents a major challenge in orthopaedic surgery. Insufficient angiogenesis is a limiting factor for engraftment of large-scale tissue transplants. Transplantation or stimulation of local mesenchymal stem cells (MSCs represents a potential solution to enhance angiogenesis. We recently identified angiogenic properties for the Toll-like receptor (TLR 2/6 agonist MALP-2 and now investigated if MALP-2 could be used to stimulate MSCs in order to promote angiogenesis in vitro and in vivo.Human MSCs from the bone marrow of healthy subjects were isolated, cultured and expanded in vitro and were shown to be positive for mesenchymal stem cells markers as well as for the MALP-2 receptors TLR2 and TLR6. MALP-2 directly enhanced migration but not proliferation of human MSCs. Conditioned medium from MALP-2 stimulated MSCs significantly increased proliferation, migration and tube formation of endothelial cells. Analysis of the conditioned medium from MSCs revealed that MALP-2 stimulation enhanced the secretion of several chemokines and growth factors including vascular endothelial growth factors (VEGF and granulocyte-macrophage colony-stimulating factor (GM-CSF. Finally, we studied MALP-2 effects on MSCs in a sheep model of tissue engineering in vivo. Therefore, MSCs were isolated from the iliac crest of black head sheep and co-cultivated with MALP-2 ex vivo. Implantation of autologous MSCs within a scaffold cylinder into the M. latissimus dorsi significantly enhanced vessel density of these constructs after 6 months.We here present the first evidence that TLR2/6-dependent stimulation of MSCs promotes angiogenesis in vitro and in vivo offering a novel strategy for therapeutic angiogenesis, e.g., for tissue engineering of bone.

  20. Role of ROBO4 Signalling in Developmental and Pathological Angiogenesis

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    Suresh Singh Yadav

    2014-01-01

    Full Text Available Transmembrane roundabout receptor family members (ROBO1–ROBO4 principally orchestrate the neuronal guidance mechanism of the nervous system. Secreted glycoprotein SLITs are the most appreciated ligands for ROBOs. Recently identified ROBO4 is the key mediator of SLIT-ROBO mediated developmental and pathological angiogenesis. Although SLIT2 has been shown to interact with ROBO4 as ligand, it remains an open question whether this protein is the physiologic partner of ROBO4. The purpose of this review is to summarise how reliable SLIT2 as ligand for ROBO4 is, if not what the other possible mechanisms demonstrated till date for ROBO4 mediated developmental and pathological angiogenesis are. We conclude that ROBO4 is expressed specially in vascular endothelial cells and maintains the vascular integrity via either SLIT2 dependent or SLIT2 independent manner. On the contrary, it promotes the pathological angiogenesis by involving different signalling arm(s/unknown ligand(s. This review explores the interactions SLIT2/ROBO1, SLIT2/ROBO1–ROBO4, ROBO1/ROBO4, and ROBO4/UNC5B which can be promising and potential therapeutic targets for developmental angiogenesis defects and pathological angiogenesis. Finally we have reviewed the ROBO4 signalling pathways and made an effort to elaborate the insight of this signalling as therapeutic target of pathological angiogenesis.

  1. Adipose tissue angiogenesis: impact on obesity and type-2 diabetes.

    Science.gov (United States)

    Corvera, Silvia; Gealekman, Olga

    2014-03-01

    The growth and function of tissues are critically dependent on their vascularization. Adipose tissue is capable of expanding many-fold during adulthood, therefore requiring the formation of new vasculature to supply growing and proliferating adipocytes. The expansion of the vasculature in adipose tissue occurs through angiogenesis, where new blood vessels develop from those pre-existing within the tissue. Inappropriate angiogenesis may underlie adipose tissue dysfunction in obesity, which in turn increases type-2 diabetes risk. In addition, genetic and developmental factors involved in vascular patterning may define the size and expandability of diverse adipose tissue depots, which are also associated with type-2 diabetes risk. Moreover, the adipose tissue vasculature appears to be the niche for pre-adipocyte precursors, and factors that affect angiogenesis may directly impact the generation of new adipocytes. Here we review recent advances on the basic mechanisms of angiogenesis, and on the role of angiogenesis in adipose tissue development and obesity. A substantial amount of data points to a deficit in adipose tissue angiogenesis as a contributing factor to insulin resistance and metabolic disease in obesity. These emerging findings support the concept of the adipose tissue vasculature as a source of new targets for metabolic disease therapies. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

  2. Accelerated coronary angiogenesis by vegfr1-knockout endocardial cells.

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    Zheng Zhang

    Full Text Available During mouse heart development, ventricular endocardial cells give rise to the coronary arteries by angiogenesis. Myocardially-derived vascular endothelial growth factor-a (Vegfa regulates embryonic coronary angiogenesis through vascular endothelial growth factor-receptor 2 (Vegfr2 expressed in the endocardium. In this study, we investigated the role of endocardially-produced soluble Vegfr1 (sVegfr1 in the coronary angiogenesis. We deleted sVegfr1 in the endocardium of the developing mouse heart and found that this deletion resulted in a precocious formation of coronary plexuses. Using an ex vivo coronary angiogenesis assay, we showed that the Vegfr1-null ventricular endocardial cells underwent excessive angiogenesis and generated extensive endothelial tubular networks. We also revealed by qPCR analysis that expression of genes involved in the Vegf-Notch pathway was augmented in the Vegfr1-null hearts. We further showed that inhibition of Notch signaling blocked the formation of coronary plexuses by the ventricular endocardial cells. These results establish that Vegfr1 produced in the endocardium negatively regulates embryonic coronary angiogenesis, possibly by limiting the Vegf-Notch signaling.

  3. Targeting angiogenesis: a review of angiogenesis inhibitors in the treatment of lung cancer.

    Science.gov (United States)

    Sridhar, Srikala S; Shepherd, Frances A

    2003-12-01

    It has now been almost 30 years since Dr J. Folkman first proposed that inhibition of angiogenesis could play a key role in treating cancer; however, it is only recently that anti-angiogenesis agents have entered the clinical setting. The search for novel therapies is particularly important in lung cancer, where the majority of patients succumb to their disease despite aggressive treatments. Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190. Drugs that are similar to endogenous inhibitors of angiogenesis including endostatin, angiostatin and interferons. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.

  4. Perspectives of SLIT/ROBO signaling in placental angiogenesis.

    Science.gov (United States)

    Liao, Wu-xiang; Wing, Deborah A; Geng, Jian-Guo; Chen, Dong-bao

    2010-09-01

    A novel family of evolutionally conserved neuronal guidance cues, including ligands (i.e., Slit, netrin, epherin, and semaphorin) and their corresponding receptors (i.e., Robo, DCC/Unc5, Eph and plexin/ neuropilin), has been identified to play a crucial role in axon pathfinding and branching as well as neuronal cell migration. The presence of commonalities in both neural and vascular developments has led to some exciting discoveries recently, which have extended the functions of these systems to vascular formation (vasculogenesis) and development (angiogenesis). Some of these ligands and receptors have been found to be expressed in the vasculature and surrounding tissues in physiological and pathological conditions. It is postulated that they regulate the formation and integrity of blood vessels. In particular, it has been shown that the Slit/Robo pair plays a novel role in angiogenesis during tumorigenesis and vascular formation during embryogenesis. Herein we summarize briefly the characteristics of this family of neuronal guidance molecules and discuss the extra-neural expression and function of the Slit/Robo pair in angiogenesis in physiological and pathological settings. We report expression of Robo1 protein in capillary endothelium and co-expression of Slit2 and Robo1 proteins in syncytiotrophoblast in healthy term human placental villi. These cellular expression patterns implicate that the Slit/Robo signaling plays an autocrine and/or paracrine role in angiogenesis and trophoblast functions. We also speculate a possible role of this system in pathophysiological placental angiogenesis.

  5. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice.

    Science.gov (United States)

    Li, Yanli; Gao, Rufei; Liu, Xueqing; Chen, Xuemei; Liao, Xinggui; Geng, Yanqing; Ding, Yubin; Wang, Yingxiong; He, Junlin

    2015-08-04

    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.

  6. Folate Deficiency Could Restrain Decidual Angiogenesis in Pregnant Mice

    Directory of Open Access Journals (Sweden)

    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.

  7. Circulating microparticles, protein C, free protein S and endothelial vascular markers in children with sickle cell anaemia

    Directory of Open Access Journals (Sweden)

    Andrea Piccin

    2015-11-01

    Full Text Available Introduction: Circulating microparticles (MP have been described in sickle cell anaemia (SCA; however, their interaction with endothelial markers remains unclear. We investigated the relationship between MP, protein C (PC, free protein S (PS, nitric oxide (NO, endothelin-1 (ET-1 and adrenomedullin (ADM in a large cohort of paediatric patients. Method: A total of 111 children of African ethnicity with SCA: 51 in steady state; 15 in crises; 30 on hydroxyurea (HU therapy; 15 on transfusion; 17 controls (HbAA of similar age/ethnicity. MP were analysed by flow cytometry using: Annexin V (AV, CD61, CD42a, CD62P, CD235a, CD14, CD142 (tissue factor, CD201 (endothelial PC receptor, CD62E, CD36 (TSP-1, CD47 (TSP-1 receptor, CD31 (PECAM, CD144 (VE-cadherin. Protein C, free PS, NO, pro-ADM and C-terminal ET-1 were also measured. Results: Total MP AV was lower in crisis (1.26×106 ml−1; 0.56–2.44×106 and steady state (1.35×106 ml−1; 0.71–3.0×106 compared to transfusion (4.33×106 ml−1; 1.6–9.2×106, p0.9, p<0.05 between total numbers of AV-positive MP (MP AV and platelet MP expressing non-activation platelet markers. There was a lower correlation between MP AV and MP CD62P (R=0.73, p<0.05 (platelet activation marker, and also a lower correlation between percentage of MP expressing CD201 (%MP CD201 and %MP CD14 (R=0.627, p<0.001. %MP CD201 was higher in crisis (11.6% compared with HbAA (3.2%, p<0.05; %MP CD144 was higher in crisis (7.6% compared with transfusion (2.1%, p<0.05; %CD14 (0.77% was higher in crisis compared with transfusion (0.0%, p<0.05 and steady state (0.0%, p<0.01; MP CD14 was detectable in a higher number of samples (92% in crisis compared with the rest (40%; %MP CD235a was higher in crisis (17.9% compared with transfusion (8.9%, HU (8.7% and steady state (9.9%, p<0.05; %CD62E did not differ significantly across the groups and CD142 was undetectable. Pro-ADM levels were raised in chest crisis: 0.38 nmol L−1 (0.31–0

  8. Imaging of angiogenesis in cardiology

    Energy Technology Data Exchange (ETDEWEB)

    Higuchi, Takahiro; Wester, Hans Juergen; Schwaiger, Markus [Nuklearmedizinische Klinik und Poliklinik der Technischen Universitaet Muenchen, Klinikum rechts der Isar, Munich (Germany)

    2007-06-15

    In the past decade, there have been major improvements in our understanding of angiogenesis at the genetic, molecular and cellular levels. Concentrated efforts in this area have led to new therapeutic approaches to ischaemic heart disease using angiogenic factors, gene therapy and progenitor cells. Despite very promising experimental results in animal studies, large clinical trials have failed to confirm the results in patients with coronary artery disease. Important questions such as selection of growth factors and donor cells, as well as the timing, dose and route of administration, have been raised and need to be answered. Molecular imaging approaches which may provide specific markers of the angiogenic process (e.g. integrin expression in endothelial cells) have been introduced and are expected to address some of these questions. Although few clinical imaging results are currently available, animal studies suggest the potential role of molecular imaging for characterisation of the angiogenetic process in vivo and for the monitoring of therapeutic effects. (orig.)

  9. LIPID PROFILE, PLASMA FIBRINOGEN, AND PLATELET COUNT AS MARKERS OF CARDIO VASCULAR DISEASE IN SMOKERS DUE TO FREE RADICAL GENERATION

    Directory of Open Access Journals (Sweden)

    N Kannan

    2013-06-01

    Full Text Available Cigarette smoking & tobacco chewing are risk factors not only for oral and lung tumours but also for the development of systemic disorders like atherosclerosis, coronary artery disease and peripheral vascular disease. This study was undertaken to evaluate the lipid profile, plasma fibrinogen and platelet count in male smokers, compared with healthy non smokers in rural area of south India, Out of 100 male healthy volunteers, 50 members were healthy smokers and 50 healthy non smokers, subjects were divided in both groups in age around 30 to 45yrs, with no past history of diabetes mellitus, hypertension, hepatic disorders and were neither on anti hypertensive, lipid lowering drugs were included in the study. Lipid profile, plasma fibrinogen and platelet count were analyzed by standard methods. Our results showed mean platelet count for smokers is 2, 86,345per mm3 and for non-smokers 2, 04,484.6per mm3. The mean plasma fibrinogen concentration for smokers is 3.48gm/dl and for non smokers is 3.12gm/dl. The platelet count and plasma fibrinogen concentration shows a higher value for smokers when compared to non- smokers. This is statistically significant. The mean total cholesterol level for smokers (186±30.10 mg/dl and non smokers (166.3±24.26 mg/dl and the mean triglyceride level for smokers (175±59.43 mg/dl and non smokers (132.09±+33.80 mg/dl are also statistically significant. The mean HDL level for smokers (40.4±4.13 mg/dl and for non smokers (44.68±4.13 mg/dl, the mean LDL level for smokers (105.8±28.16 mg/dl and non smokers (89.68±16.50 mg/dl and the mean VLDL level for smokers (28.4± 8.16 mg/dl and non smokers (14.3.±3.2 mg/dl indicate that the Lipid profile also is statistically significant between the two groups. We concluded that there is an elevated lipid profile; plasma fibrinogen and platelet count in smokers when compared to non smokers, which shows that smokers have high risk of prevalence of cardiovascular and vessel wall

  10. Urokinase plasminogen activator and plasminogen activator inhibitor type-1 in nonsmall-cell lung cancer: relation to prognosis and angiogenesis

    DEFF Research Database (Denmark)

    Offersen, Birgitte Vrou; Pfeiffer, Per; Andreasen, Peter

    2007-01-01

    years. CONCLUSIONS: The present study investigated the prognostic role of the protein levels of uPA and PAI-1 in 118 tumour specimens from patients diagnosed with NSCLC. Neither of the factors were identified as prognostic markers when evaluated with survival as endpoint. However, in tumours previously...... to angiogenesis. MATERIALS AND METHODS: Frozen tumour tissue from surgical specimens from 118 previously untreated patients diagnosed with NSCLC in the period 1984-1991 were investigated. All patients were treated with surgery, and no chemo- or radiotherapy was given. UPA and PAI-1 levels were assessed using...... a sandwich ELISA method. RESULTS: Both uPA and PAI-1 were independent of classical histopathological parameters as well as of microvessel density and vascular pattern. Using death within the first 5 years as endpoint, neither of the factors were prognostic markers in univariate analysis, however...

  11. Estrogen deprivation does not affect vascular heat shock response in female rats: a comparison with oxidative stress markers.

    Science.gov (United States)

    Miragem, Antônio Azambuja; Ludwig, Mirna Stela; Heck, Thiago Gomes; Baldissera, Fernanda Giesel; dos Santos, Analu Bender; Frizzo, Matias Nunes; Homem de Bittencourt, Paulo Ivo

    2015-09-01

    Hot flashes, which involve a tiny rise in core temperature, are the most common complaint of peri- and post-menopausal women, being tightly related to decrease in estrogen levels. On the other hand, estradiol (E2) induces the expression of HSP72, a member of the 70 kDa family of heat shock proteins (HSP70), which are cytoprotective, cardioprotective, and heat inducible. Since HSP70 expression is compromised in age-related inflammatory diseases, we argued whether the capacity of triggering a robust heat shock (HS) response would be still present after E2 withdrawal. Hence, we studied the effects of HS treatment (hot tub) in female Wistar rats subjected to bilateral ovariectomy (OVX) after a 7-day washout period. Twelve h after HS, the animals were killed and aortic arches were surgically excised for molecular analyses. The results were compared with oxidative stress markers in the plasma (superoxide dismutase, catalase, and lipoperoxidation) because HSP70 expression is also sensitive to redox regulation. Extracellular (plasma) to intracellular HSP70 ratio, an index of systemic inflammatory status, was also investigated. The results showed that HS response was preserved in OVX animals, as inferred from HSP70 expression (up to 40% rise, p oxidative stress, hematological parameters, and glycemic control either. This suggests that the lack of estrogen per se could not be solely ascribed as the unique source of low HSP70 expression as observed in long-term post-menopausal individuals. As a consequence, periodic evaluation of HSP70 status (iHSP70 vs. eHSP70) may be of clinical relevance because decreased HS response capacity is at the center of the onset of menopause-related dysfunctions.

  12. Increased Umbilical Cord PAI-1 Levels in Placental Insufficiency Are Associated with Fetal Hypoxia and Angiogenesis.

    Science.gov (United States)

    Seferovic, Maxim D; Gupta, Madhulika B

    2016-01-01

    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 PAI-1 was increased (~10-fold, p PAI-1 levels correlated to blood oxygen (r = -0.68, p PAI-1 levels (r = 0.65, p PAI-1 inhibiting antibody (p 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.

  13. 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...... poor disease-specific (p = 0.003) and overall (p = 0.004) survival. In node-negative patients, Chalkley counts were not associated with prognosis, whereas in node-positive patients, high Chalkley scores indicated poor disease-specific (p = 0.0006) and overall (p = 0.0008) survival. A multivariate...... analysis showed that positive lymph nodes, high histopathological grades, and negative oestrogen receptors were independent markers of cancer-related death. A high histopathological grade was associated with cancer-related death in node-negative patients, whereas in node-positive patients, many lymph nodes...

  14. Application of MR stem cell markers in research of temozolomide intervention gliomas angiogenesis and therapy%MR干细胞标记在替莫唑胺干预脑胶质瘤血管生成及治疗研究中的应用

    Institute of Scientific and Technical Information of China (English)

    陈伟志; 杨重恒

    2015-01-01

    目的:探究MR干细胞标记在替莫唑胺干预脑胶质瘤血管生成及治疗中的作用。方法通过C6胶质瘤细胞株静脉注射建立大鼠脑胶质瘤的动物模型,采用MR干细胞标记技术以及免疫组化观测肿瘤生长及新生血管的生成,对比影像学与免疫组化检测结果,进行2者间的相关性分析。结果本研究成功运用MR扫描示踪SPIO-PLL共同标记的骨髓干细胞,动态检测了脑胶质瘤模型大鼠脑内肿瘤血管生成情况。影像学与免疫组化相关性分析结果显示,2者呈现良好的负相关性( P<0.05)。结论 SPIO对于骨髓干细胞的磁性标记标记和MR示踪技术是活体动态观察脑胶质瘤血管生成的有效手段。%Objective To explore the role of MR stem cell markers in temozolomide intervention gliomas angiogenesis and therapy .Methods C6 glioma cells were intravenously injected in glioma model rat.MR stem cell markers and immunohistochemistry were used to observe the tumor growth and angiogenesis.Correlation of contrast imaging and immunohistochemistry results were studied.Results In this study, MR scanning was successfully used to trace the SPIO-PLL marked bone marrow stem cells, dynamic testing of angiogenesis in rat brain glioma tumor.Correlation analysis of imaging and immunohistochemical showed that they had a good negative correlation (P<0.05).Conclusion SPIO magnetic markers for bone marrow stem cells and MR tracing technique is an effective means of dynamic observation in vivo glioma angiogenesis.

  15. H pylori status and angiogenesis factors in human gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Anita Mangia; Alfredo Di Leo; Stefania Tommasi; Pasquale Berloco; Jian Ming Xu; Angelo Paradiso; Annalisa Chiriatti; Girolamo Ranieri; Ines Abbate; Maria Coviello; Giovanni Simone; Francesco Alfredo Zito; Severino Montemurro; Antonello Rucci

    2006-01-01

    AIM: To investigate H pylori expression in gastric cancer patients in relation to primary tumor angiogenic markers, such as microvessel density (MVD), thymidine phosphorylase (TP), vascular endothelial growth factor receptor-1 (VEGF-R1), p53 and circulating VEGF levels.METHODS: Angiogenic markers were analyzed immunohistochemically in 56 primary gastric cancers. H pylori cytotoxin (vacA) and the cytotoxin-associated gene (cagA) amplification were evaluated using PCR assay. Serum H pylori IgG antibodies and serum/plasma circulating VEGF levels were detected in 39 and 38 patients by ELI SA, respectively.RESULTS: A total of 69% of patients were positive for circulating IgG antibodies against H pylori. cagA-positive H pylori strains were found in 41% of gastric patients. vacA was found in 50% of patients; s1 strains were more highly expressed among vacA-positive patients. The presence of the s1 strain was significantly associated with cagA (P = 0.0001). MVD was significantly correlated with both tumor VEGF expression (r = 0.361, P = 0.009) and serum VEGF levels (r = -0.347, P = 0.041).Conversely, neither VEGF-R1 expression nor MVD was related to p53 expression. However, H pylori was not related to any angiogenic markers except for the plasma VEGF level (P = 0.026).CONCLUSION: H pylori antigen is related to higher plasma VEGF levels, but not to angiogenic character istics. It can be hypothesized that the toxic effects of H pylori on angiogenesis occurs in early preclinical disease phase or in long-lasting aggressive infections, but only when high H pylori IgG levels are persistent.

  16. Roles of sphingosine-1-phosphate signaling in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Yoh; Takuwa; Yasuo; Okamoto; Noriko; Takuwa; Kazuaki; Yoshioka

    2010-01-01

    Sphingosine-1-phosphate (S1P) is a blood-borne lipid mediator with pleiotropic biological activities. S1P acts via the specific cell surface G-protein-coupled receptors, S1P1-5. S1P1 and S1P2 were originally identified from vascular endothelial cells (ECs) and smooth muscle cells, respectively. Emerging evidence shows that S1P plays crucial roles in the regulation of vascular functions, including vascular formation, barrier protection and vascular tone via S1P1, S1P2 and S1P3. In particular, S1P regulates vascular formation through multiple mechanisms; S1P exerts both positive and negative effects on angiogenesis and vascular maturation. The positive and negative effects of S1P are mediated by S1P1 and S1P2, respectively. These effects of S1P1 and S1P2 are probably mediated by the S1P receptors expressed in multiple cell types including ECs and bone-marrow-derived cells. The receptor-subtype-specific, distinct effects ofS1P favor the development of novel therapeutic tactics for antitumor angiogenesis in cancer and therapeutic angiogenesis in ischemic diseases.

  17. High and low frequency subharmonic imaging of angiogenesis in a murine breast cancer model.

    Science.gov (United States)

    Dahibawkar, Manasi; Forsberg, Mark A; Gupta, Aditi; Jaffe, Samantha; Dulin, Kelly; Eisenbrey, John R; Halldorsdottir, Valgerdur G; Forsberg, Anya I; Dave, Jaydev K; Marshall, Andrew; Machado, Priscilla; Fox, Traci B; Liu, Ji-Bin; Forsberg, Flemming

    2015-09-01

    This project compared quantifiable measures of tumor vascularity obtained from contrast-enhanced high frequency (HF) and low frequency (LF) subharmonic ultrasound imaging (SHI) to 3 immunohistochemical markers of angiogenesis in a murine breast cancer model (since angiogenesis is an important marker of malignancy and the target of many novel cancer treatments). Nineteen athymic, nude, female rats were implanted with 5×10(6) breast cancer cells (MDA-MB-231) in the mammary fat pad. The contrast agent Definity (Lantheus Medical Imaging, N Billerica, MA) was injected in a tail vein (dose: 180μl/kg) and LF pulse-inversion SHI was performed with a modified Sonix RP scanner (Analogic Ultrasound, Richmond, BC, Canada) using a L9-4 linear array (transmitting/receiving at 8/4MHz in SHI mode) followed by HF imaging with a Vevo 2100 scanner (Visualsonics, Toronto, ON, Canada) using a MS250 linear array transmitting and receiving at 24MHz. The radiofrequency data was filtered using a 4th order IIR Butterworth bandpass filter (11-13MHz) to isolate the subharmonic signal. After the experiments, specimens were stained for endothelial cells (CD31), vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2). Fractional tumor vascularity was calculated as contrast-enhanced pixels over all tumor pixels for SHI, while the relative area stained over total tumor area was calculated from specimens. Results were compared using linear regression analysis. Out of 19 rats, 16 showed tumor growth (84%) and 11 of them were successfully imaged. HF SHI demonstrated better resolution, but weaker signals than LF SHI (0.06±0.017 vs. 0.39±0.059; p<0.001). The strongest overall correlation in this breast cancer model was between HF SHI and VEGF (r=-0.38; p=0.03). In conclusion, quantifiable measures of tumor neovascularity derived from contrast-enhanced HF SHI appear to be a better method than LF SHI for monitoring angiogenesis in a murine xenograft model of breast cancer

  18. Impact of mechanical stress and tension-stress on angiogenesis in wound healing

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Angiogenesis plays a fundamental role in the development of the embryonic vascular tree as well as in several normal and pathologic conditions during postnatal life. Blood supply, established by neovascularization, is imperative for histogenesis during wound healing as well as the limb lengthening applied extensively in the treatment of skeletal trauma sequalae. But little attention has been paid to this area. This review aims to summarize angiogenesis regulation, the process of angiogenesis in wound healing and angiogenesis under mechanical stress, particularly in association with the tension-stress principle.

  19. Metabolomic and Genomic Markers of Atherosclerosis as Related to Oxidative Stress, Inflammation, and Vascular Function in Twin Astronauts

    Science.gov (United States)

    Lee, Stuart M. C.; Rana, Brinda K.; Stenger, Michael B.; Sears, Dorothy D.; Smith, Scott M.; Macias, Brandon R.; Hargens, Alan R.; Sharma, Kumar; De Vivo, Immaculata

    2016-01-01

    atherosclerosis risk factors. Conversely, these will not be observed in the ground-based twin. Methods: We will measure blood and urine biomarkers of oxidative stress and inflammation as well as arterial structure and function (carotid intima-medial thickness and brachial artery flow-mediated dilation) in one twin astronaut before, during, and after long-duration spaceflight and in his twin serving as a ground-based control. Furthermore, we will measure metabolomics (targeted and untargeted approaches) and genomic markers (DNA methylation, mRNA gene expression, telomere length) to elucidate the molecular mechanisms involved. A panel of biomarkers of oxidative and inflammatory stress will be measured in venous blood samples and 24-hour (in-flight) and 48-hour (pre- and post-flight) urine pools twice before flight, early (flight days 15 and 60) and late (2 weeks before landing) during the mission, and early in the post-flight recovery phase (approximately 3-5 days after landing). Arterial structure, assessed from measures of intima-media thickness, will be measured at the same times. Arterial function will be assessed using brachial flow-mediated dilation, a well-validated measure used to assess endothelium-dependent vasodilation and a sensitive predictor of atherosclerotic risk, only before and after spaceflight. Discussion: Pre- and in-flight data collection is in progress for the space-flown twin, and similar data have been obtained from the ground-based twin. Blood and urine samples will be batch processed when received from ISS after the conclusion of the 1-year mission. Results from these individual subjects will be compared to the larger complement of subjects participating in the companion study currently ongoing in ISS astronauts.

  20. Roles of main pro-and anti-angiogenic factors in tumor angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Zhi Huang; Shi-Deng Bao

    2004-01-01

    Tumor growth without size restriction depends on vascular supply. The ability of tumor to induce new blood-vessel formation has been a major focus of cancer research over the past decade. It is now known that members of the vascular endothelial growth factor and angiopoietin families,mainly secreted by tumor cells, induce tumor angiogenesis,whereas other endogenous angiogenic inhibitors, including thrombospondin-1 and angiostatin, keep tumor in dormancy.Experimental and clinical evidence has suggested that the process of tumor metastasis depends on angiogenesis or lymphangiogenesis. This article summarizes the recent research progress for some basic pro- or anti-angiogenic factors in tumor angiogenesis.

  1. Cancer Immunotherapy of Targeting Angiogenesis

    Institute of Scientific and Technical Information of China (English)

    JianmeiHou; LingTian; YuquanWei

    2004-01-01

    Tumor growth and metastasis are angiogenesis-dependent. Anti-angiogenic therapy may be a useful approach to cancer therapy. This review discussed tumor angiogenesis and immunotherapy of targeting tumor angiogenesis from two main aspects: (1) active vaccination to induce effective anti-angiogenesis immunity; (2) passive immunotherapy with anti-pro-angiogenic molecules relevant antibody. Evidence from the recent years suggested that anti-angiogenic therapy should be one of the most promising approaches to cancer therapy.

  2. Confocal laser endomicroscopy and immunoendoscopy for real-time assessment of vascularization in gastrointestinal malignancies

    Institute of Scientific and Technical Information of China (English)

    Dan Ionu(t)Gheonea; Tatiana Car(ta)n(a); Tudorel Ciurea; Carmen Popescu; Anca B(a)d(a)r(a)u; Adrian S(a)ftoiu

    2011-01-01

    Gastrointestinal cancers represent a major cause of morbidity and mortality,with incomplete response to chemotherapy in the advanced stages and poor prognosis.Angiogenesis plays a crucial part in tumor growth and metastasis,with most gastrointestinal cancers depending strictly on the development of a new and devoted capillary network.Confocal laser endomicroscopy is a new technology which allows in vivo microscopic analysis of the gastrointestinal mucosa and its microvascularization during ongoing endoscopy by using topically or systemically administered contrast agents.Targeting markers of angiogenesis in association with confocal laser endomicroscopic examination(immunoendoscopy),as a future challenge,will add functional analysis to the morphological aspect of the neoplastic process.This review describes previous experience in endomicroscopic examination of the upper and lower digestive tract with emphasis on vascularization,resulting in a broad spectrum of potential clinical applications,and also preclinical research that could be translated to human studies.

  3. What "helps" tumors evade vascular targeting treatment?

    Institute of Scientific and Technical Information of China (English)

    SI Zhi-chao; LIU Jie

    2008-01-01

    Objective To throw a light on the possible factors which might induce resistance of vascular targeting treatment in tumors by reviewing the recent publications in the field of tumor angiogenesis and vascular targeting treatment.Data sources The data used in this review were mainly from Medline and PubMed for relevant English language articles published from 1971 to January 2008. The search terms were "angiogenesis", "vascular targeting treatment" and "endothelial progenitor cells".Study selection Articles involved in the possible influence factors during angiogenesis and vascular targeting treatment were selected, including angiogenic or anti-angiogenic mechanism, tumor vasculature, tumor cells, cancer stem cells and endothelial progenitor cells.Results As a promising strategy vascular targeting treatment still has experimental and clinical setbacks which may term tumor vasculature's resistance to anti-angiogenesis agents. There are several possible explanations for such a resistance that might account for clinical and preclinical failures of anti-angiogenic treatment against tumor.Proangiogenic effect of hypoxia, normal tumor vasculature, escape of tumor cells and tumor vasculogenesis are included.This review reveals some clues which might be helpful to direct future research in order to remove obstacles to vascular targeting treatment.Conclusions Generally and undoubtedly vascular targeting treatment remains a promising strategy. But we still have to realize the existence of a challenging future. Further research is required to enhance our knowledge of vascular targeting treatment strategy before it could make a more substantial success.

  4. [Emoxipin as an inhibitor of angiogenesis].

    Science.gov (United States)

    Sologub, A A; Akberova, S I; Ziangirova, G G

    1992-12-01

    The effect of emoxypin on angiogenesis in rabbit cornea in aseptic inflammation induced by intracorneal implantation of a piece of quartz and on the development of the vessels of the chick embryo yolk sac was studied. 1% emoxypin pipetted thrice a day for 10-14 days inhibited corneal neovascularization and reduced the formation of new blood vessels. We observed an inhibitory effect on the development of vascular bed of the embryo yolk sac on incubation hour 64-72. The drug affected neither general growth of the embryos no the number of somites.

  5. The Harvard angiogenesis story.

    Science.gov (United States)

    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.

  6. How phototherapy affects angiogenesis

    Science.gov (United States)

    Dyson, Mary

    2007-02-01

    Angiogenesis is essential for normal growth, tissue repair and regeneration. Its stimulation accelerates repair and regeneration including wound healing where these processes are delayed. Its inhibition can reduce the rate of growth of solid tumors. Phototherapy can accelerate the resolution of acute inflammation with the result that the proliferative phase of tissue repair, when angiogenesis occurs, begins earlier than in sham-irradiated controls. Evidence that angiogenesis is enhanced in dermal repair, tendon repair and bone regeneration in rodents is presented. The cellular mechanisms that control angiogenesis involve the interaction of endothelial cells, macrophages, pericytes and other cells in response, for example, to changes in the availability of oxygen in the local environment. Pericytes and macrophages modulate endothelial cell proliferation; pericytes guide endothelial cell migration. The stimulation of endothelial cell proliferation in vitro following exposure to red (660 nm) and infrared (820 nm) radiation, 15 mW, at 2-8 J/cm2 is presented. 1J/cm2 was ineffective. 820 nm irradiation, 15 mW, at 8 J/cm2 was observed to inhibit pericyte proliferation in vitro. Indirect effects on endothelial cell and pericyte proliferation followed stimulation of soluble mediator production by macrophages following exposure to red and infrared radiation. The potential clinical significance of the results obtained is discussed and the necessity of clinical trials emphasized.

  7. Molecular targeting of angiogenesis for imaging and therapy

    Energy Technology Data Exchange (ETDEWEB)

    Brack, Simon S.; Neri, Dario [Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology Zurich (Switzerland); Dinkelborg, Ludger M. [Research Laboratories of Schering AG, Berlin (Germany)

    2004-09-01

    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.)

  8. A pilot study on potential plasma hypoxia markers in the radiotherapy of non-small cell lung cancer. Osteopontin, carbonic anhydrase IX and vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Ostheimer, C.; Bache, M.; Guettler, A.; Vordermark, D. [Martin-Luther-University Halle-Wittenberg, Department of Radiation Oncology, Halle (Saale) (Germany); Kotzsch, M. [Technical University Dresden, Department of Pathology, Dresden (Germany)

    2014-03-15

    Hypoxic radioresistance plays a critical role in the radiotherapy of cancer and adversely impacts prognosis and treatment response. This prospective study investigated the interrelationship and the prognostic significance of several hypoxia-related proteins in non-small cell lung cancer (NSCLC) patients treated by radiotherapy ± chemotherapy. Pretreatment osteopontin (OPN), vascular endothelial growth factor (VEGF) and carbonic anhydrase IX (CA IX) plasma levels were determined by ELISA in 55 NSCLC (M0) patients receiving 66 Gy curative-intent radiotherapy or chemoradiation. Marker correlation, association with clinicopathological parameters and the prognostic value of a biomarker combination was evaluated. All biomarkers were linearly correlated and linked to different clinical parameters including lung function, weight loss (OPN), gross tumor volume (VEGF) and T stage (CA IX). High OPN (p = 0.03), VEGF (p = 0.02) and CA IX (p = 0.04) values were significantly associated with poor survival. Double marker combination additively increased the risk of death by a factor of 2 and high plasma levels of the triple combination OPN/VEGF/CA IX yielded a 5.9-fold risk of death (p = 0.009). The combined assessment of OPN/VEGF/CA IX correlated independently with prognosis (p = 0.03) in a multivariate Cox regression model including N stage, T stage and GTV. This pilot study suggests that a co-detection augments the prognostic value of single markers and that the integration of OPN, VEGF and CA IX into a hypoxic biomarker profile for the identification of patients with largely hypoxic and radioresistant tumors should be further evaluated. (orig.) [German] Hypoxische Radioresistenz spielt eine kritische Rolle in der Radiotherapie maligner Tumoren und beeinflusst Prognose und Therapieansprechen negativ. Diese prospektive Studie untersuchte den Zusammenhang und die prognostische Bedeutung einiger hypoxieassoziierter Proteine bei Patienten mit nicht-kleinzelligem Bronchialkarzinom

  9. Growth factors for therapeutic angiogenesis in hypercholesterolemic erectile dysfunction

    Institute of Scientific and Technical Information of China (English)

    Donghua Xie; Brian H. Annex; Craig F. Donatucci

    2008-01-01

    The past decade has seen an explosion of new information on the physiology of penile erection, and pathophysiology of erectile dysfunction (ED). Hypercholesterolemia is a chronic condition that can lead to degeneration in the vasculature bed and can result in ED if the penile vasculature is involved. Angiogenesis is the growth of new blood vessels from preexisting vasculature. Therapeutic angiogenesis seeks to harness the mechanisms of vascular growth to treat disorders of inadequate tissue perfusion, such as coronary artery disease and ED. There have been tremendous changes in the field of therapeutic angiogenesis over the past decade, and there is much promise for the future.Initial preclinical work with cytokine growth factor delivery resulted in a great deal of enthusiasm for the treatment of ischemic heart and/or peripheral vascular disease, though clinical studies have not achieved similar success. With an increased understanding of the complex mechanisms involved in angiogenesis, novel therapies which target multiple different angiogenic pathways are also being developed and tested. The penis is a convenient tissue target for gene therapy because of its external location and accessibility, the ubiquity of endothelial lined spaces, and low level of blood flow, especially in the flaccid state. Therapeutic angiogenesis is an exciting field that continues to evolve. This review will focus on the development of growth factors for hypercholesterolemic ED, the use of various growth factors for ED therapy, their routes of delivery, and the results in animal studies.

  10. Reversal of glial and neurovascular markers of unhealthy brain aging by exercise in middle-aged female mice.

    Directory of Open Access Journals (Sweden)

    Caitlin S Latimer

    Full Text Available Healthy brain aging and cognitive function are promoted by exercise. The benefits of exercise are attributed to several mechanisms, many which highlight its neuroprotective role via actions that enhance neurogenesis, neuronal morphology and/or neurotrophin release. However, the brain is also composed of glial and vascular elements, and comparatively less is known regarding the effects of exercise on these components in the aging brain. Here, we show that aerobic exercise at mid-age decreased markers of unhealthy brain aging including astrocyte hypertrophy, a hallmark of brain aging. Middle-aged female mice were assigned to a sedentary group or provided a running wheel for six weeks. Exercise decreased hippocampal astrocyte and myelin markers of aging but increased VEGF, a marker of angiogenesis. Brain vascular casts revealed exercise-induced structural modifications associated with improved endothelial function in the periphery. Our results suggest that age-related astrocyte hypertrophy/reactivity and myelin dysregulation are aggravated by a sedentary lifestyle and accompanying reductions in vascular function. However, these effects appear reversible with exercise initiated at mid-age. As this period of the lifespan coincides with the appearance of multiple markers of brain aging, including initial signs of cognitive decline, it may represent a window of opportunity for intervention as the brain appears to still possess significant vascular plasticity. These results may also have particular implications for aging females who are more susceptible than males to certain risk factors which contribute to vascular aging.

  11. Sleep Apnea, Sleep Duration and Brain MRI Markers of Cerebral Vascular Disease and Alzheimer's Disease: The Atherosclerosis Risk in Communities Study (ARIC.

    Directory of Open Access Journals (Sweden)

    Pamela L Lutsey

    Full Text Available A growing body of literature has suggested that obstructive sleep apnea (OSA and habitual short sleep duration are linked to poor cognitive function. Neuroimaging studies may provide insight into this relation.We tested the hypotheses that OSA and habitual short sleep duration, measured at ages 54-73 years, would be associated with adverse brain morphology at ages 67-89 years.Included in this analysis are 312 ARIC study participants who underwent in-home overnight polysomnography in 1996-1998 and brain MRI scans about 15 years later (2012-2013. Sleep apnea was quantified by the apnea-hypopnea index and categorized as moderate/severe (≥15.0 events/hour, mild (5.0-14.9 events/hour, or normal (<5.0 events/hour. Habitual sleep duration was categorized, in hours, as <7, 7 to <8, ≥8. MRI outcomes included number of infarcts (total, subcortical, and cortical and white matter hyperintensity (WMH and Alzheimer's disease signature region volumes. Multivariable adjusted logistic and linear regression models were used. All models incorporated inverse probability weighting, to adjust for potential selection bias.At the time of the sleep study participants were 61.7 (SD: 5.0 years old and 54% female; 19% had moderate/severe sleep apnea. MRI imaging took place 14.8 (SD: 1.0 years later, when participants were 76.5 (SD: 5.2 years old. In multivariable models which accounted for body mass index, neither OSA nor abnormal sleep duration were statistically significantly associated with odds of cerebral infarcts, WMH brain volumes or regional brain volumes.In this community-based sample, mid-life OSA and habitually short sleep duration were not associated with later-life cerebral markers of vascular dementia and Alzheimer's disease. However, selection bias may have influenced our results and the modest sample size led to relatively imprecise associations.

  12. Probiotic yeast inhibits VEGFR signaling and angiogenesis in intestinal inflammation.

    Directory of Open Access Journals (Sweden)

    Xinhua Chen

    Full Text Available BACKGROUND AND AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

  13. Endothelial Progenitor Cells in Sprouting Angiogenesis: Proteases Pave the Way.

    Science.gov (United States)

    Laurenzana, A; Fibbi, G; Margheri, F; Biagioni, A; Luciani, C; Del Rosso, M; Chillà, A

    2015-01-01

    Sprouting angiogenesis consists of the expansion and remodelling of existing vessels, where the vascular sprouts connect each other to form new vascular loops. Endothelial Progenitor Cells (EPCs) are a subtype of stem cells, with high proliferative potential, able to differentiate into mature Endothelial Cells (ECs) during the neovascularization process. In addition to this direct structural role EPCs improve neovascularization, also secreting numerous pro-angiogenic factors able to enhance the proliferation, survival and function of mature ECs, and other surrounding progenitor cells. While sprouting angiogenesis by mature ECs involves resident ECs, the vasculogenic contribution of EPCs is a high hurdle race. Bone marrowmobilized EPCs have to detach from the stem cell niche, intravasate into bone marrow vessels, reach the hypoxic area or tumour site, extravasate and incorporate into the new vessel lumen, thus complementing the resident mature ECs in sprouting angiogenesis. The goal of this review is to highlight the role of the main protease systems able to control each of these steps. The pivotal protease systems here described, involved in vascular patterning in sprouting angiogenesis, are the matrix-metalloproteinases (MMPs), the serineproteinases urokinase-type plasminogen activator (uPA) associated with its receptor (uPAR) and receptorassociated plasminogen/plasmin, the neutrophil elastase and the cathepsins. Since angiogenesis plays a critical role not only in physiological but also in pathological processes, such as in tumours, controlling the contribution of EPCs to the angiogenic process, through the regulation of the protease systems involved, could yield new opportunities for the therapeutic prospect of efficient control of pathological angiogenesis.

  14. Advances in the cellular and molecular biology of angiogenesis.

    Science.gov (United States)

    Egginton, Stuart; Bicknell, Roy

    2011-12-01

    Capillaries have been recognized for over a century as one of the most important components in regulating tissue oxygen transport, and their formation or angiogenesis a pivotal element of tissue remodelling during development and adaptation. Clinical interest stems from observations that both excessive and inadequate vascular growth plays a major role in human diseases, and novel developments in treatments for cancer and eye disease increasingly rely on anti-angiogenic therapies. Although the discovery of VEGF (vascular endothelial growth factor) provided the first clue for specificity of signalling in endothelial cell activation, understanding the integrative response that drives angiogenesis requires a much broader perspective. The Advances in the Cellular and Molecular Biology of Angiogenesis meeting brought together researchers at the forefront of this rapidly moving field to provide an update on current understanding, and the most recent insights into molecular and cellular mechanisms of vascular growth. The plenary lecture highlighted the integrative nature of the angiogenic process, whereas invited contributions from basic and clinician scientists described fundamental mechanisms and disease-associated issues of blood vessel formation, grouped under a number of themes to aid discussion. These articles will appeal to academic, clinical and pharmaceutical scientists interested in the molecular and cellular basis of angiogenesis, their modulation or dysfunction in human diseases, and application of these findings towards translational medicine.

  15. The enigmatic role of angiopoietin-1 in tumor angiogenesis

    Institute of Scientific and Technical Information of China (English)

    LINDA J METHENY-BARLOW; LU YUAN LI

    2003-01-01

    A tumor vasculature is highly unstable and immature, characterized by a high proliferation rate of endothelial cells,hyper-permeability, and chaotic blood flow. The dysfunctional vasculature gives rise to continual plasma leakage and hypoxia in the tumor, resulting in constant on-sets of inflammation and angiogenesis. Tumors are thus likened to wounds that will not heal. The lack of functional mural cells, including pericytes and vascular smooth muscle cells,in tumor vascular structure contributes significantly to the abnormality of tumor vessels. Angiopoietin- 1 (Angl) is a physiological angiogenesis promoter during embryonic development. The function of Ang 1 is essential to endothelial cell survival, vascular branching, and pericyte recruitment. However, an increasing amount of experimental data suggest that Ang 1-stimulated association of mural cells with endothelial cells lead to stabilization of newly formed blood vessels. This in turn may limit the otherwise continuous angiogenesis in the tumor, and consequently give rise to inhibition of tumor growth. We discuss the enigmatic role of Ang1 in tumor angiogenesis in this review.

  16. Role of Jagged1-Hey1 Signal in Angiotensin II-induced Impairment of Myocardial Angiogenesis

    Science.gov (United States)

    Guan, Ai-Li; He, Tao; Shao, Yi-Bing; Chi, Yi-Fan; Dai, Hong-Yan; Wang, Yan; Xu, Li; Yang, Xuan; Ding, Hua-Min; Cai, Shang-Lang

    2017-01-01

    Background: Angiotensin II (Ang II) is a major contributor to the development of heart failure. However, the molecular and cellular mechanisms that underlie this process remain elusive. Inadequate angiogenesis in the myocardium leads to a transition from cardiac hypertrophy to dysfunction, and our previous study showed that Ang II significantly impaired the angiogenesis response. The current study was designed to examine the role of Jagged1-Notch signaling in the effect of Ang II during impaired angiogenesis and cardiac hypertrophy. Methods: Ang II was subcutaneously infused into 8-week-old male C57BL/6 mice at a dose of 200 ng·kg−1·min−1 for 2 weeks using Alzet micro-osmotic pumps. N-[N-(3, 5-difluorophenacetyl)-L-alanyl]-S-phenylglycine tert-butyl ester (DAPT), a γ-secretase inhibitor, was injected subcutaneously during Ang II infusion at a dose of 10.0 mg·kg−1·d−1. Forty mice were divided into four groups (n = 10 per group): control group; Ang II group, treated with Ang II; DAPT group, treated with DAPT; and Ang II + DAPT group, treated with both Ang II and DAPT. At the end of experiments, myocardial (left ventricle [LV]) tissue from each experimental group was evaluated using immunohistochemistry, Western blotting, and real-time polymerase chain reaction. Data were analyzed using one-way analysis of variance test followed by the least significant difference method or independent samples t-test. Results: Ang II treatment significantly induced cardiac hypertrophy and impaired the angiogenesis response compared to controls, as shown by hematoxylin and eosin (HE) staining and immunohistochemistry for CD31, a vascular marker (P < 0.05 for both). Meanwhile, Jagged1 protein was significantly increased, but gene expression for both Jag1 and Hey1 was decreased in the LV following Ang II treatment, compared to that in controls (relative ratio for Jag1 gene: 0.45 ± 0.13 vs. 0.84 ± 0.15; relative ratio for Hey1 gene: 0.51 ± 0.08 vs. 0.91 ± 0.09; P < 0

  17. Analysis of p53 and vascular endothelial growth factor expression in human gallbladder carcinoma for the determination of tumor vascularity

    Institute of Scientific and Technical Information of China (English)

    Yu Tian; Ren-Yu Ding; Ying-Hui Zhi; Ren-Xuan Guo; Shuo-Dong Wu

    2006-01-01

    AIM: To examine the expression of p53 and vascular endothelial growth factor (VEGF) as well as microvessel count (MVC) and to investigate the role of VEGF as an angiogenic marker and the possible role of p53 in the regulation of angiogenesis in human gallbladder carcinoma.METHODS: Surgically resected specimens of 49 gallbladder carcinomas were studied by immunohistochemical staining for p53 protein, VEGF, and factor Ⅷ-related antigen. VEGF expression and mutant p53 expression were then correlated with Nevin stage,differentiation grade, MVC, and lymph node metastasis.RESULTS: Positive p53 protein and VEGF expressions were found in 61.2% and 63.3% of tumors, respectively.p53 and VEGF staining status was identical in 55.1%of tumors. The Nevin staging of p53- or VEGF-positive tumors was significantly later than that of negative tumors. The MVC in p53- or VEGF-positive tumors was significantly higher than that in negative tumors,and MVC in both p53- and VEGF-negative tumors was significantly lower than that in the other subgroups.CONCLUSION: Our findings suggest that p53-VEGF pathway can regulate tumor angiogenesis in human gallbladder carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the tumor vascularity of gallbladder cancer.

  18. Sphingosine-1-phosphate signaling in vasculogenesis and angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Kelley; M; Argraves; Brent; A; Wilkerson; W; Scott; Argraves

    2010-01-01

    Blood vessels either form de novo through the process of vasculogenesis or through angiogenesis that involves the sprouting and proliferation of endothelial cells in pre-existing blood vessels. A complex interactive network of signaling cascades downstream from at least three of the nine known G-protein-coupled sphingosine-1-phosphate (S1P) receptors act as a prime effector of neovascularization that occurs in embryonic development and in association with various pathologies. This review focuses on the current knowledge of the roles of S1P signaling in vasculogenesis and angiogenesis, with particular emphasis on vascular cell adhesion and motility responses.

  19. Roxarsone induces angiogenesis via PI3K/Akt signaling

    OpenAIRE

    2016-01-01

    Background 3-Nitro-4-hydroxy phenyl arsenic acid, roxarsone, is widely used as an organic arsenic feed additive for livestock and poultry, which may increase the level of arsenic in the environment and the risk of exposure to arsenic in human. Little information is focused on the angiogenesis roxarsone-induced and its mechanism at present. This paper aims to study the role of PI3K/Akt signaling in roxarsone-induced angiogenesis in rat vascular endothelial cells and a mouse B16–F10 melanoma xe...

  20. Tumor-derived mural-like cells coordinate with endothelial cells: role of YKL-40 in mural cell-mediated angiogenesis.

    Science.gov (United States)

    Francescone, R; Ngernyuang, N; Yan, W; Bentley, B; Shao, R

    2014-04-17

    Tumor neo-vasculature is characterized by spatial coordination of endothelial cells with mural cells, which delivers oxygen and nutrients. Here, we explored a key role of the secreted glycoprotein YKL-40, a mesenchymal marker, in the interaction between endothelial cells and mesenchymal mural-like cells for tumor angiogenesis. Xenotransplantation of tumor-derived mural-like cells (GSDCs) expressing YKL-40 in mice developed extensive and stable blood vessels covered with more GSDCs than those in YKL-40 gene knockdown tumors. YKL-40 expressed by GSDCs was associated with increased interaction of neural cadherin/β-catenin/smooth muscle alpha actin; thus, mediating cell-cell adhesion and permeability. YKL-40 also induced the interaction of vascular endothelial cadherin/β-catenin/actin in endothelial cells (HMVECs). In cell co-culture systems, YKL-40 enhanced both GSDC and HMVEC contacts, restricted vascular leakage, and stabilized vascular networks. Collectively, the data inform new mechanistic insights into the cooperation of mural cells with endothelial cells induced by YKL-40 during tumor angiogenesis, and also enhance our understanding of YKL-40 in both mural and endothelial cell biology.

  1. Angiogenesis and antiangiogenic agents in cervical cancer

    Directory of Open Access Journals (Sweden)

    Tomao F

    2014-12-01

    Full Text Available Federica Tomao,1 Anselmo Papa,2 Luigi Rossi,2 Eleonora Zaccarelli,2 Davide Caruso,2 Federica Zoratto,2 Pierluigi Benedetti Panici,1 Silverio Tomao2 1Department of Gynecology and Obstetrics, Sapienza University of Rome, Policlinico Umberto I, Rome, 2Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Oncology Unit, ICOT, Latina, Italy Abstract: Standard treatment of cervical cancer (CC consists of surgery in the early stages and of chemoradiation in locally advanced disease. Metastatic CC has a poor prognosis and is usually treated with palliative platinum-based chemotherapy. Current chemotherapeutic regimens are associated with significant adverse effects and only limited activity, making identification of active and tolerable novel targeted agents a high priority. Angiogenesis is a complex process that plays a crucial role in the development of many types of cancer. The dominant role of angiogenesis in CC seems to be directly related to human papillomavirus-related inhibition of p53 and stabilization of hypoxia-inducible factor-1α. Both of these mechanisms are able to increase expression of vascular endothelial growth factor (VEGF. Activation of VEGF promotes endothelial cell proliferation and migration, favoring formation of new blood vessels and increasing permeability of existing blood vessels. Since bevacizumab, a recombinant humanized monoclonal antibody binding to all isoforms of VEGF, has been demonstrated to significantly improve survival in gynecologic cancer, some recent clinical research has explored the possibility of using novel therapies directed toward inhibition of angiogenesis in CC too. Here we review the main results from studies concerning the use of antiangiogenic drugs that are being investigated for the treatment of CC. Keywords: cervical cancer, angiogenesis, human papillomavirus, bevacizumab, target therapies

  2. Endostatin derivative angiogenesis inhibitors

    Institute of Scientific and Technical Information of China (English)

    ZHENG Meng-jie

    2009-01-01

    Objective To throw light on the superiority of the anti-angiogenesis activity of endostatin (ES) derivatives by reviewing the recent progress in the field of ES molecular structure modification.Data sources The data used in this article were mainly from PubMed with relevant English articles published from 1971 to May 2008.The search terms were "endostatin" and "angiothesis".Study selection Articles involved in the ES molecular structure modification and the original milestone articles were selected.Results A number of ES derivatives were designed and studied to improve its clinical relevance.The modified ES with polyethylene glycol (PEG),low molecular weight heparin (LMWH) and IgG Fc domain extended the circulation half-life.Meanwhile the recombinant ESs showed more potent anti-tumor activity than native ES in mouse xenografts.Mutated ES also changed its anti-angiogenesis activity.Conclusions The anti-angiogenesis treatment remains a promising tumor therapeutic strategy.New ES derivatives would be a good choice to meet the future challenge on clinical application of ES.

  3. Inflamed tumor-associated adipose tissue is a depot for macrophages that stimulate tumor growth and angiogenesis

    NARCIS (Netherlands)

    Wagner, Marek; Bjerkvig, Rolf; Wiig, Helge; Melero-Martin, Juan M.; Lin, Ruei-Zeng; Klagsbrun, Michael; Dudley, Andrew C.

    2012-01-01

    Tumor-associated stroma is typified by a persistent, non-resolving inflammatory response that enhances tumor angiogenesis, growth and metastasis. Inflammation in tumors is instigated by heterotypic interactions between malignant tumor cells, vascular endothelium, fibroblasts, immune and inflammatory

  4. 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....

  5. Involvement of microparticles in diabetic vascular complications.

    Science.gov (United States)

    Tsimerman, Gala; Roguin, Ariel; Bachar, Anat; Melamed, Eyal; Brenner, Benjamin; Aharon, Anat

    2011-08-01

    Type 2 diabetes mellitus (T2DM) is associated with increased coagulability and vascular complications. Circulating microparticles (MPs) are involved in thrombosis, inflammation, and angiogenesis. However, the role of MPs in T2DM vascular complications is unclear. We characterised the cell origin and pro-coagulant profiles of MPs obtained from 41 healthy controls and 123 T2DM patients with coronary artery disease, retinopathy and foot ulcers. The effects of MPs on endothelial cell coagulability and tube formation were evaluated. Patients with severe diabetic foot ulcers expressed the highest levels of MPs originated from platelet and endothelial cells and negatively-charged phospholipid-bearing MPs. MP coagulability, calculated from MP tissue factor (TF) and TF pathway inhibitor (TFPI) ratio, was low in healthy controls and in diabetic retinopathy patients (1.8, p≥0.002). MPs of all T2DM patients induced a more than two-fold increase in endothelial cell TF (antigen and gene expression) but did not affect TFPI levels. Tube networks were longest and most stable in endothelial cells that were incubated with MPs of healthy controls, whereas no tube formation occurred in MPs of diabetic patients with coronary artery disease. MPs of diabetic retinopathy and diabetic foot ulcer patients induced branched tube networks that were unstable and collapsed over time. This study demonstrates that MP characteristics are related to the specific type of vascular complications and may serve as a bio-marker for the pro- coagulant state and vascular pathology in patients with T2DM.

  6. Association between vascular-poor area of primary tumors and epidermal growth factor receptor gene status in advanced lung adenocarcinoma.

    Science.gov (United States)

    Togashi, Yosuke; Masago, Katsuhiro; Kubo, Takeshi; Fujimoto, Daichi; Sakamori, Yuichi; Nagai, Hiroki; Kim, Young Hak; Togashi, Kaori; Mishima, Michiaki

    2012-12-01

    Mutation of the epidermal growth factor receptor gene (EGFR mutation) is a very important marker in the treatment for non-small cell lung cancer. Since signaling from this receptor induces tumor-associated angiogenesis, we hypothesized that lung cancers with EGFR mutations tend to develop locally with increased angiogenesis. Thus, the association between vascular-poor area of primary tumors and EGFR status was retrospectively investigated in advanced lung adenocarcinomas. To assess vascular-poor area, contrast-enhanced computed tomography scans taken before initial treatment for lung cancer were analyzed, together with primary tumor location (peripheral or central) and size. We analyzed 178 patients with advanced lung adenocarcinoma. EGFR mutations were detected in 95 of the 178 patients (53.4 %). EGFR mutation was found to be significantly related to women (P = 0.0070), never-smokers (P area (P area (P = 0.0001), and tumor size >30 mm (P = 0.0080). EGFR mutations were found in 41 of 51 never-smokers without vascular-poor area (80.4 %), 19 of 36 never-smokers with vascular-poor area (52.8 %), 19 of 37 current or former-smokers without vascular-poor area (51.4 %), and 16 of 54 current or former-smokers with vascular-poor area (29.6 %). This study showed an association between vascular-poor area of primary tumors and EGFR status. As a consequence, evaluation using a combination of smoking status and vascular-poor area allows us to predict presence of EGFR mutations at a high frequency.

  7. Vascular Cures

    Science.gov (United States)

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  8. The ligands of CXCR4 in vascularization

    OpenAIRE

    Tuchscheerer, Nancy

    2012-01-01

    The formation of a functional and integrated vascular network is a basic process in the growth and maintenance of tissues and can be established by two forms of blood vessel growth in adults: angiogenesis and arteriogenesis. In this study, the ligands of the chemokine receptor CXCR4 and its role in angiogenesis (represented by the experimental myocardial infarction) and arteriogenesis (represented by the murine hind limb ischemia model) was investigated. The first approach identified the CXCL...

  9. Airway vascular reactivity and vascularisation in human chronic airway disease

    NARCIS (Netherlands)

    Bailey, Simon R; Boustany, Sarah; Burgess, Janette K; Hirst, Stuart J; Sharma, Hari S; Simcock, David E; Suravaram, Padmini R; Weckmann, Markus

    2009-01-01

    Altered bronchial vascular reactivity and remodelling including angiogenesis are documented features of asthma and other chronic inflammatory airway diseases. Expansion of the bronchial vasculature under these conditions involves both functional (vasodilation, hyperperfusion, increased microvascular

  10. Angiogenesis Inhibition in Prostate Cancer: Current Uses and Future Promises

    Directory of Open Access Journals (Sweden)

    Jeanny B. Aragon-Ching

    2010-01-01

    Full Text Available Angiogenesis has been well recognized as a fundamental part of a multistep process in the evolution of cancer progression, invasion, and metastasis. Strategies for inhibiting angiogenesis have been one of the most robust fields of cancer investigation, focusing on the vascular endothelial growth factor (VEGF family and its receptors. There are numerous regulatory drug approvals to date for the use of these agents in treating a variety of solid tumors. While therapeutic efficacy has been established, challenges remain with regards to overcoming resistance and assessing response to antiangiogenic therapies. Prostate cancer is the most common noncutaneous malignancy among American men and angiogenesis plays a role in disease progression. The use of antiangiogenesis agents in prostate cancer has been promising and is hereby explored.

  11. Acetazolamide inhibits aquaporin-1 protein expression and angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Yang XIANG; Bing MA; Tao LI; Jun-wei GAO; He-ming YU; Xue-jun LI

    2004-01-01

    AIM: To study effects of acetazolamide on aquaporin-1 (AQP1) protein expression and angiogenesis. METHODS:Establishing Lewis-lung-carcinoma model, the localization of AQP1 in tumor tissues was investigated by immunohistochemical methods; The biological activity of acetazolamide was detected by endothelial cells proliferation test (MTT) assay and chorioallantoic membrane (CAM) vascular inhibition test. RESULTS: Immunohistochemical localization of AQP1 in mice tumor was labeled in capillaries, post capillary venules endothelial cells. After being treated with acetazolamide, the number of capillaries and post capillary venules was significantly decreased in tumor tissue. Acetazolamide showed significant inhibitory effect on angiogenesis in CAM and endothelial cell proliferation.CONCLUSION: Acetazolamide might be identified and developed as one of potential lead compounds for a new therapeutic intervention in inhibiting cancer angiogenesis.

  12. Ultrasound -- Vascular

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Ultrasound - Vascular Vascular ultrasound uses sound waves to evaluate ... the limitations of Vascular Ultrasound? What is Vascular Ultrasound? Ultrasound is safe and painless, and produces pictures ...

  13. Moderation of calpain activity promotes neovascular integration and lumen formation during VEGF-induced pathological angiogenesis.

    Directory of Open Access Journals (Sweden)

    Mien V Hoang

    Full Text Available BACKGROUND: Successful neovascularization requires that sprouting endothelial cells (ECs integrate to form new vascular networks. However, architecturally defective, poorly integrated vessels with blind ends are typical of pathological angiogenesis induced by vascular endothelial growth factor-A (VEGF, thereby limiting the utility of VEGF for therapeutic angiogenesis and aggravating ischemia-related pathologies. Here we investigated the possibility that over-exuberant calpain activity is responsible for aberrant VEGF neovessel architecture and integration. Calpains are a family of intracellular calcium-dependent, non-lysosomal cysteine proteases that regulate cellular functions through proteolysis of numerous substrates. METHODOLOGY/PRINCIPAL FINDINGS: In a mouse skin model of VEGF-driven angiogenesis, retroviral transduction with dominant-negative (DN calpain-I promoted neovessel integration and lumen formation, reduced blind ends, and improved vascular perfusion. Moderate doses of calpain inhibitor-I improved VEGF-driven angiogenesis similarly to DN calpain-I. Conversely, retroviral transduction with wild-type (WT calpain-I abolished neovessel integration and lumen formation. In vitro, moderate suppression of calpain activity with DN calpain-I or calpain inhibitor-I increased the microtubule-stabilizing protein tau in endothelial cells (ECs, increased the average length of microtubules, increased actin cable length, and increased the interconnectivity of vascular cords. Conversely, WT calpain-I diminished tau, collapsed microtubules, disrupted actin cables, and inhibited integration of cord networks. Consistent with the critical importance of microtubules for vascular network integration, the microtubule-stabilizing agent taxol supported vascular cord integration whereas microtubule dissolution with nocodazole collapsed cord networks. CONCLUSIONS/SIGNIFICANCE: These findings implicate VEGF-induction of calpain activity and impairment of

  14. Increased angiogenesis in portal hypertensive rats: role of nitric oxide.

    Science.gov (United States)

    Sumanovski, L T; Battegay, E; Stumm, M; van der Kooij, M; Sieber, C C

    1999-04-01

    Systemic and especially splanchnic arterial vasodilation accompany chronic portal hypertension. Different soluble mediators causing this vasodilation have been proposed, the strongest evidence being for nitric oxide (NO). No data exist if structural vascular changes may partly account for this vasodilatory state. Here, we developed a new in vivo quantitative angiogenesis assay in the abdominal cavity and determined if: 1) portal hypertensive rats show increased angiogenesis; and 2) angiogenesis is altered by inhibiting NO formation. Portal hypertension was induced by partial portal vein ligation (PVL). Sham-operated rats served as controls (CON). During the index operation (day 0), a teflon ring filled with collagen I (Vitrogen 100) was sutured in the mesenteric cavity. After 16 days, rings were explanted, embedded in paraffin, and ingrown vessels counted using a morphometry system. The role of NO was tested by adding an antagonist of NO formation (Nomega-nitro-L-arginine [NNA], 3.3 mg/kg/d) into the drinking water. The mean number of ingrown vessels per implant was significantly higher in PVL rats compared with CON rats, i.e., 1,453 +/- 187 versus 888 +/- 116, respectively (P <.05; N = 5 per group). NNA significantly (P <.01) inhibited angiogenesis in PVL (202 +/- 124; N = 5) and in CON (174 +/- 25; N = 6) rats, respectively. In contrast, the beta-adrenergic blocker, propranolol, did not prevent angiogenesis either in PVL or CON rats in a separate set of experiments (data not shown). The conclusions drawn from this study are that: 1) rats with portal hypertension show increased angiogenesis; and 2) inhibition of NO formation significantly prevents angiogenesis in both PVL and CON rats. Therefore, splanchnic vasodilation in chronic portal hypertension may also be a result of structural changes.

  15. Angiogenesis-regulating microRNAs and Ischemic Stroke.

    Science.gov (United States)

    Yin, Ke-Jie; Hamblin, Milton; Chen, Y Eugene

    2015-01-01

    Stroke is a leading cause of death and disability worldwide. Ischemic stroke is the dominant subtype of stroke and results from focal cerebral ischemia due to occlusion of major cerebral arteries. Thus, the restoration or improvement of reduced regional cerebral blood supply in a timely manner is very critical for improving stroke outcomes and poststroke functional recovery. The recovery from ischemic stroke largely relies on appropriate restoration of blood flow via angiogenesis. Newly formed vessels would allow increased cerebral blood flow, thus increasing the amount of oxygen and nutrients delivered to affected brain tissue. Angiogenesis is strictly controlled by many key angiogenic factors in the central nervous system, and these molecules have been well-documented to play an important role in the development of angiogenesis in response to various pathological conditions. Promoting angiogenesis via various approaches that target angiogenic factors appears to be a useful treatment for experimental ischemic stroke. Most recently, microRNAs (miRs) have been identified as negative regulators of gene expression in a post-transcriptional manner. Accumulating studies have demonstrated that miRs are essential determinants of vascular endothelial cell biology/angiogenesis as well as contributors to stroke pathogenesis. In this review, we summarize the knowledge of stroke-associated angiogenic modulators, as well as the role and molecular mechanisms of stroke-associated miRs with a focus on angiogenesis-regulating miRs. Moreover, we further discuss their potential impact on miR-based therapeutics in stroke through targeting and enhancing post-ischemic angiogenesis.

  16. Tumour angiogenesis regulation by the miR-200 family

    Science.gov (United States)

    Pecot, Chad V.; Ivan, Cristina; Lu, Chunhua; Wu, Sherry; Han, Hee-Dong; Shah, Maitri Y.; Rodriguez-Aguayo, Cristian; Bottsford-Miller, Justin; Liu, Yuexin; Kim, Sang Bae; Unruh, Anna; Gonzalez-Villasana, Vianey; Huang, Li; Zand, Behrouz; Moreno-Smith, Myrthala; Mangala, Lingegowda S.; Taylor, Morgan; Dalton, Heather J.; Sehgal, Vasudha; Wen, Yunfei; Kang, Yu; Baggerly, Keith A.; Lee, Ju-Seog; Ram, Prahlad T.; Ravoori, Murali K.; Kundra, Vikas; Zhang, Xinna; Ali-Fehmi, Rouba; Gonzalez-Angulo, Ana-Maria; Massion, Pierre P.; Calin, George A.; Lopez-Berestein, Gabriel; Zhang, Wei; Sood, Anil K.

    2013-01-01

    The miR-200 family is well known to inhibit the epithelial–mesenchymal transition, suggesting it may therapeutically inhibit metastatic biology. However, conflicting reports regarding the role of miR-200 in suppressing or promoting metastasis in different cancer types have left unanswered questions. Here we demonstrate a difference in clinical outcome based on miR-200's role in blocking tumour angiogenesis. We demonstrate that miR-200 inhibits angiogenesis through direct and indirect mechanisms by targeting interleukin-8 and CXCL1 secreted by the tumour endothelial and cancer cells. Using several experimental models, we demonstrate the therapeutic potential of miR-200 delivery in ovarian, lung, renal and basal-like breast cancers by inhibiting angiogenesis. Delivery of miR-200 members into the tumour endothelium resulted in marked reductions in metastasis and angiogenesis, and induced vascular normalization. The role of miR-200 in blocking cancer angiogenesis in a cancer-dependent context defines its utility as a potential therapeutic agent. PMID:24018975

  17. The functional role of platelets in the regulation of angiogenesis.

    Science.gov (United States)

    Walsh, Tony G; Metharom, Pat; Berndt, Michael C

    2015-01-01

    Functionally, platelets are primarily recognized as key regulators of thrombosis and hemostasis. Upon vessel injury, the typically quiescent platelet interacts with subendothelial matrix to regulate platelet adhesion, activation and aggregation, with subsequent induction of the coagulation cascade forming a thrombus. Recently, however, newly described roles for platelets in the regulation of angiogenesis have emerged. Platelets possess an armory of pro- and anti-angiogenic proteins, which are actively sequestered and highly organized in α-granule populations. Platelet activation facilitates their release, eliciting potent angiogenic responses through mechanisms that appear to be tightly regulated. In conjunction, the release of platelet-derived phospholipids and microparticles has also earned merit as synergistic regulators of angiogenesis. Consequently, platelets have been functionally implicated in a range of angiogenesis-dependent processes, including physiological roles in wound healing, vascular development and blood/lymphatic vessel separation, whilst facilitating aberrant angiogenesis in a range of diseases including cancer, atherosclerosis and diabetic retinopathy. Whilst the underlying mechanisms are only starting to be elucidated, significant insights have been established, suggesting that platelets represent a promising therapeutic strategy in diseases requiring angiogenic modulation. Moreover, anti-platelet therapies targeting thrombotic complications also exert protective effects in disorders characterized by persistent angiogenesis.

  18. Module-based multiscale simulation of angiogenesis in skeletal muscle

    Directory of Open Access Journals (Sweden)

    Mac Gabhann Feilim

    2011-04-01

    Full Text Available Abstract Background Mathematical modeling of angiogenesis has been gaining momentum as a means to shed new light on the biological complexity underlying blood vessel growth. A variety of computational models have been developed, each focusing on different aspects of the angiogenesis process and occurring at different biological scales, ranging from the molecular to the tissue levels. Integration of models at different scales is a challenging and currently unsolved problem. Results We present an object-oriented module-based computational integration strategy to build a multiscale model of angiogenesis that links currently available models. As an example case, we use this approach to integrate modules representing microvascular blood flow, oxygen transport, vascular endothelial growth factor transport and endothelial cell behavior (sensing, migration and proliferation. Modeling methodologies in these modules include algebraic equations, partial differential equations and agent-based models with complex logical rules. We apply this integrated model to simulate exercise-induced angiogenesis in skeletal muscle. The simulation results compare capillary growth patterns between different exercise conditions for a single bout of exercise. Results demonstrate how the computational infrastructure can effectively integrate multiple modules by coordinating their connectivity and data exchange. Model parameterization offers simulation flexibility and a platform for performing sensitivity analysis. Conclusions This systems biology strategy can be applied to larger scale integration of computational models of angiogenesis in skeletal muscle, or other complex processes in other tissues under physiological and pathological conditions.

  19. Angiogenesis-Related Pathways in the Pathogenesis of Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    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.

  20. Angiogenesis-associated crosstalk between collagens, CXC chemokines, and thrombospondin domain-containing proteins

    OpenAIRE

    Rivera, Corban G; Bader, Joel S.; Popel, Aleksander S

    2011-01-01

    Excessive vascularization is a hallmark of many diseases including cancer, rheumatoid arthritis, diabetic nephropathy, pathologic obesity, age-related macular degeneration, and asthma. Compounds that inhibit angiogenesis represent potential therapeutics for many diseases. Karagiannis and Popel (PNAS, 2008) used a bioinformatics approach to idenify more than 100 peptides with sequence homology to known angiogenesis inhibitors. The peptides could be grouped into families by the conserved domain...

  1. Novel Tissue‐Specific Mechanism of Regulation of Angiogenesis and Cancer Growth in Response to Hyperglycemia

    OpenAIRE

    Bhattacharyya, Sanghamitra; Sul, Kristina; Krukovets, Irene; Nestor, Carla; Li, Jianbo; Adognravi, Olga Stenina

    2012-01-01

    Background Hyperglycemia is an independent risk factor for the development of vascular diabetic complications, which are characterized by endothelial dysfunction and tissue‐specific aberrant angiogenesis. Tumor growth is also dependent on angiogenesis. Diabetes affects several cancers in a tissue‐specific way. For example, it positively correlates with the incidence of breast cancer but negatively correlates with the incidence of prostate cancer. The tissue‐specific molecular mechanisms activ...

  2. ELK3 suppresses angiogenesis by inhibiting the transcriptional activity of ETS-1 on MT1-MMP.

    Science.gov (United States)

    Heo, Sun-Hee; Cho, Je-Yoel

    2014-01-01

    Ets transcription factors play important roles in vasculogenesis and angiogenesis. Knockout of the Ets gene family members in mice resulted in disrupted angiogenesis and malformed vascular systems. In this study, the role and mechanism of ELK3, an Ets factor, in angiogenesis was investigated using ELK3-specific siRNA in human vascular endothelial cells (HUVECs) and in vivo implantation assay. The suppression of ELK3 expression resulted in the reinforcement of VEGF-induced tube formation in HUVECs. The in vivo Matrigel plug assay also showed that ELK3 knockdown resulted in increased angiogenesis. Luciferase activity of the MT1-MMP promoter induced by ETS-1 factor was attenuated ELK3 co-transfection. CHIP assay showed the binding of ELK3 on the MT1-MMP promoter. MT1-MMP knockdown in the ELK3 knockdowned cells resulted in the decrease of tube formation suggesting that MT1-MMP transcriptional repression is required for ELK3-mediated anti-angiogenesis effect. Our data also showed that the suppressive effect of ELK3 on the angiogenesis was partly due to the inhibitory effect of ELK3 to the ETS-1 transcriptional activity on the MT1-MMP promoter rather than direct suppression of ELK3 on the target gene, since the expression level of co-repressor Sin3A is low in endothelial cells. Our results suggest that ELK3 plays a negative role of VEGF-induced angiogenesis through indirectly inhibiting ETS-1 function.

  3. Molecular mechanisms linking thrombosis and angiogenesis in cancer.

    Science.gov (United States)

    Shoji, M; Abe, K; Nawroth, P P; Rickles, F R

    1997-02-01

    In this brief review, the authors concentrate on selected issues related to the newly described role of tissue factor (TF), the major activator of mammalian blood coagulation, as a regulator of angiogenesis and of tumor growth and metastasis. Previously, TF had been considered strictly as the primary activator of the coagulation cascade; however, it has recently been demonstrated that overexpression of the TF gene in murine tumor cells leads to increased transcription of the gene for vascular permeability factor/vascular endothelial growth factor (VEGF), a proangiogenic factor, and decreased transcription of the gene for thrombospondin (TSP), an antiangiogenic factor. Conversely, underexpression of TF leads to decreased VEGF and increased TSP transcription. When grown in mice and compared with low TF-producing tumor cells, high TF-producing tumor cells stimulate angiogenesis by approximately twofold. This effect of TF appears to be independent of its clot-promoting procoagulant activity (PCA) and suggests that TF regulates the angiogenic properties of tumor cells by altering the production of growth regulatory molecules (for example, VEGF) that can act on vascular endothelial cells (VECs). There is substantial preliminary evidence that the regulation of tumor angiogenesis can be mediated by TF via both fibrin clotting-dependent and fibrin clotting-independent mechanisms. (Trends Cardiovasc Med 1997;7:52-59). © 1997, Elsevier Science Inc.

  4. Harnessing developmental processes for vascular engineering and regeneration.

    Science.gov (United States)

    Park, Kyung Min; Gerecht, Sharon

    2014-07-01

    The formation of vasculature is essential for tissue maintenance and regeneration. During development, the vasculature forms via the dual processes of vasculogenesis and angiogenesis, and is regulated at multiple levels: from transcriptional hierarchies and protein interactions to inputs from the extracellular environment. Understanding how vascular formation is coordinated in vivo can offer valuable insights into engineering approaches for therapeutic vascularization and angiogenesis, whether by creating new vasculature in vitro or by stimulating neovascularization in vivo. In this Review, we will discuss how the process of vascular development can be used to guide approaches to engineering vasculature. Specifically, we will focus on some of the recently reported approaches to stimulate therapeutic angiogenesis by recreating the embryonic vascular microenvironment using biomaterials for vascular engineering and regeneration.

  5. Influence of Levamisole and Other Angiogenesis Inhibitors on Angiogenesis and Endothelial Cell Morphology in Vitro

    Energy Technology Data Exchange (ETDEWEB)

    Friis, Tina; Engel, Anne-Marie; Bendiksen, Christine D.; Larsen, Line S.; Houen, Gunnar, E-mail: gh@ssi.dk [Department of Clinical Biochemistry, Immunology and Genetics, Statens Serum Institut, Artillerivej 5, DK-2300 Copenhagen (Denmark)

    2013-06-24

    Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC) receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF) and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI) IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs) results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti-angiogenic activity

  6. Influence of levamisole and other angiogenesis inhibitors on angiogenesis and endothelial cell morphology in vitro.

    Science.gov (United States)

    Friis, Tina; Engel, Anne-Marie; Bendiksen, Christine D; Larsen, Line S; Houen, Gunnar

    2013-01-01

    Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC) receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF) and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI) IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs) results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti-angiogenic activity

  7. Influence of Levamisole and Other Angiogenesis Inhibitors on Angiogenesis and Endothelial Cell Morphology in Vitro

    Science.gov (United States)

    Friis, Tina; Engel, Anne-Marie; Bendiksen, Christine D.; Larsen, Line S.; Houen, Gunnar

    2013-01-01

    Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC) receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF) and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI) IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs) results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti-angiogenic activity

  8. Influence of Levamisole and Other Angiogenesis Inhibitors on Angiogenesis and Endothelial Cell Morphology in Vitro

    Directory of Open Access Journals (Sweden)

    Gunnar Houen

    2013-06-01

    Full Text Available Angiogenesis, the formation of new blood vessels from existing vessels is required for many physiological processes and for growth of solid tumors. Initiated by hypoxia, angiogenesis involves binding of angiogenic factors to endothelial cell (EC receptors and activation of cellular signaling, differentiation, migration, proliferation, interconnection and canalization of ECs, remodeling of the extracellular matrix and stabilization of newly formed vessels. Experimentally, these processes can be studied by several in vitro and in vivo assays focusing on different steps in the process. In vitro, ECs form networks of capillary-like tubes when propagated for three days in coculture with fibroblasts. The tube formation is dependent on vascular endothelial growth factor (VEGF and omission of VEGF from the culture medium results in the formation of clusters of undifferentiated ECs. Addition of angiogenesis inhibitors to the coculture system disrupts endothelial network formation and influences EC morphology in two distinct ways. Treatment with antibodies to VEGF, soluble VEGF receptor, the VEGF receptor tyrosine kinase inhibitor SU5614, protein tyrosine phosphatase inhibitor (PTPI IV or levamisole results in the formation of EC clusters of variable size. This cluster morphology is a result of inhibited EC differentiation and levamisole can be inferred to influence and block VEGF signaling. Treatment with platelet factor 4, thrombospondin, rapamycin, suramin, TNP-470, salubrinal, PTPI I, PTPI II, clodronate, NSC87877 or non-steriodal anti-inflammatory drugs (NSAIDs results in the formation of short cords of ECs, which suggests that these inhibitors have an influence on later steps in the angiogenic process, such as EC proliferation and migration. A humanized antibody to VEGF is one of a few angiogenesis inhibitors used clinically for treatment of cancer. Levamisole is approved for clinical treatment of cancer and is interesting with respect to anti

  9. Safrole oxide inhibits angiogenesis by inducing apoptosis.

    Science.gov (United States)

    Zhao, Jing; Miao, Junying; Zhao, Baoxiang; Zhang, Shangli; Yin, Deling

    2005-06-01

    Our previous studies indicate that 3, 4-(methylenedioxy)-1-(2', 3'-epoxypropyl)-benzene (safrole oxide), a newly synthesized compound, induces apoptosis in vascular endothelial cells (VECs) and A549 lung cancer cells. To our knowledge, the inhibition of angiogenesis by safrole oxide has not been reported yet. We report here that cultured rat aorta treated with safrole oxide exhibited a significant microvessel reduction as determined by counting the number of microvessels in a phase contrast microscope. There were more microvessels formed in the presence of A549 lung cancer cells in rat aorta model, while a dramatic inhibition of angiogenesis was obtained by adding 220-450 micromol l(-1) of safrole oxide to the growth medium (Psafrole oxide produced only some abortive endothelial cells but not microvessels. Furthermore, safrole oxide induced antiangiogenic effect in the chorioallantoic membranes (CAM) as a dose dependent manner. Eggs treated with 2-11 micromol 100 microl(-1) per egg of the safrole oxide for 48 h exhibited a significant reduction in blood vessel area of the CAM, a process likely mediated by apoptosis as demonstrated by DNA fragmentation. Our results suggest that safrole oxide has antiangiogenic activity and this effect might occur by induction of cellular apoptosis.

  10. Evaluation of Tumor Angiogenesis by MRI Study Using Iron Nanoparticles

    Directory of Open Access Journals (Sweden)

    Mansour Ashoor

    2010-05-01

    Full Text Available Angiogenesis is the growth of new blood vessels from existing ones and it is a perquisite for the growth, invasion and metastasis of solid tumors. This complex process involves multiple steps and pathways dependent on the local balance between positive and negative regulatory factors, as well as interactions among the tumor, its vasculature and the surrounding extracellular tissue matrix. Tumors lay dormant yet viable, unable to grow beyond 2-3 mm3 in size without angiogenesis."nWith the development of novel therapies for treat-ment of several diseases, directed noninvasive imaging strategies will be critical for defining the pathophysiology of angiogenesis. Imaging modalities used to detect angiogenesis include PET, SPECT, MRI, CT, US and near-infrared optical imaging. For these modalities, methods have been developed to measure blood volume, blood flow and several other semi quantitative and quantitative kinetic hemodynamic parameters such as vascular permeability. Characteristic molecular makers of angiogenesis may be visualized with the aid of molecular imaging agents such as VEGFs or the α vß3 integrin. "nMRI is a practical modality for assessing angiogenesis over time because it is already widely used clinically to assess tumor growth and for response evaluation. Anatomical information can be co registered with functional and molecular information within a single imaging method. Moreover, MRI does not involve ionizing radiation and the commonly used contrast agent has low toxicity. "nSuper paramagnetic iron oxides (SPIO are FDA-approved contrast agents for use in magnetic reson-ance (MR imaging. Most of the administered SPIO end up in the reticuloendotelial system via endocytosis and the iron core released from the SPIO is utilized in normal iron metabolism pathways. We utilize the paramagnetic characteristics of SPIO to improve the contrast of the image in MRI."nFor the first time we will introduce a method for evaluating angiogenesis

  11. 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.

  12. 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

  13. Potential of dietary nitrate in angiogenesis.

    Science.gov (United States)

    Rammos, Christos; Luedike, Peter; Hendgen-Cotta, Ulrike; Rassaf, Tienush

    2015-10-26

    Endothelial dysfunction with impaired bioavailability of nitric oxide (NO) is the hallmark in the development of cardiovascular disease. Endothelial dysfunction leads to atherosclerosis, characterized by chronic inflammation of the arterial wall and stepwise narrowing of the vessel lumen. Atherosclerosis causes deprivation of adequate tissue blood flow with compromised oxygen supply. To overcome this undersupply, remodeling of the vascular network is necessary to reconstitute and sustain tissue viability. This physiological response is often not sufficient and therapeutic angiogenesis remains an unmet medical need in critical limb ischemia or coronary artery disease. Feasible approaches to promote blood vessel formation are sparse. Administration of pro-angiogenic factors, gene therapy, or targeting of microRNAs has not yet entered the daily practice. Nitric oxide is an important mediator of angiogenesis that becomes limited under ischemic conditions and the maintenance of NO availability might constitute an attractive therapeutic target. Until recently it was unknown how the organism provides NO under ischemia. In recent years it could be demonstrated that NO can be formed independently of its enzymatic synthesis in the endothelium by reduction of inorganic nitrite under hypoxic conditions. Circulating nitrite derives from oxidation of NO or reduction of inorganic nitrate by commensal bacteria in the oral cavity. Intriguingly, nitrate is a common constituent of our everyday diet and particularly high concentrations are found in leafy green vegetables such as spinach, lettuce, or beetroot. Evidence suggests that dietary nitrate supplementation increases the regenerative capacity of ischemic tissue and that this effect may offer an attractive nutrition-based strategy to improve ischemia-induced revascularization. We here summarize and discuss the regenerative capacity of dietary nitrate on the vascular system.

  14. Potential of dietary nitrate in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Christos; Rammos; Peter; Luedike; Ulrike; Hendgen-Cotta; Tienush; Rassaf

    2015-01-01

    Endothelial dysfunction with impaired bioavailability of nitric oxide(NO) is the hallmark in the development of cardiovascular disease. Endothelial dysfunction leads to atherosclerosis, characterized by chronic inflammation of the arterial wall and stepwise narrowing of the vessel lumen. Atherosclerosis causes deprivation of adequate tissue blood flow with compromised oxygen supply. To overcome this undersupply, remodeling of the vascular network is necessary to reconstitute and sustain tissue viability. This physiological response is often not sufficient and therapeutic angiogenesis remains an unmet medical need in critical limb ischemia or coronary artery disease. Feasible approaches to promote blood vessel formation are sparse. Administration of pro-angiogenic factors, gene therapy, or targeting of micro RNAs has not yet entered the daily practice. Nitric oxide is an important mediator of angiogenesis that becomes limited under ischemic conditions and the maintenance of NO availability might constitute an attractive therapeutic target. Until recently it was unknown how the organism provides NO under ischemia. In recent years it could be demonstrated that NO can be formed independently of its enzymatic synthesis in the endothelium by reduction of inorganic nitrite under hypoxic conditions. Circulating nitrite derives from oxidation of NO or reduction of inorganic nitrate by commensal bacteria in the oral cavity. Intriguingly, nitrate is a common constituent of our everyday diet and particularly high concentrations are found in leafy green vegetables such as spinach, lettuce, or beetroot. Evidence suggests that dietary nitrate supplementation increases the regenerative capacity of ischemic tissue and that this effect may offer an attractive nutrition-based strategy to improve ischemia-induced revascularization. We here summarize and discuss the regenerative capacity of dietary nitrate on the vascular system.

  15. Tumor vasculature is regulated by FGF/FGFR signaling-mediated angiogenesis and bone marrow-derived cell recruitment: this mechanism is inhibited by SSR128129E, the first allosteric antagonist of FGFRs.

    Science.gov (United States)

    Fons, Pierre; Gueguen-Dorbes, Geneviève; Herault, Jean-Pascal; Geronimi, Fabien; Tuyaret, Joël; Frédérique, Dol; Schaeffer, Paul; Volle-Challier, Cécile; Herbert, Jean-Marc; Bono, Françoise

    2015-01-01

    Tumor angiogenesis is accompanied by vasculogenesis, which is involved in the differentiation and mobilization of human bone marrow cells. In order to further characterize the role of vasculogenesis in the tumor growth process, the effects of FGF2 on the differentiation of human bone marrow AC133(+) cells (BM-AC133(+)) into vascular precursors were studied in vitro. FGF2, like VEGFA, induced progenitor cell differentiation into cell types with endothelial cell characteristics. SSR128129E, a newly discovered specific FGFR antagonist acting by allosteric interaction with FGFR, abrogated FGF2-induced endothelial cell differentiation, showing that FGFR signaling is essential during this process. To assess the involvement of the FGF/FRGR signaling in vivo, the pre-clinical model of Lewis lung carcinoma (LL2) in mice was used. Subcutaneous injection of LL2 cells into mice induced an increase of circulating EPCs from peripheral blood associated with tumor growth and an increase of intra-tumoral vascular index. Treatment with the FGFR antagonist SSR128129E strongly decreased LL2 tumor growth as well as the intra-tumoral vascular index (41% and 50% decrease vs. vehicle-treated mice respectively, P FGFR pathway by SSR128129E reduces EPC recruitment during angiogenesis-dependent tumor growth. In this context, circulating EPCs could be a reliable surrogate marker for tumor growth and angiogenic activity.

  16. Nasal administration of interleukin-33 induces airways angiogenesis and expression of multiple angiogenic factors in a murine asthma surrogate.

    Science.gov (United States)

    Shan, Shan; Li, Yan; Wang, Jingjing; Lv, Zhe; Yi, Dawei; Huang, Qiong; Corrigan, Chris J; Wang, Wei; Quangeng, Zhang; Ying, Sun

    2016-05-01

    The T-helper cell type 2-promoting cytokine interleukin-33 (IL-33) has been implicated in asthma pathogenesis. Angiogenesis is a feature of airways remodelling in asthma. We hypothesized that IL-33 induces airways angiogenesis and expression of angiogenic factors in an established murine surrogate of asthma. In the present study, BALB/c mice were subjected to serial intranasal challenge with IL-33 alone for up to 70 days. In parallel, ovalbumin (OVA) -sensitized mice were subjected to serial intranasal challenge with OVA or normal saline to serve as positive and negative controls, respectively. Immunohistochemical analysis of expression of von Willebrand factor and erythroblast transformation-specific-related gene, both blood vessel markers, and angiogenic factors angiogenin, insulin-like growth factor-1, endothelin-1, epidermal growth factor and amphiregulin was performed in lung sections ex vivo. An established in-house assay was used to test whether IL-33 was able to induce microvessel formation by human vascular endothelial cells. Results showed that serial intranasal challenge of mice with IL-33 or OVA resulted in proliferation of peribronchial von Willebrand factor-positive blood vessels to a degree closely related to the total expression of the angiogenic factors amphiregulin, angiogenin, endothelin-1, epidermal growth factor and insulin-like growth factor-1. IL-33 also induced microvessel formation by human endothelial cells in a concentration-dependent fashion in vitro. Our data are consistent with the hypothesis that IL-33 has the capacity to induce angiogenesis at least partly by increasing local expression of multiple angiogenic factors in an allergen-independent murine asthma surrogate, and consequently that IL-33 or its receptor is a potential novel molecular target for asthma therapy.

  17. The relationship between angiogenesis and cyclooxygenase-2 expression in prostate cancer

    OpenAIRE

    Mukherjee, R.; Edwards, J; Underwood, M.A.; Bartlett, J M S

    2005-01-01

    OBJECTIVE: To test the hypothesis that angiogenesis in prostate cancer is associated with tumour invasion and metastasis, and that this is mediated through increased cyclooxygenase-2 (COX-2) expression.\\ud \\ud PATIENTS AND METHODS: Angiogenesis was assessed in 105 patients with either prostate cancer (79) or benign prostatic hyperplasia (BPH, 26) and these data correlated with levels of COX-2 expression in the same dataset. The mean microvessel density (MVD) was analysed as a marker of angiog...

  18. ETS transcription factors in embryonic vascular development.

    Science.gov (United States)

    Craig, Michael P; Sumanas, Saulius

    2016-07-01

    At least thirteen ETS-domain transcription factors are expressed during embryonic hematopoietic or vascular development and potentially function in the formation and maintenance of the embryonic vasculature or blood lineages. This review summarizes our current understanding of the specific roles played by ETS factors in vasculogenesis and angiogenesis and the implications of functional redundancies between them.

  19. Epo is involved in angiogenesis in human glioma.

    Science.gov (United States)

    Nico, Beatrice; Annese, Tiziana; Guidolin, Diego; Finato, Nicoletta; Crivellato, Enrico; Ribatti, Domenico

    2011-03-01

    In this study, the extent of angiogenesis, evaluated as microvascular density, and the immunoreactivity of tumor cells to erythropoietin (Epo) and of endothelial cells to Epo receptor (EpoR) have been correlated in human glioma specimens, and the effect of anti-Epo antibody on glioma-induced angiogenesis in vivo in the chick embryo chorioallantoic membrane (CAM) has been investigated. Results show that: (1) Epo/EpoR expression correlates with angiogenesis, (2) in the CAM assay, tumor bioptic specimens induce a strong angiogenic response, comparable to that induced by VEGF, and (3) an anti-Epo antibody co-administered with tumor bioptic specimens significantly inhibits the angiogenic response. These findings suggest the presence of a loop in the Epo/EpoR system, i.e. Epo is secreted by glioma tumor cells and it affects glioma vascular endothelial cells via its receptor and promotes angiogenesis in a paracrine manner. Moreover, as demonstrated by in vivo experiments, Epo is responsible for the strong angiogenic response induced by human glioma bioptic specimens, because an anti-Epo antibody is able to significantly inhibit this response.

  20. Inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration

    Science.gov (United States)

    Shergill, U.; Das, A.; Langer, D.; Adluri, RS.; Maulik, N.

    2010-01-01

    Angiogenesis occurs through a convergence of diverse signaling mechanisms with prominent pathways that include autocrine effects of endothelial nitric oxide (NO) synthase (eNOS)-derived NO and vascular endothelial growth factor (VEGF). However, the redundant and distinct roles of NO and VEGF in angiogenesis remain incompletely defined. Here, we use the partial hepatectomy model in mice genetically deficient in eNOS to ascertain the influence of eNOS-derived NO on the angiogenesis that accompanies liver regeneration. While sinusoidal endothelial cell (SEC) eNOS promotes angiogenesis in vitro, surprisingly the absence of eNOS did not influence the angiogenesis that occurs after partial hepatectomy in vivo. While this observation could not be attributed to induction of alternate NOS isoforms, it was associated with induction of VEGF signaling as evidenced by enhanced levels of VEGF ligand in regenerating livers from mice genetically deficient in eNOS. However, surprisingly, mice that were genetically heterozygous for deficiency in the VEGF receptor, fetal liver kinase-1, also maintained unimpaired capacity for liver regeneration. In summary, inhibition of VEGF- and NO-dependent angiogenesis does not impair liver regeneration, indicating signaling redundancies that allow liver regeneration to continue in the absence of this canonical vascular pathway. PMID:20421635

  1. VEGF Spliced Variants: Possible Role of Anti-Angiogenesis Therapy

    Directory of Open Access Journals (Sweden)

    Caroline Hilmi

    2012-01-01

    Full Text Available Angiogenesis has been targeted in retinopathies, psoriasis, and a variety of cancers (colon, breast, lung, and kidney. Among these tumour types, clear cell renal cell carcinomas (RCCs are the most vascularized tumours due to mutations of the von Hippel Lindau gene resulting in HIF-1 alpha stabilisation and overexpression of Vascular Endothelial Growth Factor (VEGF. Surgical nephrectomy remains the most efficient curative treatment for patients with noninvasive disease, while VEGF targeting has resulted in varying degrees of success for treating metastatic disease. VEGF pre-mRNA undergoes alternative splicing generating pro-angiogenic isoforms. However, the recent identification of novel splice variants of VEGF with anti-angiogenic properties has provided some insight for the lack of current treatment efficacy. Here we discuss an explanation for the relapse to anti-angiogenesis treatment as being due to either an initial or acquired resistance to the therapy. We also discuss targeting angiogenesis via SR (serine/arginine-rich proteins implicated in VEGF splicing.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. Aminoacyl-tRNA synthetase dependent angiogenesis revealed by a bioengineered macrolide inhibitor.

    Science.gov (United States)

    Mirando, Adam C; Fang, Pengfei; Williams, Tamara F; Baldor, Linda C; Howe, Alan K; Ebert, Alicia M; Wilkinson, Barrie; Lounsbury, Karen M; Guo, Min; Francklyn, Christopher S

    2015-08-14

    Aminoacyl-tRNA synthetases (AARSs) catalyze an early step in protein synthesis, but also regulate diverse physiological processes in animal cells. These include angiogenesis, and human threonyl-tRNA synthetase (TARS) represents a potent pro-angiogenic AARS. Angiogenesis stimulation can be blocked by the macrolide antibiotic borrelidin (BN), which exhibits a broad spectrum toxicity that has discouraged deeper investigation. Recently, a less toxic variant (BC194) was identified that potently inhibits angiogenesis. Employing biochemical, cell biological, and biophysical approaches, we demonstrate that the toxicity of BN and its derivatives is linked to its competition with the threonine substrate at the molecular level, which stimulates amino acid starvation and apoptosis. By separating toxicity from the inhibition of angiogenesis, a direct role for TARS in vascular development in the zebrafish could be demonstrated. Bioengineered natural products are thus useful tools in unmasking the cryptic functions of conventional enzymes in the regulation of complex processes in higher metazoans.

  5. Effects of infection with recombinant adenovirus on human vascular endothelial and smooth muscle cells

    NARCIS (Netherlands)

    Quax, P.H.A.; Lamfers, M.L.M.; Grimbergen, J.M.; Teeling, J.; Hoeben, R.C.; Nieuw Amerongen, G.P. van; Hinsbergh, V.W.M. van

    1996-01-01

    The plasminogen activation (PA) system is involved in vascular remodelling. Modulating its activity in vascular cells might be a way to interfere in processes such as angiogenesis and restenosis. Adenoviral vectors have become a favourable tool for direct gene transfer into vascular cells. In the in

  6. Value of determining the cerebrospinal fluid protein markers of amyloidosis and neurodegeneration in the diagnosis of vascular and neurodegenerative cognitive impairments

    Directory of Open Access Journals (Sweden)

    Vladimir Yuryevich Lobzin

    2013-01-01

    Full Text Available The article presents data on different forms of moderate cognitive impairments (MCI and the specific features of their transformation to dementia. Cerebrospinal fluid (CSF was investigated in 60 patients with the amnestic and neurodynamic types of MCI, in 15 patients with vascular dementia (VD, 50 patients with Alzheimer’s disease (AD, and 23 patients with mixed vascular and neurodegenerative dementia (MVND. The specific features of β-amyloid and τ-protein concentrations were established in the preclinical stages of dementia, which reflects the main components of the pathogenesis of neurodegeneration. In the amnestic form of MCI and AD, there was drastically decreased Aβ-42 and increased τ-protein levels in SCF. As cognitive impairments progressed, there was a rise in the concentration of τ-protein; its level correlated with the severity of dementia. In MND, the level of Aβ-42 was significantly reduced while the concentration of τ-protein was much increased; moreover, to a greater extent than in AD and VD. Cerebrovascular damage and neurodegeneration were related to each other and mutually worsened clinical and pathogenic effects.

  7. 血管生成素对糖尿病大鼠股骨头血管新生及渗漏的影响%The effects of Ang- 1 on the angiogenesis and vascular leakage of diabetic rats' femoral head

    Institute of Scientific and Technical Information of China (English)

    陈海英; 王秀国; 陈少强; 刘文革; 唐军民

    2011-01-01

    目的 探讨血管生成素1 (angi.Poietin-1,Ang-1)对糖尿病大鼠股骨头微血管新生及渗漏的影响.方法 建立速发型链脲佐菌素(streptozotocin,STZ)糖尿病大鼠模型,随机分为正常5周组(CON1)、10周组(CON2)及15周组(CON3),糖尿病5周组(DM1)、10周组(DM2)及15周组(DM3),每组10只.墨汁灌注观测股骨头微血管密度;摘取模型动物股骨头组织,免疫组化分析凝血因子Ⅷ(FⅧ)表达;原位杂交分析血管内皮生长因子(VEGFmRNA)表达强度;RT-PCR分析Ang-l的mRNA表达. 结果 糖尿病大鼠股骨头随病程发展,Ang-l、FⅧ因子表达上升,与正常组相比有显著性差异(P<0.01).VEGFmRNA表达量均高于正常组(P<0.01);微血管密度加大,显示血管增生、渗漏.结论 糖尿病股骨头Ang-1与VEGFmRNA相互协同或拮抗分别促进微血管增生、抗血管渗漏.表达于血管内皮细胞的FⅧ及VEGFmRNA与微血管密度(MVD)变化存在正相关.%Objective To probe into the effects of Ang-1 on the angiogenesis and microvascular leakage of diabetic rats' femoral head. Methods By establishing models of the rats with STZ diabetes, and randomly dividing them into the normal groups (C0N1, CON2 and CON3) and the diabetic groups (DM1, DM2 and DM3) with 10 rats each group, the microvascular density through infusion with ink, the expression of blood coagulation factor VHI with immunohistochemistry, and the expression of the mRNA of both VEGF by hybridization in situ and Ang-1 by RT-PCR, were performed. Results The diabetic rats'femoral head varied in the course of illness. Their expression of Ang-1, blood coagulation factorVlD, and VEGF mRNA significantly rose, as compared with those of rats in the normal groups (P<0.01). The microvascular density enlarged with vascular proliferation and leakage. Conclusions The interaction and antagonism between Ang-1 and VEGF mRNA of diabetic rats' femoral head can promote microvascular proliferation and resist vascular leakage

  8. Molecular and hormonal regulation of angiogenesis in proliferative endometrium

    Directory of Open Access Journals (Sweden)

    Yousef Rezaei Chianeh

    2014-02-01

    Full Text Available Angiogenesis is a hallmark of wound healing, the menstrual cycle, cancer, and various ischemic and inflammatory diseases. A rich variety of pro and anti-angiogenic molecules have already been identified. Vascular endothelial growth factor (VEGF is an interesting inducer of angiogenesis and lymphangiogenesis, because it is a highly specific mitogen for endothelial cells. Signal transduction involves binding to tyrosine kinase receptors and results in endothelial cell proliferation, migration, and new vessel formation. In this article, the role of VEGF and other growth factors in the pathology of dysfunctional uterine bleeding is reviewed. We also discuss the role of VEGF expression and interaction with extracellular matrix that lead to possible inhibition or stimulation of Angiogenic factor on endometrium of dysfunctional uterine bleeding patients. [Int J Res Med Sci 2014; 2(1.000: 1-9

  9. 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...... an improvement in clinical results can be obtained with a cocktail of growth factors or by a combination of gene and stem cell therapy in patients with severe coronary artery disease, which cannot be treated effectively with current treatment strategies....

  10. Correlation between vascular endothelial growth factor expression and presence of lymph node metastasis in advanced squamous cell carcinoma of the larynx

    Directory of Open Access Journals (Sweden)

    Rodrigo Gonzalez Bonhin

    2015-02-01

    Full Text Available Introduction: Squamous cell carcinoma is the most common neoplasm of the larynx, and its evolution depends on tumor staging. Vascular endothelial growth factor is a marker of angiogenesis, and its expression may be related to increased tumor aggressiveness, as evidenced by the presence of cervical lymphatic metastases. Objectives: To evaluate the expression of the vascular endothelial growth factor marker in non-glottic advanced squamous cell carcinoma of the larynx (T3/T4 and correlate it with the presence of cervical lymph node metastases. Methods: Retrospective clinical study and immunohistochemical analysis of vascular endothelial growth factor through the German scale of immunoreactivity in products of non-glottic squamous cell carcinomas. Results: This study analyzed 15 cases of advanced non-glottic laryngeal tumors (T3/T4, four of which exhibited cervical lymphatic metastases. There was no correlation between vascular endothelial growth factor expression and the presence of cervical metastases. Conclusion: Although vascular endothelial growth factor was expressed in a few cases, there was no correlation with the spread of cervical lymph metastases.

  11. 4-Hydroxy-7-oxo-5-heptenoic Acid Lactone Induces Angiogenesis through Several Different Molecular Pathways.

    Science.gov (United States)

    Guo, Junhong; Linetsky, Mikhail; Yu, Annabelle O; Zhang, Liang; Howell, Scott J; Folkwein, Heather J; Wang, Hua; Salomon, Robert G

    2016-12-19

    Oxidative stress and angiogenesis have been implicated not only in normal phenomena such as tissue healing and remodeling but also in many pathological processes. However, the relationships between oxidative stress and angiogenesis still remain unclear, although oxidative stress has been convincingly demonstrated to influence the progression of angiogenesis under physiological and pathological conditions. The retina is particularly susceptible to oxidative stress because of its intensive oxygenation and high abundance of polyunsaturated fatty acyls. In particular, it has high levels of docosahexanoates, whose oxidative fragmentation produces 4-hydroxy-7-oxo-5-heptenoic acid lactone (HOHA-lactone). Previously, we found that HOHA-lactone is a major precursor of 2-(ω-carboxyethyl)pyrrole (CEP) derivatives, which are tightly linked to age-related macular degeneration (AMD). CEPs promote the pathological angiogenesis of late-stage AMD. We now report additional mechanisms by which HOHA-lactone promotes angiogenesis. Using cultured ARPE-19 cells, we observed that HOHA-lactone induces secretion of vascular endothelial growth factor (VEGF), which is correlated to increases in reactive oxygen species and decreases in intracellular glutathione (GSH). Wound healing and tube formation assays provided, for the first time, in vitro evidence that HOHA-lactone induces the release of VEGF from ARPE-19 cells, which promotes angiogenesis by human umbilical vein endothelial cells (HUVEC) in culture. Thus, HOHA-lactone can stimulate vascular growth through a VEGF-dependent pathway. In addition, results from MTT and wound healing assays as well as tube formation experiments showed that GSH-conjugated metabolites of HOHA-lactone stimulate HUVEC proliferation and promote angiogenesis in vitro. Previous studies demonstrated that HOHA-lactone, through its CEP derivatives, promotes angiogenesis in a novel Toll-like receptor 2-dependent manner that is independent of the VEGF receptor or VEGF

  12. Study of angiogenesis induced by metastatic and non-metastatic liver cancer by corneal micropocket model in nude mice

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    AIM To study the angiogenesis induced by liver cancer with different metastatic potentials using corneal micropocket model in nude mice.METHODS Corneal micropockets were created in nude mice. Tumor tissues and liver tissues were implanted into the corneal micropockets. Angiogenesis was observed using a digital camera under slit-lamp biomicroscope, and compared among different grafts and incision alone. Vascular responses were recorded in regard to the range, number and length of new blood vessels toward the grafts or incisions.RESULTS Vascular responses induced by tumor tissues were greater than those by incision alone and liver tissue grafts. LCI-D20 induced more intensive angiogenesis than LCI-D35.CONCLUSION Highly metastatic liver cancer LCI D20 was more angiogenic than low metastatic cancer LCI D35 and liver tissue. Micropocket was a useful model to study dynamic process of angiogenesis in vivo.

  13. Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway

    OpenAIRE

    Paré-Brunet, Laia; Glubb, Dylan; Evans, Patrick; Berenguer-Llergo, Antoni; Etheridge, Amy S.; Skol, Andrew D.; Di Rienzo, Anna; Duan, Shiwei; Gamazon, Eric R.; Innocenti, Federico

    2013-01-01

    Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU a...

  14. 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...

  15. Hypoxia precondition promotes adipose-derived mesenchymal stem cells based repair of diabetic erectile dysfunction via augmenting angiogenesis and neuroprotection.

    Directory of Open Access Journals (Sweden)

    XiYou Wang

    Full Text Available The aim of the present study was to examine whether hypoxia preconditioning could improve therapeutic effects of adipose derived mesenchymal stem cells (AMSCs for diabetes induced erectile dysfunction (DED. AMSCs were pretreated with normoxia (20% O2, N-AMSCs or sub-lethal hypoxia (1% O2, H-AMSCs. The hypoxia exposure up-regulated the expression of several angiogenesis and neuroprotection related cytokines in AMSCs, including vascular endothelial growth factor (VEGF and its receptor FIK-1, angiotensin (Ang-1, basic fibroblast growth factor (bFGF, brain-derived neurotrophic factor (BDNF, glial cell-derived neurotrophic factor (GDNF, stromal derived factor-1 (SDF-1 and its CXC chemokine receptor 4 (CXCR4. DED rats were induced via intraperitoneal injection of streptozotocin (60 mg/kg and were randomly divided into three groups-Saline group: intracavernous injection with phosphate buffer saline; N-AMSCs group: N-AMSCs injection; H-AMSCs group: H-AMSCs injection. Ten rats without any treatment were used as normal control. Four weeks after injection, the mean arterial pressure (MAP and intracavernosal pressure (ICP were measured. The contents of endothelial, smooth muscle, dorsal nerve in cavernoursal tissue were assessed. Compared with N-AMSCs and saline, intracavernosum injection of H-AMSCs significantly raised ICP and ICP/MAP (p<0.05. Immunofluorescent staining analysis demonstrated that improved erectile function by MSCs was significantly associated with increased expression of endothelial markers (CD31 and vWF (p<0.01 and smooth muscle markers (α-SMA (p<0.01. Meanwhile, the expression of nNOS was also significantly higher in rats receiving H-AMSCs injection than those receiving N-AMSCs or saline injection. The results suggested that hypoxic preconditioning of MSCs was an effective approach to enhance their therapeutic effect for DED, which may be due to their augmented angiogenesis and neuroprotection.

  16. Cyclooxygenase-2 overexpression and vascular endothelial growth factor expression in pharyngeal tissue of patients with OSAHS correlates with angiogenesis%OSAHS患者腭咽组织中COX-2、VEGF的表达及其与新生血管生成的关系

    Institute of Scientific and Technical Information of China (English)

    曾海环; 董伟; 谢于鹏; 刘灵洁; 王良兴

    2011-01-01

    目的:探讨阻塞性睡眠呼吸暂停低通气综合症(OSAHS)患者腭咽组织中环氧化酶-2(COX-2)、血管内皮生长因子(VEGF)的表达及其与新生血管生成的关系及意义.方法:经多导睡眠监测仪(PSG)确诊的40例OSAHS患者(其中轻度组7例,中度12例,重度21例)及6例无鼾症患者的软腭组织,采用HE染色光镜观察腭咽部组织的病理组织学改变,免疫组化技术检测COX-2,VEGF及微血管密度(MVD)的表达情况.结果:COX-2、VEGF主要表达于OSAHS患者软腭组织的黏膜鳞状上皮和导管腺上皮,中、重度OSAHS组与对照组比较,COX-2,VEGF,MVD表达均有显著差异(P0.05);COX-2、VEGF均与MVD的表达呈正相关(P<0.01),COX-2与VEGF的表达呈正相关(P<0.01),COX-2,VEGF,MVD均与睡眠呼吸暂停低通气指数(AHI)呈正相关(P<0.01),与夜间最低氧饱和度呈负相关(P<0.01).结论:OSAHS患者腭咽部存在新生血管增生,与缺氧程度有关,COX-2及VEGF在其发生发展过程中可能起到重要作用.%Objective: To reseach the correlations between cyclooxygenase-2(COX-2) and vascular endothelial growth factor(VEGF) expressions and angiogenesis in pharyngeal tissue of patients with obstructive sleep apnea hypopnea synclnome(OSAHS). Methods: Biopsies were obtained by uvulopalatopharyngoplasty from 40 patients with mild to severe OSAHS. Control specimens of palatopharyngeal and palatoglos sal arch mucosa were retreved from 6 patients with chronic tonsillitis and proved have no related disorders. HE was used to observe the changes of pharyngeal tissue, immunohistochemical staining with antibodies against COX-2, VEGF, microvessel density (MVD) (marked with CD34).Results: COX-2 and VEGF mainly expressed at pavement-epithelium and glandular epithelium of pharyngeal tissue, and stronger COX-2 and VEGF expression was found in midrange and severe OSAHS than mild and control group( P < 0.01 ), so as MVD. COX-2 expression was correlated positively with VEGF expression, and

  17. Epidermal growth factor treatment of the adult brain subventricular zone leads to focal microglia/macrophage accumulation and angiogenesis.

    Science.gov (United States)

    Lindberg, Olle R; Brederlau, Anke; Kuhn, H Georg

    2014-04-01

    One of the major components of the subventricular zone (SVZ) neurogenic niche is the specialized vasculature. The SVZ vasculature is thought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF) is a mitogen with a wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion, dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis in the adult brain.

  18. Vascular permeability and drug delivery in cancers

    Directory of Open Access Journals (Sweden)

    Sandy eAzzi

    2013-08-01

    Full Text Available The endothelial barrier strictly maintains vascular and tissue homeostasis, and therefore modulates many physiological processes such as angiogenesis, immune responses, and dynamic exchanges throughout organs. Consequently, alteration of this finely tuned function may have devastating consequences for the organism. This is particularly obvious in cancers, where a disorganized and leaky blood vessel network irrigates solid tumors. In this context, vascular permeability drives tumor-induced angiogenesis, blood flow disturbances, inflammatory cell infiltration, and tumor cell extravasation. This can directly restrain the efficacy of conventional therapies by limiting intravenous drug delivery. Indeed, for more effective anti-angiogenic therapies, it is now accepted that not only should excessive angiogenesis be alleviated, but also that the tumor vasculature needs to be normalized. Recovery of normal state vasculature requires diminishing hyperpermeability, increasing pericyte coverage, and restoring the basement membrane, to subsequently reduce hypoxia and interstitial fluid pressure. In this review, we will introduce how vascular permeability accompanies tumor progression and, as a collateral damage, impacts on efficient drug delivery. The molecular mechanisms involved in tumor-driven vascular permeability will next be detailed, with a particular focus on the main factors produced by tumor cells, especially the emblematic vascular endothelial growth factor (VEGF. Finally, new perspectives in cancer therapy will be presented, centered on the use of anti-permeability factors and normalization agents.

  19. Quantitative analysis using ELISA of vascular endothelial growth factor and basic fibroblast growth factor in human colorectal cancer, liver metastasis of colorectal cancer and hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Muriel Mathonnet; Bernard Descottes; Denis Valleix; Fran(c)ois Labrousse; Véronique Truffinet; Yves Denizot

    2006-01-01

    @@ TO THE EDITOR Angiogenesis consists of the sprouting of capillaries from pre-existing vessels[1]. It is well-known that tumor growth is angiogenesis-dependent. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)stimulated vascular endothelial cell proliferation and are involved in the neoplastic angiogenesis of several types of tumors including those of the intestinal tract[1-5].

  20. Vascular Endothelial Growth Factor Gene Polymorphism (rs2010963 and Its Receptor, Kinase Insert Domain-Containing Receptor Gene Polymorphism (rs2071559, and Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Sebastjan Merlo

    2016-01-01

    Full Text Available Background. The current study was designed to reveal possible associations between the polymorphisms of the vascular endothelial growth factor (VEGF gene (rs2010963 and its receptor, kinase insert domain-containing receptor (KDR gene polymorphism (rs2071559, and markers of carotid atherosclerosis in patients with type 2 diabetes mellitus (T2DM. Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled. The carotid intima-media thickness (CIMT and plaque characteristics (presence and structure were assessed ultrasonographically. Biochemical analyses were performed using standard biochemical methods. Genotyping of VEGF/KDR polymorphisms (rs2010963, rs2071559 was performed using KASPar assays. Results. Genotype distributions and allele frequencies of the VEGF/KDR polymorphisms (rs2010963, rs2071559 were not statistically significantly different between diabetic patients and controls. In our study, we demonstrated an association between the rs2071559 of KDR and either CIMT or the sum of plaque thickness in subjects with T2DM. We did not, however, demonstrate any association between the tested polymorphism of VEGF (rs2010963 and either CIMT, the sum of plaque thickness, the number of involved segments, hsCRP, the presence of carotid plaques, or the presence of unstable carotid plaques. Conclusions. In the present study, we demonstrated minor effect of the rs2071559 of KDR on markers of carotid atherosclerosis in subjects with T2DM.

  1. Neuronal sFlt1 and Vegfaa determine venous sprouting and spinal cord vascularization

    DEFF Research Database (Denmark)

    Wild, Raphael; Klems, Alina; Takamiya, Masanari

    2017-01-01

    -Kdrl mediated angiogenesis at the neurovascular interface. Neuron-specific loss of flt1 or increased neuronal vegfaa expression promotes angiogenesis and peri-neural tube vascular network formation. Combining loss of neuronal flt1 with gain of vegfaa promotes sprout invasion into the neural tube. On loss...

  2. Reduced expression of tissue factor pathway inhibitor-2 contributes to apoptosis and angiogenesis in cervical cancer

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    Zhang Qiao

    2012-01-01

    Full Text Available Abstract Background Tissue factor pathway inhibitor-2 (TFPI-2 is an extracellular matrix associated broad-spectrum Kunitz-type serine proteinase inhibitor. Recently, down regulation of TFPI-2 was suggested to be involved in tumor invasion and metastasis in some cancers. Methods This study involved 12 normal cervical squamous epithelia, 48 cervical intraepithelial neoplasia (CIN, and 68 cervical cancer. The expression of TFPI-2, Ki-67 and vascular endothelial growth factor (VEGF were investigated by immunohistochemistry staining. The apoptolic index(AI was determined with an in situ end-labeling assay(TUNEL. And the marker of CD34 staining was used as an indicator of microvessel density (MVD. Results TFPI-2 expression has a decreasing trend with the progression of cervical cancer and was significantly correlated with FIGO stage, lymph node metastasis and HPV infection. In addition, there were significant positive correlations between the grading of TFPI-2 expression and AI(P = 0.004. In contrast, the expression of TFPI-2 and VEGF or MVD was negatively correlated (both p Conclusions The results suggested that the expression of TFPI-2 had a decreasing trend with tumor progression of cervical cancer. There was a close association between the expression of TFPI-2 and tumor cell apoptosis and angiogenesis in patients with cervical cancer. TFPI-2 may play an inhibitive role during the development of cervical cancer.

  3. CD133(+) human umbilical cord blood stem cells enhance angiogenesis in experimental chronic hepatic fibrosis.

    Science.gov (United States)

    Elkhafif, Nagwa; El Baz, Hanan; Hammam, Olfat; Hassan, Salwa; Salah, Faten; Mansour, Wafaa; Mansy, Soheir; Yehia, Hoda; Zaki, Ahmed; Magdy, Ranya

    2011-01-01

    The in vivo angiogenic potential of transplanted human umbilical cord blood (UCB) CD133(+) stem cells in experimental chronic hepatic fibrosis induced by murine schistosomiasis was studied. Enriched cord blood-derived CD133(+) cells were cultured in primary medium for 3 weeks. Twenty-two weeks post-Schistosomiasis infection in mice, after reaching the chronic hepatic fibrotic stage, transplantation of stem cells was performed and mice were sacrificed 3 weeks later. Histopathology and electron microscopy showed an increase in newly formed blood vessels and a decrease in the fibrosis known for this stage of the disease. By immunohistochemical analysis the newly formed blood vessels showed positive expression of the human-specific angiogenic markers CD31, CD34 and von Willebrand factor. Few hepatocyte-like polygonal cells showed positive expression of human vascular endothelial growth factor and inducible nitric oxide synthase. The transplanted CD133(+) human stem cells primarily enhanced hepatic angiogenesis and neovascularization and contributed to repair in a paracrine manner by creating a permissive environment that enabled proliferation and survival of damaged cells rather than by direct differentiation to hepatocytes. A dual advantage of CD133(+) cell therapy in hepatic disease is suggested based on its capability of hematopoietic and endothelial differentiation.

  4. Xanthohumol modulates inflammation, oxidative stress, and angiogenesis in type 1 diabetic rat skin wound healing.

    Science.gov (United States)

    Costa, Raquel; Negrão, Rita; Valente, Inês; Castela, Ângela; Duarte, Delfim; Guardão, Luísa; Magalhães, Paulo J; Rodrigues, José A; Guimarães, João T; Gomes, Pedro; Soares, Raquel

    2013-11-22

    Type 1 diabetes mellitus is responsible for metabolic dysfunction, accompanied by chronic inflammation, oxidative stress, and endothelium dysfunction, and is often associated with impaired wound healing. Phenol-rich food improves vascular function, contributing to diabetes prevention. This study has evaluated the effect of phenol-rich beverage consumption in diabetic rats on wound healing, through angiogenesis, inflammation, and oxidative stress modulation. A wound-healing assay was performed in streptozotocin-induced diabetic Wistar rats drinking water, 5% ethanol, and stout beer with and without 10 mg/L xanthohumol (1), for a five-week period. Wounded skin microvessel density was reduced to normal values upon consumption of 1 in diabetic rats, being accompanied by decreased serum VEGF-A and inflammatory markers (IL-1β, NO, N-acetylglucosaminidase). Systemic glutathione and kidney and liver H2O2, 3-nitrotyrosine, and protein carbonylation also decreased to healthy levels after treatment with 1, implying an improvement in oxidative stress status. These findings suggest that consumption of xanthohumol (1) by diabetic animals consistently decreases inflammation and oxidative stress, allowing neovascularization control and improving diabetic wound healing.

  5. Vasculogenesis and angiogenesis: vascular damage in systemic sclerosis

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    M. Matucci Cerinic

    2011-06-01

    Full Text Available La sclerosi sistemica (SSc è una malattia multisistemica del connettivo caratterizzata dalla presenza di alterazioni microvascolari con deficit angiogenetico (1. Suddividendo la patogenesi della SSc in momenti successivi è possibile considerare il microcircolo come la struttura colpita dalla malattia che in più fasi coinvolge l’organismo del paziente affetto da SSc (2. La cellula endoteliale (CE viene inizialmente attivata tramite una noxa ignota alla produzione di molecole di adesione, chemiochine, citochine e fattori di crescita. In tal modo viene facilitato il passaggio (homing linfocitario nei tessuti. Inizialmente si ha un danno a carico della CE seguito da un ispessimento dell’intima e da un progressivo restringimento del lume fino alla completa ostruzione del vaso...

  6. Anti-VEGF Agents for Ocular Angiogenesis and Vascular Permeability

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    Kenichi Kimoto

    2012-01-01

    Full Text Available We review articles describing intravitreal injection of anti-VEGF drug trials, while discussing the mechanisms of the action of anti-VEGF antibodies, and also evaluating their outcomes. Intraocular injections of anti-VEGF drug are considered to be an effective treatment for macular edema after retinal vein occlusion, however, recurrent/persistent edema is common. The recent reports may lead to a shift in treatment paradigm for DME, from laser photocoagulation, to newer approaches using anti-VEGF drugs. There have been several well-publicized prospective, randomized studies that demonstrated the efficacy of intravitreal injection of anti-VEGF drugs for patients with AMD. Adjuvant bevacizumab for neovascular glaucoma may prevent further PAS formation, and it is likely to open up a therapeutic window for a panretinal photocoagulation and trabeculectomy. Intravitreal injection of bevacizumab (IVB results in a substantial decrease in bleeding from the retinal vessels or new vessels during a standard vitrectomy. IVB has also been reported to be effective for inducing the regression of new vessels in proliferative diabetic retinopathy. The use of bevacizumab in stage 4 or 5 retinopahty of permaturity (ROP is to reduce the plus sign to help reduce hemorrhage during the subsequent vitrectomy. Some authors reported cases of resolution of stage 4 A ROP after bevacizumab injection.

  7. Overexpression of Dimethylarginine Dimethylaminohydrolase Enhances Tumor Hypoxia: An Insight into the Relationship of Hypoxia and Angiogenesis In Vivo

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    Vassiliki Kostourou

    2004-07-01

    Full Text Available The oxygenation status of tumors derived from wild-type C6 glioma cells and clone D27 cells overexpressing dimethylarginine dimethylaminohydrolase (DDAH was assessed in vivo using a variety of direct and indirect assays of hypoxia. Clone D27 tumors exhibit a more aggressive and better-vascularized phenotype compared to wild-type C6 gliomas. Immunohistochemical analyses using the 2-nitroimidazole hypoxia marker pimonidazole, fiber optic OxyLite measurements of tumor pO2, and localized 31P magnetic resonance spectroscopy measurements of tumor bioenergetic status and pH clearly demonstrated that the D27 tumors were more hypoxic compared to C6 wild type. In the tumor extracts, only glucose concentrations were significantly lower in the D27 tumors. Elevated Glut-1 expression, a reliable functional marker for hypoxia-inducible factor-1-mediated metabolic adaptation, was observed in the D27 tumors. Together, the data show that overexpression of DDAH results in C6 gliomas that are more hypoxic compared to wild-type tumors, and point strongly to an inverse relationship of tumor oxygenation and angiogenesis in vivo-a concept now being supported by the enhanced understanding of oxygen sensing at the molecular level.

  8. Gestational diabetes, pregnancy hypertension, and late vascular disease.

    Science.gov (United States)

    Carpenter, Marshall W

    2007-07-01

    The complexity of the several pathogenic pathways that cause hypertension and vascular disease and the prolonged interval that appears to predate clinical morbidity have hindered inquiry into the association between GDM and vascular disorders. As a forme fruste of later type 2 diabetes, GDM-affected gravidas are identified as at risk of diabetes-related atherosclerosis, glomerular disruption, and pathogenic retinal angio-genesis. That GDM is evidence for underlying chronic conditions such as dysregulation of innate immune response that, independent of the diabetic state, produces vascular disease is difficult state, produces vascular disease is difficult to assert with the present published literature. Cross-sectional studies of patients with established gestational hypertension or preeclampsia are ambiguous as to the possible pathogenic effect of insulin resistance. Cohort studies initiated in early and mid-pregnancy show evidence that both gestational hypertension and preeclampsia may be more prevalent in gravidas with greater insulin resistance. The association of gestational glucose intolerance with gestational hypertension appears to be independent of obesity and ambient glycemia but explained in part by insulin resistance. Late pregnancy preeclampsia is associated with elevated mid-pregnancy BMI, blood pressure, fasting glucose and insulin, urate, and C-reactive protein, suggestive of metabolic and immune dysregulation. GDM appears to be associated with overexpressed innate immune response, which, in turn, is associated with vascular dysfunction and vascular disease. Among women with GDM, markers of insulin resistance do not appear to correlate with hypertension in short-term cohort studies. However, when non-GDM subjects are compared with subjects with GDM, postpregnancy studies do show an associated with vascular dysfunction and vascular disease. Among women with GDM, markers of insulin resistance do not appear to correlate with hypertension in short

  9. 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.

  10. Zebrafish as an emerging model organism to study angiogenesis in development and regeneration

    Directory of Open Access Journals (Sweden)

    Myra Noemi Chavez

    2016-03-01

    Full Text Available Angiogenesis is the process through which new blood vessels are formed from preexisting ones and plays a critical role in several conditions including embryonic development, tissue repair and disease. Moreover, enhanced therapeutic angiogenesis is a major goal in the field of regenerative medicine and efficient vascularization of artificial tissues and organs is one of the main hindrances in the implementation of tissue engineering approaches, while, on the other hand, inhibition of angiogenesis is a key therapeutic target to inhibit for instance tumor growth. During the last decades, the understanding of cellular and molecular mechanisms involved in this process has been matter of intense research. In this regard, several in vitro and in vivo models have been established to visualize and study migration of endothelial progenitor cells, formation of endothelial tubules and the generation of new vascular networks, while assessing the conditions and treatments that either promote or inhibit such processes. In this review, we address and compare the most commonly used experimental models to study angiogenesis in vitro and in vivo. In particular, we focus on the implementation of the zebrafish (Danio rerio as a model to study angiogenesis and discuss the advantages and not yet explored possibilities of its use as model organism.

  11. TMA Vessel Segmentation Based on Color and Morphological Features: Application to Angiogenesis Research

    Science.gov (United States)

    Fernández-Carrobles, M. Milagro; Tadeo, Irene; Bueno, Gloria; Noguera, Rosa; Déniz, Oscar; Salido, Jesús; García-Rojo, Marcial

    2013-01-01

    Given that angiogenesis and lymphangiogenesis are strongly related to prognosis in neoplastic and other pathologies and that many methods exist that provide different results, we aim to construct a morphometric tool allowing us to measure different aspects of the shape and size of vascular vessels in a complete and accurate way. The developed tool presented is based on vessel closing which is an essential property to properly characterize the size and the shape of vascular and lymphatic vessels. The method is fast and accurate improving existing tools for angiogenesis analysis. The tool also improves the accuracy of vascular density measurements, since the set of endothelial cells forming a vessel is considered as a single object. PMID:24489494

  12. BMP4 promotes formation of primitive vascular networks in human embryonic stem cell-derived embryoid bodies.

    Science.gov (United States)

    Boyd, N L; Dhara, S K; Rekaya, R; Godbey, E A; Hasneen, K; Rao, R R; West, F D; Gerwe, B A; Stice, S L

    2007-06-01

    The vasculature develops primarily through two processes, vasculogenesis and angiogenesis. Although much work has been published on angiogenesis, less is known of the mechanisms regulating the de novo formation of the vasculature commonly called vasculogenesis. Human embryonic stem cells (hESC) have the capability to produce all of the cells of the body and have been used as in vitro models to study the molecular signals controlling differentiation and vessel assembly. One such regulatory molecule is bone morphogenetic protein-4 (BMP4), which is required for mesoderm formation and vascular/hematopoietic specification in several species. However, hESC grown in feeder-free conditions and treated with BMP4 differentiate into a cellular phenotype highly expressing a trophoblast gene profile. Therefore, it is unclear what role, if any, BMP4 plays in regulating vascular development in hESC. Here we show in two National Institutes of Health-registered hESC lines (BG02 and WA09) cultured on a 3D substrate of Matrigel in endothelial cell growth medium-2 that the addition of BMP4 (100 ng/ml) for 3 days significantly increases the formation and outgrowth of a network of cells reminiscent of capillary-like structures formed by mature endothelial cells (P<0.05). Analysis of the expression of 45 genes by quantitative real time-polymerase chain reaction on a low-density array of the entire culture indicates a rapid and significant downregulation of pluripotent and most ectodermal markers with a general upregulation of endoderm, mesoderm, and endothelial markers. Of the genes assayed, BMPR2 and RUNX1 were differentially affected by exposure to BMP4 in both cell lines. Immunocytochemistry indicates the morphological structures formed were negative for the mature endothelial markers CD31 and CD146 as well as the neural marker SOX2, yet positive for the early vascular markers of endothelium (KDR, NESTIN) and smooth muscle cells (alpha-smooth muscle actin [alpha SMA]). Together, these

  13. Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells Derived from Human Arteries: A Novel Strategy to Accelerate Vascular Ulcer Wound Healing

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    Sabrina Valente

    2016-01-01

    Full Text Available Vascular ulcers are a serious complication of peripheral vascular disease, especially in diabetics. Several approaches to treat the wounds are proposed but they show poor outcomes and require long healing times. Hepatocyte Growth Factor/Scatter Factor (HGF/SF is a pleiotropic cytokine exerting many biological activities through the c-Met receptor. This study was aimed at verifying whether HGF/SF influences proliferation, migration, and angiogenesis on mesenchymal stem cells isolated from human arteries (hVW-MSCs. hVW-MSCs were exposed to NIBSC HGF/SF (2.5, 5, 10, and 70 ng/mL from 6 hrs to 7 days. HGF and c-MET mRNA and protein expression, cell proliferation (Alamar Blue and Ki–67 assay, migration (scratch and transwell assays, and angiogenesis (Matrigel were investigated. hVW-MSCs displayed stemness features and expressed HGF and c-MET. HGF/SF did not increase hVW-MSC proliferation, whereas it enhanced the cell migration, the formation of capillary-like structures, and the expression of angiogenic markers (vWF, CD31, and KDR. The HGF/SF effects on hVW-MSC migration and angiogenic potential are of great interest to accelerate wound healing process. Local delivery of HGF/SF could therefore improve the healing of unresponsive vascular ulcers.

  14. Hepatocyte Growth Factor Effects on Mesenchymal Stem Cells Derived from Human Arteries: A Novel Strategy to Accelerate Vascular Ulcer Wound Healing.

    Science.gov (United States)

    Valente, Sabrina; Ciavarella, Carmen; Pasanisi, Emanuela; Ricci, Francesca; Stella, Andrea; Pasquinelli, Gianandrea

    2016-01-01

    Vascular ulcers are a serious complication of peripheral vascular disease, especially in diabetics. Several approaches to treat the wounds are proposed but they show poor outcomes and require long healing times. Hepatocyte Growth Factor/Scatter Factor (HGF/SF) is a pleiotropic cytokine exerting many biological activities through the c-Met receptor. This study was aimed at verifying whether HGF/SF influences proliferation, migration, and angiogenesis on mesenchymal stem cells isolated from human arteries (hVW-MSCs). hVW-MSCs were exposed to NIBSC HGF/SF (2.5, 5, 10, and 70 ng/mL) from 6 hrs to 7 days. HGF and c-MET mRNA and protein expression, cell proliferation (Alamar Blue and Ki-67 assay), migration (scratch and transwell assays), and angiogenesis (Matrigel) were investigated. hVW-MSCs displayed stemness features and expressed HGF and c-MET. HGF/SF did not increase hVW-MSC proliferation, whereas it enhanced the cell migration, the formation of capillary-like structures, and the expression of angiogenic markers (vWF, CD31, and KDR). The HGF/SF effects on hVW-MSC migration and angiogenic potential are of great interest to accelerate wound healing process. Local delivery of HGF/SF could therefore improve the healing of unresponsive vascular ulcers.

  15. LPS induces HUVEC angiogenesis in vitro through miR-146a-mediated TGF-β1 inhibition

    Science.gov (United States)

    Li, Yize; Zhu, Huayu; Wei, Xu; Li, Heng; Yu, Zhicao; Zhang, Hongmei; Liu, Wenchao

    2017-01-01

    Angiogenesis is an essential process for tissue growth and embryo development. However, inflammation, abnormal wound healing, vascular diseases, and tumor development and progression can result from inappropriate angiogenesis. Lipopolysaccharide (LPS) can activate various cells and alter endothelium function and angiogenesis. This study investigated the underlying molecular events involved in LPS-induced angiogenesis and revealed a novel strategy for controlling abnormal angiogenesis. LPS treatment promoted wound healing and tube formation in human umbilical vein endothelial cell (HUVEC) cultures and induced their expression of miR-146a. miR-146a was previously shown to regulate angiogenesis in HUVECs. Knockdown of miR-146a expression antagonized LPS-induced angiogenesis in vitro. Moreover, bioinformatic analyses predicted TGF-β1 as a target gene for miR-146a, which was confirmed by aluciferase reporter assay. Expression of miR-146a in HUVECs resulted in downregulation of TGF-β1 in HUVECs, whereas a miR-146a inhibitor upregulated the expression of TGF-β1 and TGF-β1 downstream proteins, such as phosphoraylation-Smad2 and plasminogen activator inhibitor type 1 (PAI-1). Furthermore, the TGF-β1 signaling inhibitor SB431542 impaired the ability of miR-146a knockdown to suppress LPS-induced angiogenesis. Thus, LPS-induced angiogenesis of HUVECs functions through miR-146a upregulation and TGF-β1 inhibition. This study suggests that knockdown of miR-146a could activate TGF-β1 signaling to inhibit angiogenesis as a potential therapy for angiogenesis-related diseases.

  16. By Different Cellular Mechanisms, Lymphatic Vessels Sprout by Endothelial Cell Recruitment Whereas Blood Vessels Grow by Vascular Expansion

    Science.gov (United States)

    Parsons-Wingerter, Patricia; McKay, Terri L.; Leontiev, Dmitry; Condrich, Terence K.; DiCorleto, Paul E.

    2005-01-01

    The development of effective vascular therapies requires the understanding of all modes of vessel formation contributing to vasculogenesis, angiogenesis (here termed hemangiogenesis) and lymphangiogenesis. We show that lymphangiogenesis proceeds by blind-ended vessel sprouting via recruitment of isolated endothelial progenitor cells to the tips of growing vessels, whereas hemangiogenesis occurs by non-sprouting vessel expansion from the capillary network, during middevelopment in the quail chorioallantoic membrane (CAM). Blood vessels expanded out of capillaries that displayed transient expression of alpha smooth muscle actin (alphaSMA), accompanied by mural recruitment of migratory progenitor cells expressing SMA. Lymphatics and blood vessels were identified by confocal/fluorescence microscopy of vascular endothelial growth factor (VEGF) receptors VEGFR-1 and VEGFR-2, alphaSMA (expressed on CAM blood vessels but not on lymphatics), homeobox transcription factor Prox-1 (specific to CAM lymphatic endothelium), and the quail hematopoetic/vascular marker, QH-1. Expression of VEGFR-1 was highly restricted to blood vessels (primarily capillaries). VEGFR-2 was expressed intensely in isolated hematopoietic cells, lymphatic vessels and moderately in blood vessels. Prox-1 was absent from endothelial progenitor cells prior to lymphatic recruitment. Although vascular endothelial growth factor-165 (VEGF(sub 165)) is a key regulator of numerous cellular processes in hemangiogenesis and vasculogenesis, the role of VEGF(sub 165) in lymphangiogenesis is less clear. Exogenous VEGF(sub 165) increased blood vessel density without changing endogenous modes of vascular/lymphatic vessel formation or marker expression patterns. However, VEGF(sub 165) did increase the frequency of blood vascular anastomoses and strongly induced the antimaturational dissociation of lymphatics from blood vessels, with frequent formation of homogeneous lymphatic networks.

  17. Soluble fms-like tyrosine kinase-1 and vascular endothelial growth factor:Novel markers for unexplained early recurrent pregnancy loss

    Institute of Scientific and Technical Information of China (English)

    Mahmoud Fathy; Hassan

    2014-01-01

    Objective:To evaluate the role of soluble fms-like tyrosine kinase-1(sFlt-1) and vascular endothelial growth factor(VEGF) for prediction of pregnancy loss in patients with history of unexplained early recurrent pregnancy loss(RPL).Methods:A prospective case control study was conducted in42 women with history of unexplained earlyRPL, and170 pregnant controls with history of uncomplicated pregnancy.We measured maternal serum sFlt-1 andVEGF at gestational age6-9 weeks as predictor for pregnancy loss.Results:Mean serum levels of sFlt-1 andVEGF were significantly higher inRPL group than controls(10439.7±385.4vs3304.5±104.8;P<0.0001, for sFlt-1, and1885.0±98.3 vs709.8±24.8;P<0.0001, forVEGF).Receiver operating characteristic(ROC) curves analyses established that sFlt-1 andVEGF were able to discriminate women at risk of developing pregnancy loss with area underROC curve0.970 for sFlt-1 and0.953 forVEGF.Cutoff value of5159.5 pg/mL for sFlt-1 was predictor for early pregnancy loss with 95.2% sensitivity,91.2% specificity, and odds ratio(OR)206 [95%confidence interval(CI),45.4-941].Cutoff value of915.5 pg/mL forVEGF was predictor for early pregnancy loss with92.9% sensitivity,90.6% specificity, andOR125 [95%CI:34.7-451].Conclusion:These data advocate a relationship between sFlt-1,VEGF, andRPL suggesting that the high levels of sFlt-1 andVEGF might be associated with the pathogenesis ofRPL.

  18. Characterization of zofenoprilat as an inducer of functional angiogenesis through increased H2S availability

    Science.gov (United States)

    Terzuoli, E; Monti, M; Vellecco, V; Bucci, M; Cirino, G; Ziche, M; Morbidelli, L

    2015-01-01

    Background and Purpose Hydrogen sulfide (H2S), an endogenous volatile mediator with pleiotropic functions, promotes vasorelaxation, exerts anti-inflammatory actions and regulates angiogenesis. Previously, the SH-containing angiotensin-converting enzyme inhibitor (ACEI), zofenopril, was identified as being effective in preserving endothelial function and inducing angiogenesis among ACEIs. Based on the H2S donor property of its active metabolite zofenoprilat, the objective of this study was to evaluate whether zofenoprilat-induced angiogenesis was due to increased H2S availability. Experimental Approach HUVECs were used for in vitro studies of angiogenesis, whereas the Matrigel plug assay was used for in vivo assessments. Key Results Zofenoprilat-treated HUVECs showed an increase in all functional features of the angiogenic process in vitro. As zofenoprilat induced the expression of CSE (cystathionine-γ-lyase) and the continuous production of H2S, CSE inhibition or silencing blocked the ability of zofenoprilat to induce angiogenesis, both in vitro and in vivo. The molecular mechanisms underlying H2S/zofenoprilat-induced angiogenesis were dependent on Akt, eNOS and ERK1/2 cascades. ATP-sensitive potassium (KATP) channels, the molecular target that mediates part of the vascular functions of H2S, were shown to be involved in the upstream activation of Akt and ERK1/2. Moreover, the up-regulation of fibroblast growth factor-2 was dependent on CSE-derived H2S response to H2S and KATP activation. Conclusions and Implications Zofenoprilat induced a constant production of H2S that stimulated the angiogenic process through a KATP channel/Akt/eNOS/ERK1/2 pathway. Thus, zofenopril can be considered as a pro-angiogenic drug acting through H2S release and production, useful in cardiovascular pathologies where vascular functions need to be re-established and functional angiogenesis induced. PMID:25631232

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

    Directory of Open Access Journals (Sweden)

    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.

  20. Functional and pharmacological characterization of a VEGF mimetic peptide on reparative angiogenesis.

    Science.gov (United States)

    Finetti, Federica; Basile, Anna; Capasso, Domenica; Di Gaetano, Sonia; Di Stasi, Rossella; Pascale, Maria; Turco, Caterina Maria; Ziche, Marina; Morbidelli, Lucia; D'Andrea, Luca Domenico

    2012-08-01

    Vascular endothelial growth factor (VEGF) is the main regulator of physiological and pathological angiogenesis. Low molecular weight molecules able to stimulate angiogenesis have interesting medical application for example in regenerative medicine, but at present none has reached the clinic. We reported that a VEGF mimetic helical peptide, QK, designed on the VEGF helix sequence 17-25, is able to bind and activate the VEGF receptors, producing angiogenesis. In this study we evaluate the pharmacological properties of peptide QK with the aim to propose it as a VEGF-mimetic drug to be employed in reparative angiogenesis. We show that the peptide QK is able to recapitulate all the biological activities of VEGF in vivo and on endothelial cells. In experiments evaluating sprouting from aortic ring and vessel formation in an in vivo angiogenesis model, the peptide QK showed biological effects comparable with VEGF. At endothelial level, the peptide up-regulates VEGF receptor expression, activates intracellular pathways depending on VEGFR2, and consistently it induces endothelial cell proliferation, survival and migration. When added to angiogenic factors (VEGF and/or FGF-2), QK produces an improved biological action, which resulted in reduced apoptosis and accelerated in vitro wound healing. The VEGF-like activity of the short peptide QK, characterized by lower cost of production and easier handling compared to the native glycoprotein, suggests that it is an attractive candidate to be further developed for application in therapeutic angiogenesis.

  1. Isthmin is a novel secreted angiogenesis inhibitor that inhibits tumour growth in mice.

    Science.gov (United States)

    Xiang, Wei; Ke, Zhiyuan; Zhang, Yong; Cheng, Grace Ho-Yuet; Irwan, Ishak Darryl; Sulochana, K N; Potturi, Padma; Wang, Zhengyuan; Yang, He; Wang, Jingyu; Zhuo, Lang; Kini, R Manjunatha; Ge, Ruowen

    2011-02-01

    Anti-angiogenesis represents a promising therapeutic strategy for the treatment of various malignancies. Isthmin (ISM) is a gene highly expressed in the isthmus of the midbrain-hindbrain organizer in Xenopus with no known functions. It encodes a secreted 60 kD protein containing a thrombospondin type 1 repeat domain in the central region and an adhesion-associated domain in MUC4 and other proteins (AMOP) domain at the C-terminal. In this work, we demonstrate that ISM is a novel angiogenesis inhibitor. Recombinant mouse ISM inhibited endothelial cell (EC) capillary network formation on Matrigel through its C-terminal AMOP domain. It also suppressed vascular endothelial growth factor (VEGF)-basic fibroblast growth factor (bFGF) induced in vivo angiogenesis in mouse. It mitigated VEGF-stimulated EC proliferation without affecting EC migration. Furthermore, ISM induced EC apoptosis in the presence of VEGF through a caspase-dependent pathway. ISM binds to αvβ(5) integrin on EC surface and supports EC adhesion. Overexpression of ISM significantly suppressed mouse B16 melanoma tumour growth through inhibition of tumour angiogenesis without affecting tumour cell proliferation. Knockdown of isthmin in zebrafish embryos using morpholino antisense oligonucleotides led to disorganized intersegmental vessels in the trunk. Our results demonstrate that ISM is a novel endogenous angiogenesis inhibitor with functions likely in physiological as well as pathological angiogenesis.

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

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    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.

  3. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone

    Science.gov (United States)

    Ramasamy, Saravana K.; Kusumbe, Anjali P.; Wang, Lin; Adams, Ralf H.

    2014-03-01

    Blood vessel growth in the skeletal system and osteogenesis seem to be coupled, suggesting the existence of molecular crosstalk between endothelial and osteoblastic cells. Understanding the nature of the mechanisms linking angiogenesis and bone formation should be of great relevance for improved fracture healing or prevention of bone mass loss. Here we show that vascular growth in bone involves a specialized, tissue-specific form of angiogenesis. Notch signalling promotes endothelial cell proliferation and vessel growth in postnatal long bone, which is the opposite of the well-established function of Notch and its ligand Dll4 in the endothelium of other organs and tumours. Endothelial-cell-specific and inducible genetic disruption of Notch signalling in mice not only impaired bone vessel morphology and growth, but also led to reduced osteogenesis, shortening of long bones, chondrocyte defects, loss of trabeculae and decreased bone mass. On the basis of a series of genetic experiments, we conclude that skeletal defects in these mutants involved defective angiocrine release of Noggin from endothelial cells, which is positively regulated by Notch. Administration of recombinant Noggin, a secreted antagonist of bone morphogenetic proteins, restored bone growth and mineralization, chondrocyte maturation, the formation of trabeculae and osteoprogenitor numbers in endothelial-cell-specific Notch pathway mutants. These findings establish a molecular framework coupling angiogenesis, angiocrine signals and osteogenesis, which may prove significant for the development of future therapeutic applications.

  4. Angiogenesis inhibitors under study for the treatment of lung cancer.

    Science.gov (United States)

    Shepherd, Frances A; Sridhar, Srikala S

    2003-08-01

    Several classes of agents now exist that target the different steps involved in angiogenesis. These include drugs inhibiting matrix breakdown, the matrix metalloproteinase inhibitors (MMPIs), such as marimastat, prinomastat, BMS275291, BAY12-9566, and neovastat. Trials of this class of agents have all been negative to date. Drugs that block endothelial cell signaling via vascular endothelial growth factor (VEGF) and its receptor (VEGFR) including rhuMAb VEGF, SU5416, SU6668, ZD6474, CP-547,632 and ZD4190 are all in earlier stages of clinical trial. Drugs that are similar to endogenous inhibitors of angiogenesis including interferons have also been evaluated without success. Endostatin has been shown to have an acceptable toxicity profile, but clinical evidence of activity has not yet been demonstrated. There has also been renewed interest in thalidomide. Drugs such as squalamine, celecoxib, ZD6126, TNP-470 and those targeting the integrins are also being evaluated in lung cancer. Despite early enthusiasm for many of these agents, Phase III trials have not yet demonstrated significant increases in overall survival and toxicity remains an issue. It is hoped that as our understanding of the complex process of angiogenesis increases, so will our ability to design more effective targeted therapies.

  5. Injectable fibroblast growth factor-2 coacervate for persistent angiogenesis.

    Science.gov (United States)

    Chu, Hunghao; Gao, Jin; Chen, Chien-Wen; Huard, Johnny; Wang, Yadong

    2011-08-16

    Enhancing the maturity of the newly formed blood vessels is critical for the success of therapeutic angiogenesis. The maturation of vasculature relies on active participation of mural cells to stabilize endothelium and a basal level of relevant growth factors. We set out to design and successfully achieved robust angiogenesis using an injectable polyvalent coacervate of a polycation, heparin, and fibroblast growth factor-2 (FGF2). FGF2 was loaded into the coacervate at nearly 100% efficiency. In vitro assays demonstrated that the matrix protected FGF2 from proteolytic degradations. FGF2 released from the coacervate was more effective in the differentiation of endothelial cells and chemotaxis of pericytes than free FGF2. One injection of 500 ng of FGF2 in the coacervate elicited comprehensive angiogenesis in vivo. The number of endothelial and mural cells increased significantly, and the local tissue contained more and larger blood vessels with increased circulation. Mural cells actively participated during the whole angiogenic process: Within 7 d of the injection, pericytes were recruited to close proximity of the endothelial cells. Mature vasculature stabilized by vascular smooth muscle cells persisted till at least 4 wk. On the other hand, bolus injection of an identical amount of free FGF2 induced weak angiogenic responses. These results demonstrate the potential of polyvalent coacervate as a new controlled delivery platform.

  6. Weight loss induced by tyrosine kinase inhibitors of the vascular endothelial growth factor pathway.

    Science.gov (United States)

    Desar, Ingrid M E; Thijs, Annemarie M J; Mulder, Sasja F; Tack, Cees J J; van Herpen, Carla M L; van der Graaf, Winette T A

    2012-02-01

    Weight loss, cachexia and sarcopenia are profound problems in the frail oncologic patients. With the development and increasing use of angiogenesis inhibitors in metastatic cancer patients, the question arises as to their influence on body weight and composition. Angiogenesis is not only important for the growth, development and metastatic potential of tumors but also for physiological processes in adipogenesis. A less known approach of angiogenesis inhibitors is their experimental use in obese models. This review focuses on the effects on the body weight and composition of angiogenesis inhibitors, especially of those targeting the vascular endothelial growth factor pathway.

  7. The New Role of CD163 in the Differentiation of Bone Marrow Stromal Cells into Vascular Endothelial-Like Cells

    Directory of Open Access Journals (Sweden)

    Wei Lu

    2016-01-01

    Full Text Available Bone marrow stromal cells (BMSCs can differentiate into vascular endothelial cells (VECs. It is regarded as an important solution to cure many diseases, such as ischemic diseases and diabetes. However, the mechanisms underlying BMSC differentiation into VECs are not well understood. Recent reports showed that CD163 expression was associated with angiogenesis. In this study, overexpression of CD163 in BMSCs elevated the protein level of the endothelial-associated markers CD31, Flk-1, eNOS, and VE-cadherin, significantly increased the proportion of Alexa Fluor 488-acetylated-LDL-positive VECs, and promoted angiogenesis on Matrigel. Furthermore, we demonstrated that CD163 acted downstream homeobox containing 1 (Hmbox1 and upstream fibroblast growth factor 2 (FGF-2. These data suggested that CD163 was involved in Hmbox1/CD163/FGF-2 signal pathway in BMSC differentiation into vascular endothelial-like cells. We found a new signal pathway and a novel target for further investigating the gene control of BMSC differentiation into a VEC lineage.

  8. 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

    with epidermal expression of human TGF-ß1, we have demonstrated that antiangiogenic non-viral somatic gene therapy reduces the cutaneous microvasculature and alleviates chronic inflammatory skin disorders. Transient muscular expression of the recombinant disintegrin domain (RDD) of metargidin (also known as ADAM...... in all models. Thus, non-viral antiangiogenic gene therapy can alleviate psoriasis and may do so in other angiogenesis-related inflammatory skin disorders.......-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...

  9. Effect of FGF-BP on angiogenesis in squamous cell carcinoma

    Institute of Scientific and Technical Information of China (English)

    李为民; 陈文彬

    2004-01-01

    @@ Angiogenesis, the formation of new blood vessels, is a critical cellular process for cancer growth and metastasis.Ribozyme targeting studies on overexpression and reduced expression of fibroblast growth factors binding protein (FGF-BP) have indicated that this protein plays a direct role in angiogenesis during tumor development. 1 To explore the effect of FGF-BP on neovascularization of squamous cell carcinoma, we investigated FGF-BP mRNA expression using in situ hybridization on squamous cell carcinoma. To further define the potential role of FGF-BP in individual stages of metastasis, we studied the association of FGF-BP with vascularity.

  10. Glial cell line-derived neurotrophic factor induced the differentiation of amniotic fluid-derived stem cells into vascular endothelial-like cells in vitro.

    Science.gov (United States)

    Zhang, Ruyu; Lu, Ying; Li, Ju; Wang, Jia; Liu, Caixia; Gao, Fang; Sun, Dong

    2016-02-01

    Amniotic fluid-derived stem cells (AFSCs) are a novel source of stem cells that are isolated and cultured from second trimester amniocentesis. Glial cell line-derived neurotrophic factor (GDNF) acts as a tissue morphogen and regulates stem cell proliferation and differentiation. This study investigated the effect of an adenovirus-mediated GDNF gene, which was engineered into AFSCs, on the cells' biological properties and whether GDNF in combination with AFSCs can be directionally differentiated into vascular endothelial-like cells in vitro. AFSCs were isolated and cultured using the plastic adherence method in vitro and identified by the transcription factor Oct-4, which is the primary marker of pluripotent stem cells. AFSCs were efficiently transfected by a GFP-labeled plasmid system of an adenovirus vector carrying the GDNF gene (Ad-GDNF-GFP). Transfected AFSCs stably expressed GDNF. Transfected AFSCs were cultured in endothelial growth medium-2 containing vascular endothelial growth factor. After 1 week, AFSCs were positive for von Willebrand factor (vWF) and CD31, which are markers of endothelial cells, and the recombinant GDNF group was significantly higher than undifferentiated controls and the GFP only group. These results demonstrated that AFSCs differentiated into vascular endothelial-like cells in vitro, and recombinant GDNF promoted differentiation. The differentiation-induced AFSCs may be used as seed cells to provide a new manner of cell and gene therapies for transplantation into the vascular injury site to promote angiogenesis.

  11. Ageing and vascular ageing

    Science.gov (United States)

    Jani, B; Rajkumar, C

    2006-01-01

    There is an age related decline in various physiological processes. Vascular ageing is associated with changes in the mechanical and the structural properties of the vascular wall, which leads to the loss of arterial elasticity and reduced arterial compliance. Arterial compliance can be measured by different parameters like pulse wave velocity, augmentation index, and systemic arterial compliance. There is evidence that arterial compliance is reduced in disease states such as hypertension, diabetes, and end stage renal failure. Changes in arterial compliance can be present before the clinical manifestation of cardiovascular disease. Pharmacological and non‐pharmacological measures have been shown to improve arterial compliance. Arterial compliance may constitute an early cardiovascular risk marker and may be useful in assessing the effects of drugs on the cardiovascular system. Pharmacogenetics and genetics of arterial compliance in the future will improve our knowledge and understanding about vascular ageing. PMID:16754702

  12. Angiogenic Factor AGGF1 Activates Autophagy with an Essential Role in Therapeutic Angiogenesis for Heart Disease

    Science.gov (United States)

    Hu, Zhenkun; Hu, Changqing; Song, Qixue; Ye, Jian; Xu, Chengqi; Wang, Annabel Z.; Wang, Qing Kenneth

    2016-01-01

    AGGF1 is an angiogenic factor with therapeutic potential to treat coronary artery disease (CAD) and myocardial infarction (MI). However, the underlying mechanism for AGGF1-mediated therapeutic angiogenesis is unknown. Here, we show for the first time that AGGF1 activates autophagy, a housekeeping catabolic cellular process, in endothelial cells (ECs), HL1, H9C2, and vascular smooth muscle cells. Studies with Atg5 small interfering RNA (siRNA) and the autophagy inhibitors bafilomycin A1 (Baf) and chloroquine demonstrate that autophagy is required for AGGF1-mediated EC proliferation, migration, capillary tube formation, and aortic ring-based angiogenesis. Aggf1+/- knockout (KO) mice show reduced autophagy, which was associated with inhibition of angiogenesis, larger infarct areas, and contractile dysfunction after MI. Protein therapy with AGGF1 leads to robust recovery of myocardial function and contraction with increased survival, increased ejection fraction, reduction of infarct areas, and inhibition of cardiac apoptosis and fibrosis by promoting therapeutic angiogenesis in mice with MI. Inhibition of autophagy in mice by bafilomycin A1 or in Becn1+/- and Atg5 KO mice eliminates AGGF1-mediated angiogenesis and therapeutic actions, indicating that autophagy acts upstream of and is essential for angiogenesis. Mechanistically, AGGF1 initiates autophagy by activating JNK, which leads to activation of Vps34 lipid kinase and the assembly of Becn1-Vps34-Atg14 complex involved in the initiation of autophagy. Our data demonstrate that (1) autophagy is essential for effective therapeutic angiogenesis to treat CAD and MI; (2) AGGF1 is critical to induction of autophagy; and (3) AGGF1 is a novel agent for treatment of CAD and MI. Our data suggest that maintaining or increasing autophagy is a highly innovative strategy to robustly boost the efficacy of therapeutic angiogenesis. PMID:27513923

  13. Activation of VEGF and FGF induced angiogenesis under influence of low level laser radiation in vitro

    Science.gov (United States)

    Gasparyan, Levon; Brill, Grigory; Makela, Anu

    2006-02-01

    One of the feasible explanations for long-term treatment effects of laser therapy of diseases connected with tissue ischemia and altered blood circulation is activation of angiogenesis after low level laser irradiation. The aim of the current study was to investigate if laser irradiation can enhance vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (FGF) induced angiogenesis in vitro. The study was conducted on rat thoracic aortal rings. Samples of group 1 served as control, samples of groups 2 and 3 were incubated with VEGF or FGF, group 4 samples were irradiated with laser (660 nm, 20 mW) during 10 min, samples of groups 5 and 6 were incubated with VEGF or FGF accordingly and received 10 min of laser irradiation. In the control group no noticeable angiogenesis occurred. The application of VEGF activated angiogenesis: the area covered by new vessels was 1,3+/-0,24 mm2 and the maximal length of vessels was 0,93+/-0,11 mm. Laser light irradiation (group 4) activated angiogenesis (1,9+/-0,29 mm2 and 0,75+/-0,10 mm). The combined influence of laser light and VEGF on angiogenesis (group 5) was significantly stronger (p FGF also activated angiogenesis: the area covered by new vessels was 2,76+/-0,22 mm2 and the maximal length of vessels was 1,19+/-0,12 mm. Combined influence of laser light and FGF on angiogenesis (group 6) was again significantly stronger (p <0,001), than each of the factors separately (5,43+/-0,28 mm2 and 1,99+/-0,10 mm). Studies show that laser irradiation can intensify effects of growth factors in vitro.

  14. Antimyeloma effects of resveratrol through inhibition of angiogenesis

    Institute of Scientific and Technical Information of China (English)

    HU Yu; SUN Chun-yan; HUANG Jing; HONG Liu; ZHANG Lu; CHU Zhang-bo

    2007-01-01

    Background In multiple myeloma (MM), bone marrow angiogenesis parallels tumour progression and correlates with disease activity. Recent studies have proved resveratrol possesses antiangiogenic activity in vitro and in vivo. In this study, we examined the effects of resveratrol on myeloma cell dependent angiogenesis and the effects of resveratrol on some important angiogenic factors of RPMI 8226 cells.Methods RPMI 8226 cells were cocultured with human umbilical vein endothelial cells (HUVECs) to evaluate the effects of myeloma cells on angiogenesis. The RPMI 8226 cells were treated with various concentrations of resveratrol (6.25-50.00 μmol/L) for different times (12-72 hours). Reverse transcriptase polymerase chain reaction (RT-PCR) was used to assay vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), metalloproteinases (MMP)-2 and MMP-9 mRNA. Gelatin zymography was used to analyze MMP-2 and MMP-9 activity. VEGF and bFGF proteins secreted by the cells in the medium were quantified by enzyme linked immunosorbent assay (ELISA).Results Cell proliferation, migration and differentiation of HUVECs markedly increased by coculture with RPMI 8226 cells. Resveratrol inhibited proliferation, migration and tube formation of HUVECs cocultured with myeloma cells in a dose dependent manner. Treatment of RPMI 8226 cells with resveratrol caused a decrease in MMP-2 and MMP-9 activity.Resveratrol inhibited VEGF and bFGF protein expression in a dose and time dependent manner. Furthermore,decreased levels of VEGF, bFGF, MMP-2 and MMP-9 mRNA from cells treated with various concentrations of resveratrol confirmed its antiangiogenic action at the level of gene expression.Conclusions Resveratrol inhibits multiple myeloma angiogenesis by regulating expression and secretion of VEGF,bFGF, MMP-2 and MMP-9. Resveratrol may be a potential candidate for the treatment of multiple myeloma.

  15. Lymphangiogenesis by blind-ended vessel sprouting is concurrent with hemangiogenesis by vascular splitting.

    Science.gov (United States)

    Parsons-Wingerter, Patricia; McKay, Terri L; Leontiev, Dmitry; Vickerman, Mary B; Condrich, Terence K; Dicorleto, Paul E

    2006-03-01

    Development of effective vascular therapies requires the understanding of all modes of vessel formation involved in angiogenesis (here termed "hemangiogenesis") and lymphangiogenesis. Two major modes of vessel morphogenesis include sprouting of a new vessel from a preexisting vessel and splitting of a preexisting parent vessel into two offspring vessels. In the quail chorioallantoic membrane (CAM) during mid-development (embryonic days E6-E9), lymphangiogenesis progressed primarily via blind-ended vessel sprouting. Isolated lymphatic endothelial progenitor cells were recruited to the tips of growing vessels. During concurrent hemangiogenesis, parent blood vessels expanded from the capillary network and split into offspring vessels, accompanied by transient capillary expression of alpha smooth muscle actin (alphaSMA) and recruitment of polarized mural progenitor cells. Lymphatics and blood vessels were identified by confocal/fluorescence microscopy of vascular endothelial growth factor (VEGF) receptor VEGFR-2, alphaSMA (specific to CAM blood vessels), homeobox transcription factor Prox1 (specific to lymphatics), and the quail hematopoetic marker, QH-1. VEGFR-2 was expressed intensely in isolated cells and lymphatics, and moderately in blood vessels. Prox1 was absent from isolated progenitor cells prior to lymphatic recruitment. Exogenous vascular endothelial growth factor-165 (VEGF165) increased blood vessel density and anastomotic frequency without changing endogenous modes of vascular/lymphatic vessel formation or marker expression. Although VEGF165 is a key cellular regulator of hemangiogenesis and vasculogenesis, the role of VEGF165 in lymphangiogenesis is less clear. Interestingly, VEGF165 increased lymphatic vessel diameter and density as measured by novel Euclidean distance mapping, and the antimaturational dissociation of lymphatics from blood vessels, accompanied by lymphatic reassociation into homogeneous networks.

  16. Regulation of a vascular plexus by gata4 is mediated in zebrafish through the chemokine sdf1a.

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    Ingrid Torregroza

    Full Text Available Using the zebrafish model we describe a previously unrecognized requirement for the transcription factor gata4 controlling embryonic angiogenesis. The development of a vascular plexus in the embryonic tail, the caudal hematopoietic tissue (CHT, fails in embryos depleted of gata4. Rather than forming a normal vascular plexus, the CHT of gata4 morphants remains fused, and cells in the CHT express high levels of osteogenic markers ssp1 and runx1. Definitive progenitors emerge from the hemogenic aortic endothelium, but fail to colonize the poorly vascularized CHT. We also found abnormal patterns and levels for the chemokine sdf1a in gata4 morphants, which was found to be functionally relevant, since the embryos also show defects in development of the lateral line, a mechano-sensory organ system highly dependent on a gradient of sdf1a levels. Reduction of sdf1a levels was sufficient to rescue lateral line development, circulation, and CHT morphology. The result was surprising since neither gata4 nor sdf1a is obviously expressed in the CHT. Therefore, we generated transgenic fish that conditionally express a dominant-negative gata4 isoform, and determined that gata4 function is required during gastrulation, when it is co-expressed with sdf1a in lateral mesoderm. Our study shows that the gata4 gene regulates sdf1a levels during early embryogenesis, which impacts embryonic patterning and subsequently the development of the caudal vascular plexus.

  17. 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.

  18. Evaluation of tumor angiogenesis in patients with non-small cell lung carcinoma

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    Suciu B.A.

    2015-05-01

    Full Text Available The aim of this study is to evaluate tumor angiogenesis in patients with non-small cell lung carcinoma. A total of 20 patients with pulmonary adenocarinoma have been included in the study. In order to evaluate tumor angiogenesis we studied the importance of CD34 expression. Evaluation of vascular density was performed with a semiautomated method using the dedicated software called ImageJ. We introduced in our study 20 patients with lung adenocarcinoma. We were able to identify tumor angiogenesis in 19 cases (95%. Immunolabeling of CD34 positive endothelial cells provided a good overview of tumor vascularization. Immunohistochemical staining of CD34 positive endothelium cells provided a good basis for tumor vascularity assessment, and also an excellent contrast for computer assisted morphometric measurements. Also we studied the intensity of the immunohistochemical staining of CD34 in the tumoral cells. We obtained the following results: a minor expression in 4 cases (20%, a moderate expression in 9 cases (45% and an intense expression in 6 cases (30%. The histological type of adenocarcinomas influences the architecture and branching of the vessels. The density of newly developed vessels is higher in patients with papillary pulmonary adenocarcinomas, which may indicate a possible relationship between the histological type and development of vascular supply.

  19. Therapeutics targeting angiogenesis: genetics and epigenetics, extracellular miRNAs and signaling networks (Review).

    Science.gov (United States)

    Katoh, Masaru

    2013-10-01

    Angiogenesis is a process of neovascular formation from pre-existing blood vessels, which consists of sequential steps for vascular destabilization, angiogenic sprouting, lumen formation and vascular stabilization. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), angiopoietin, Notch, transforming growth factor-β (TGF-β), Hedgehog and WNT signaling cascades orchestrate angiogenesis through the direct or indirect regulation of quiescence, migration and the proliferation of endothelial cells. Small-molecule compounds and human/humanized monoclonal antibodies interrupting VEGF signaling have been developed as anti-angiogenic therapeutics for cancer and neovascular age-related macular degeneration (AMD). Gene or protein therapy delivering VEGF, FGF2 or FGF4, as well as cell therapy using endothelial progenitor cells (EPCs), mesenchymal stem cells (MSCs) or induced pluripotent stem cells (iPSCs) have been developed as pro-angiogenic therapeutics for ischemic heart disease and peripheral vascular disease. Anti-angiogenic therapy for cancer and neovascular AMD is more successful than pro-angiogenic therapy for cardiovascular diseases, as VEGF-signal interruption is technically feasible compared with vascular re-construction. Common and rare genetic variants are detected using array-based technology and personal genome sequencing, respectively. Drug and dosage should be determined based on personal genotypes of VEGF and other genes involved in angiogenesis. As epigenetic alterations give rise to human diseases, polymer-based hydrogel film may be utilized for the delivery of drugs targeting epigenetic processes and angiogenesis as treatment modalities for cardiovascular diseases. Circulating microRNAs (miRNAs) in exosomes and microvesicles are applied as functional biomarkers for diagnostics and prognostics, while synthetic miRNAs in polymer-based nanoparticles are applicable for therapeutics. A more profound understanding of the spatio

  20. Angiogenesis and Anti-Angiogenic Treatments

    Directory of Open Access Journals (Sweden)

    Ersin Demirer

    2013-10-01

    Full Text Available Blood vessels in our body is developed by vasculogenesis and angiogenesis. There have been new advances in molecular pathology and tumor biology areas in recent years. Angiogenesis is modulated by the balance between angiogenic and anti-angiogenic factors. Angiogenesis plays a key role in tumor growth. Drugs inhibiting angiogenesis have been in use in various malign or non-malign diseases. Inhibition of angiogenesis in malign diseases is a very attractive subject in medicine and studies are going on about long term affects and toxicities. Inhibition of angiogenesis is not an only treatment choice alone. It is a supplemental treatment option applied with conventional chemotherapy, radiotherapy, surgery, immunotherapy and hormonal therapy. It has been used in colorectal carcinoma, renal cell carcinoma, non-small cell lung cancer, glioblastoma, heoatocellular carcinoma, pancreatic neuroendocrine tumor, tyroid medullary cancer.

  1. Monitoring angiogenesis using magnetic resonance methods

    DEFF Research Database (Denmark)

    Holm, David Alberg

    2008-01-01

    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......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...... 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...

  2. KR-31831, benzopyran derivative, inhibits VEGF-induced angiogenesis of HUVECs through suppressing KDR expression.

    Science.gov (United States)

    Park, Shi-Young; Seo, Eun-Hee; Song, Hyun Seok; Jung, Seung-Youn; Lee, Young-Kyoung; Yi, Kyu-Yang; Yoo, Sung-Eun; Kim, Yung-Jin

    2008-06-01

    Angiogenesis is important in the development and progression of cancer, therefore the therapeutic approach based on anti-angiogenesis may represent a promising therapeutic option. KR-31831 is a novel anti-ischemic agent. Previously, we reported the anti-angiogenic activity of KR-31831. In the present study we investigated the molecular mechanisms underlying anti-angiogenic activity of KR-31831. We show that KR-31831 inhibits vascular endothelial growth factor (VEGF)-induced proliferation and tube formation via release of intracellular Ca2+ and phosphorylation of extra-cellular regulated kinase 1/2 (Erk 1/2) in human umbilical vein endothelial cells (HUVECs). Moreover, the expression of VEGF receptor 2 (VEGFR2, known as Flk-1 or KDR) was reduced by the treatment of KR-31831. These results suggest that KR-31831 may have inhibitory effects on tumor angiogenesis through down-regulation of KDR expression.

  3. In Vivo Monitoring of Neovascularization in Tumour Angiogenesis by Photoacoustic Tomography

    Institute of Scientific and Technical Information of China (English)

    XIANG Liang-Zhong; XING Da; GU Huai-Min; ZHOU Fei-Fan; YANG Di-Wu; ZENG Lv-Ming; YANG Si-Hua

    2007-01-01

    Photoacoustic tomography (PAT) is presented to in vivo monitor neovascularization in tumout angiogenesis with high resolution and high contrast images in a rat. With a circular scan system, the photoacoustic signal, generated by laser pulses at a wavelength of 532nm from a Q-switched Nd:YAG laser, is captured by a hydrophone with a diameter of 1 mm and a sensitivity of 850nV/Pa. The vascular structure around the rat tumour is imaged clearly, with optimal contrast, because blood has strong absorption near this wavelength. Serial noninvasive photoacoustic images of neovascularization in tumour angiogenesis are also obtained consecutively from a growing tumour implanted under the skin of a rat over a period of two weeks. This work demonstrates that PAT can potentially provide a powerful tool for tumour angiogenesis detection in cancer research. It will bring us closer to clinical applications for tumour diagnosis and treatment monitoring.

  4. Lysyl oxidase plays a critical role in endothelial cell stimulation to drive tumor angiogenesis

    Science.gov (United States)

    Baker, Ann-Marie; Bird, Demelza; Welti, Jonathan C.; Gourlaouen, Morgane; Lang, Georgina; Murray, Graeme I.; Reynolds, Andrew R.; Cox, Thomas R.; Erler, Janine T.

    2012-01-01

    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 LOX activates Akt through platelet derived growth factor receptor β (PDGFRβ) stimulation, resulting in increased vascular endothelial growth factor (VEGF) expression. LOX-driven angiogenesis can be abrogated through targeting LOX directly, or using inhibitors of PDGFRβ, Akt and VEGF signaling. Furthermore, we show that LOX is clinically correlated with VEGF expression and blood vessel formation in 515 colorectal cancer patient samples. Finally, we validate our findings in a breast cancer model, demonstrating the universality of these observations. Taken together, our findings have broad clinical and therapeutic implications for a wide variety of solid tumor types. PMID:23188504

  5. Dihydroartemisinin promotes angiogenesis during the early embryonic development of zebrafish

    Institute of Scientific and Technical Information of China (English)

    Qian BA; Juan DUAN; Jia-qiang TIAN; Zi-liang WANG; Tao CHEN; Xiao-guang LI; Pei-zhan CHEN

    2013-01-01

    Aim:To investigate the embryotoxicity of dihydroartemisinin (DHA),the main active metabolite of artemisinin,in zebrafish,and explore the corresponding mechanisms.Methods:The embryos of wild type and TG (flk1:GFP) transgenic zebrafish were exposed to DHA.Developmental phenotypes of the embryos were observed.Development of blood vessels was directly observed in living embryos of TG (flk1:GFP) transgenic zebrafish under fluorescence microscope.The expression of angiogenesis marker genes vegfa,flk1,and flt1 in the embryos was detected using real-time PCR and RNA in situ hybridization assays.Results:Exposure to DHA (1-10 mg/L) dose-dependently caused abnormal zebrafish embryonic phenotypes in the early developmental stage.Furthermore,exposure to DHA (10 mg/L) resulted in more pronounced embryonic angiogenesis in TG (flk1:GFP)zebrafish line.Exposure to DHA (10 mg/L) significantly increased the mRNA expression of vegfa,flk1,and flt1 in the embryos.Knockdown of the ilk1 protein partially blocked the effects of DHA on embryogenesis.Conclusion:DHA causes abnormal embryonic phenotypes and promotes angiogenesis in zebrafish early embryonic development,demonstrating the potential embryotoxicity of DHA.

  6. 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.

  7. Age-related macular degeneration: beyond anti-angiogenesis.

    Science.gov (United States)

    Kent, David L

    2014-01-06

    Recently, anti-vascular endothelial growth factor therapies for neovascular age-related macular degeneration have been developed. These agents, originally developed for their anti-angiogenic mechanism of action, probably also work through an anti-permeability effect in preventing or reducing the amount of leakage from submacular neovascular tissue. Other treatment modalities include laser photocoagulation, photodynamic therapy with verteporfin, and submacular surgery. In reality, these latter treatments can be similarly categorized as anti-angiogenic because their sole aim is destroying or removing choroidal neovascularization (CNV). At the cellular level, CNV resembles stereotypical tissue repair that consists of several matricellular components in addition to neovascularization. In the retina, the clinical term CNV is a misnomer since the term may more appropriately be referred to as aberrant submacular repair. Furthermore, CNV raises a therapeutic conundrum: To complete or correct any reparative process in the body, angiogenesis becomes an essential component. Anti-angiogenic therapy, in all its guises, arrests repair and causes the hypoxic environment to persist, thus fueling pro-angiogenesis and further development of CNV as a component of aberrant repair. However, we realize that anti-vascular endothelial growth factor therapy preserves vision in patients with age-related macular degeneration, albeit temporarily and therefore, repeated treatment is needed. More importantly, however, anti-angiogenic therapy demonstrates that we can at the very least tolerate neovascular tissue beneath the macula and preserve vision in contrast to our historical approach of total vascular destruction. In this clinical scenario, it may be possible to look beyond anti-angiogenesis if our goal is facilitating submacular repair without destroying the neurosensory retina. Thus, in this situation of neovascular tolerance, it may be timely to consider treatments that facilitate

  8. [Vascular dementia

    NARCIS (Netherlands)

    Leeuw, H.F. de; Gijn, J. van

    2004-01-01

    Vascular dementia is one of the most frequently occurring dementia syndromes. Its prevalence is about 5% among subjects above 85 years of age. Elevated blood pressure and atherosclerosis are the most important risk factors. According to international criteria, vascular dementia usually occurs within

  9. Expression of Vascular Endothelial Growth Factor-C and Vascular Endothelial Growth Factor Receptor-3 in Ovarian Epithelial Tumors

    Institute of Scientific and Technical Information of China (English)

    FU Xiao-yan; DING Ming-xing; ZHANG Ning; LIN Xing-qiu; LI Ji-cheng

    2007-01-01

    Objective: To explore the role of vascular endothelial growth factor-C (VEGF-C) in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods: In situ hybridization and immunohistochemical staining for VEGF-C were performed in 30 epithelial ovarian carcinomas, 9 borderline tumors and 26 benign tumors. Endothelial cells were immunostained with anti-VEGFR-3 pAb and anti-CD31 mAb, and VEGFR-3 positive vessels and microvessel density (MVD) were assessed by image analysis. Results: VEGF-C mRNA and protein expression were detected in cytoplasm of carcinoma cells. VEGF-C mRNA and protein expression in ovarian epithelial carcinomas were significantly higher than those in borderline tumors and benign tumors (P<0.05 or P<0.01). In ovarian epithelial carcinomas, VEGF-C protein expression, VEGFR-3 positive vessels and MVD were significantly higher in the cases of clinical stage Ⅲ-Ⅳ and with lymph node metastasis than those of clinical stage Ⅰ-Ⅱ and without lymph node metastasis respectively (P<0.05 or P<0.01). VEGFR-3 positive vessels and MVD were significantly higher in VEGF-C protein positive tumors than negative tumors (P<0.05). VEGFR-3 positive vessels was significantly correlated with MVD(P<0.01). Conclusion: VEGF-C might play a role in lymphatic metastasis via lymphangiogenesis and angiogenesis in epithelial ovarian tumors, and VBEGF-C could be used as a biologic marker of metastasis in ovarian epithelial tumors.

  10. Stem Cells Derived from Tooth Periodontal Ligament Enhance Functional Angiogenesis by Endothelial Cells

    Science.gov (United States)

    Yeasmin, Shamima; Ceccarelli, Jacob; Vigen, Marina; Carrion, Bita; Putnam, Andrew J.; Tarle, Susan A.

    2014-01-01

    In regenerative medicine approaches involving cell therapy, selection of the appropriate cell type is important in that the cells must directly (differentiation) or indirectly (trophic effects) participate in the regenerative response. Regardless of the mode of action of the cells, angiogenesis underlies the success of these approaches. Stem cells derived from tooth tissues, specifically the periodontal ligament of teeth (periodontal ligament stem cells [PDLSCs]), have recently been identified as a good source of multipotent cells for cell therapies. PDLSCs have demonstrated properties similar to mesenchymal stem cells (MSCs), yet, unlike MSCs, their vascular potential has not been previously demonstrated. Thus, the aim of this study was to determine if PDLSCs could modulate angiogenesis. In comparison to MSCs and stem cells derived from tooth pulp tissues (SHEDs), we first determined if PDLSCs released soluble proangiogenic factors with the capacity to induce vessel formation by endothelial cells (ECs). Next, the ability of PDLSCs to modulate angiogenesis was examined through their cotransplantation with ECs in subcutaneous sites of immunocompromised mice. Finally, the stability of the PDLSC-mediated vasculature was determined through evaluation of the maturity and functionality of the vessels formed following PDLSC transplantation. It was determined that PDLSCs produced appreciable levels of vascular endothelial growth factor and basic fibroblast growth factor-2, and additionally, were able to initiate in vitro angiogenesis of ECs comparable to MSC- and SHED-mediated angiogenesis. In vivo cotransplantation of ECs with PDLSCs significantly (>50% increase) enhanced the number of blood vessels formed relative to transplantation of ECs alone. Finally, vessels formed following PDLSC cotransplantation were more mature and less permeable than those formed after transplantation of EC alone. These data demonstrate for the first time that PDLSCs have vascular potential

  11. Blood flow controls bone vascular function and osteogenesis

    Science.gov (United States)

    Ramasamy, Saravana K.; Kusumbe, Anjali P.; Schiller, Maria; Zeuschner, Dagmar; Bixel, M. Gabriele; Milia, Carlo; Gamrekelashvili, Jaba; Limbourg, Anne; Medvinsky, Alexander; Santoro, Massimo M.; Limbourg, Florian P.; Adams, Ralf H.

    2016-01-01

    While blood vessels play important roles in bone homeostasis and repair, fundamental aspects of vascular function in the skeletal system remain poorly understood. Here we show that the long bone vasculature generates a peculiar flow pattern, which is important for proper angiogenesis. Intravital imaging reveals that vessel growth in murine long bone involves the extension and anastomotic fusion of endothelial buds. Impaired blood flow leads to defective angiogenesis and osteogenesis, and downregulation of Notch signalling in endothelial cells. In aged mice, skeletal blood flow and endothelial Notch activity are also reduced leading to decreased angiogenesis and osteogenesis, which is reverted by genetic reactivation of Notch. Blood flow and angiogenesis in aged mice are also enhanced on administration of bisphosphonate, a class of drugs frequently used for the treatment of osteoporosis. We propose that blood flow and endothelial Notch signalling are key factors controlling ageing processes in the skeletal system. PMID:27922003

  12. Molecular profiling of angiogenesis in hypericin mediated photodynamic therapy

    Directory of Open Access Journals (Sweden)

    Ali Seyed M

    2008-06-01

    Full Text Available Abstract Background Photodynamic therapy (PDT involves the administration of a tumor-localizing photosensitizing drug, which is activated by light of specific wavelength in the presence of molecular oxygen thus generating reactive oxygen species that is toxic to the tumor cells. PDT selectively destroys photosensitized tissue leading to various cellular and molecular responses. The present study was designed to examine the angiogenic responses at short (0.5 h and long (6 h drug light interval (DLI hypericin-PDT (HY-PDT treatment at 24 h and 30 days post treatment in a human bladder carcinoma xenograft model. As short DLI targets tumor vasculature and longer DLI induces greater cellular damage, we hypothesized a differential effect of these treatments on the expression of angiogenic factors. Results Immunohistochemistry (IHC results showed minimal CD31 stained endothelium at 24 h post short DLI PDT indicating extensive vascular damage. Angiogenic proteins such as vascular endothelial growth factor (VEGF, tumor necrosis growth factor-α (TNF-α, interferon-α (IFN-α and basic fibroblast growth factor (bFGF were expressed to a greater extent in cellular targeting long DLI PDT compared to vascular mediated short DLI PDT. Gene expression profiling for angiogenesis pathway demonstrated downregulation of adhesion molecules – cadherin 5, collagen alpha 1 and 3 at 24 h post treatment. Hepatocyte growth factor (HGF and Ephrin-A3 (EFNA3 were upregulated in all treatment groups suggesting a possible activation of c-Met and Ephrin-Eph signaling pathways. Conclusion In conclusion, long DLI HY-PDT induces upregulation of angiogenic proteins. Differential expression of genes involved in the angiogenesis pathway was observed in the various groups treated with HY-PDT.

  13. New molecular connections in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Qiling Xu; David Wilkinson

    2010-01-01

    @@ In vertebrates, oxygen and nutrients are delivered to tissues by the circula-tion of blood through vessels, comprised of a branched network of endothelial tubes termed the vasculature. Crucial for the formation of blood vessels during development is the process of angiogenesis, in which new sprouts form from pre-existing vessels in a complex cascade of cellular events. This involves the activation of an endothelial cell in the vessel to become a highly exploratory 'tip' cell that migrates to invade the surrounding tissues, while remaining tightly connected to the fol-lowing cells that subsequently generate the tubular structures of a new vessel.

  14. Effect of DAPT, a gamma secretase inhibitor, on tumor angiogenesis in control mice

    Directory of Open Access Journals (Sweden)

    Elmira Kalantari

    2013-01-01

    Full Text Available Background: Notch signaling is a key factor for angiogenesis in physiological and pathological condition and γ-secretase is the regulator of Notch signaling. The main goal of this study was to assess the effect of (N-[N-(3,5-Diflurophenaacetyl-L-alanyl]-S-phenylglycine t-Butyl Ester DAPT, a γ-secretase inhibitor, on serum angiogenic biomarkers, and tumor angiogenesis in control mice. Materials and Methods: Tumor was induced by inoculation of colon adenocarcinoma cells (CT26 in 12 male Balb/C mice. When tumors size is reached to a 350 ± 50 mm 3 , the animals were randomly divided into two groups: control and DAPT (n = 6/group. DAPT was injected subcutaneously 10 mg/kg/day. After 14 days, blood samples were taken and the tumors were harvested for immunohistochemical staining. Results: Administration of DAPT significantly increased serum nitric oxide concentration and reduced vascular endothelial growth factor receptors-1 (VEGFR1 concentration without changes on serum VEGF concentration. DAPT reduced tumor vascular density in control mice (280.6 ± 81 vs. 386 ± 59.9 CD31 positive cells/mm 2 , although, it was not statistically significant. Conclusion: It seems that γ-secretase inhibitors can be considered for treatment of disorders with abnormal angiogenesis such as tumor angiogenesis.

  15. Endothelial Progenitor Cells in Tumor Angiogenesis: Another Brick in the Wall

    Directory of Open Access Journals (Sweden)

    Marina Marçola

    2015-01-01

    Full Text Available Until 15 years ago, vasculogenesis, the formation of new blood vessels from undifferentiated cells, was thought to occur only during embryonic development. The discovery of circulating cells that are able to promote vascular regeneration and repair—the so-called endothelial progenitor cells (EPCs—changed that, and EPCs have since been studied extensively. It is already known that EPCs include many subtypes of cells that play a variety of roles in promoting vascular growth. Some EPCs are destined to differentiate into endothelial cells, whereas others are capable of promoting and sustaining angiogenesis through paracrine mechanisms. Vasculogenesis and angiogenesis might constitute complementary mechanisms for postnatal neovascularization, and EPCs could be at the core of this process. Although the formation of new blood vessels from preexisting vasculature plays a beneficial role in many physiological processes, such as wound healing, it also contributes to tumor growth and metastasis. However, many aspects of the role played by EPCs in tumor angiogenesis remain unclear. This review aims to address the main aspects of EPCs differentiation and certain characteristics of their main function, especially in tumor angiogenesis, as well as the potential clinical applications.

  16. The transcriptional coactivator PGC-1alpha mediates exercise-induced angiogenesis in skeletal muscle.

    Science.gov (United States)

    Chinsomboon, Jessica; Ruas, Jorge; Gupta, Rana K; Thom, Robyn; Shoag, Jonathan; Rowe, Glenn C; Sawada, Naoki; Raghuram, Srilatha; Arany, Zoltan

    2009-12-15

    Peripheral arterial disease (PAD) affects 5 million people in the US and is the primary cause of limb amputations. Exercise remains the single best intervention for PAD, in part thought to be mediated by increases in capillary density. How exercise triggers angiogenesis is not known. PPARgamma coactivator (PGC)-1alpha is a potent transcriptional co-activator that regulates oxidative metabolism in a variety of tissues. We show here that PGC-1alpha mediates exercise-induced angiogenesis. Voluntary exercise induced robust angiogenesis in mouse skeletal muscle. Mice lacking PGC-1alpha in skeletal muscle failed to increase capillary density in response to exercise. Exercise strongly induced expression of PGC-1alpha from an alternate promoter. The induction of PGC-1alpha depended on beta-adrenergic signaling. beta-adrenergic stimulation also induced a broad program of angiogenic factors, including vascular endothelial growth factor (VEGF). This induction required PGC-1alpha. The orphan nuclear receptor ERRalpha mediated the induction of VEGF by PGC-1alpha, and mice lacking ERRalpha also failed to increase vascular density after exercise. These data demonstrate that beta-adrenergic stimulation of a PGC-1alpha/ERRalpha/VEGF axis mediates exercise-induced angiogenesis in skeletal muscle.

  17. A peptide fusion protein in hibits angiogenesis and tumorgrowth by blocking VEGF binding to KDR

    Institute of Scientific and Technical Information of China (English)

    2002-01-01

    Vascular endothelial growth factor (VEGF) binding to its tyrosine kinase receptors (KDR/FLK1, Flt-1) induces angiogenesis. In search of the peptides blocking VEGF binding to its receptor KDR/FLK1 to inhibit tumor- angiogenesis and growth, we screened a phage display peptide library with KDR as target protein, and some candidate peptides were isolated. In this study, we cloned the DNA fragment coding the peptide K237 from the library, into a vector pQE42 to express fusion protein DHFR-K237 in E. coli M15. The affection of fusion protein DHFR-K237 on endothelial cell proliferation and angiogenesis was investigated. In vitro, DHFR-K237 could completely block VEGF binding to KDR and significantly inhibit the VEGF-medi- ated proliferation of the human vascular endothelial cells. In vivo, DHFR-K237 inhibited angiogenesis in chick embryo chorioa- llantoric membrane and tumor growth in nude mice. These results suggest that K237 is an effective antagonist of VEGF binding to KDR, and could be a potential agent for cancer biotherapy.

  18. Fetal kidney stem cells ameliorate cisplatin induced acuterenal failure and promote renal angiogenesis

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    AIM To investigate whether fetal kidney stem cells(fKSC) ameliorate cisplatin induced acute renal failure(ARF) in rats and promote renal angiogenesis.METHODS: The fKSC were isolated from rat fetusesof gestation day 16 and expanded in vitro up to 3rdpassage. They were characterized for the expressionof mesenchymal and renal progenitor markers by flowcytometry and immunocytochemistry, respectively.The in vitro differentiation of fKSC towards epitheliallineage was evaluated by the treatment with specificinduction medium and their angiogenic potential bymatrigel induced tube formation assay. To study theeffect of fKSC in ARF, fKSC labeled with PKH26 wereinfused in rats with cisplatin induced ARF and, the bloodand renal tissues of the rats were collected at differenttime points. Blood biochemical parameters werestudied to evaluate renal function. Renal tissues wereevaluated for renal architecture, renal cell proliferationand angiogenesis by immunohistochemistry, renal cellapoptosis by terminal deoxynucleotidyl transferase nickendlabeling assay and early expression of angiogenicmolecules viz . vascular endothelial growth factor (VEGF),hypoxia-inducible factor (HIF)-1α and endothelial nitricoxide synthase (eNOS) by western blot.RESULTS: The fKSC expressed mesenchymal markersviz . CD29, CD44, CD73, CD90 and CD105 as well as renal progenitor markers viz . Wt1, Pax2 and Six2. Theyexhibited a potential to form CD31 and Von Willebrandfactor expressing capillary-like structures and could bedifferentiated into cytokeratin (CK)18 and CK19 positiveepithelial cells. Administration of fKSC in rats with ARF ascompared to administration of saline alone, resulted in asignificant improvement in renal function and histology onday 3 (2.33 ± 0.33 vs 3.50 ± 0.34, P 〈 0.05) and on day7 (0.83 ± 0.16 vs 2.00 ± 0.25, P 〈 0.05). The infusedPKH26 labeled fKSC were observed to engraft in damagedrenal tubules and showed increased proliferation andreduced

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

    Science.gov (United States)

    Martínez, Constanza E.; Smith, Patricio C.; Palma Alvarado, Verónica A.

    2015-01-01

    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. PMID:26539125

  20. Deletion of the endothelial Bmx tyrosine kinase decreases tumor angiogenesis and growth.

    Science.gov (United States)

    Holopainen, Tanja; López-Alpuche, Vanessa; Zheng, Wei; Heljasvaara, Ritva; Jones, Dennis; He, Yun; Tvorogov, Denis; D'Amico, Gabriela; Wiener, Zoltan; Andersson, Leif C; Pihlajaniemi, Taina; Min, Wang; Alitalo, Kari

    2012-07-15

    Bmx, [corrected] also known as Etk, is a member of the Tec family of nonreceptor tyrosine kinases. Bmx is expressed mainly in arterial endothelia and in myeloid hematopoietic cells. Bmx regulates ischemia-mediated arteriogenesis and lymphangiogenesis, but its role in tumor angiogenesis is not known. In this study, we characterized the function of Bmx in tumor growth using both Bmx knockout and transgenic mice. Isogenic colon, lung, and melanoma tumor xenotransplants showed reductions in growth and tumor angiogenesis in Bmx gene-deleted ((-/-)) mice, whereas developmental angiogenesis was not affected. In addition, growth of transgenic pancreatic islet carcinomas and intestinal adenomas was also slower in Bmx(-/-) mice. Knockout mice showed high levels of Bmx expression in endothelial cells of tumor-associated and peritumoral arteries. Moreover, endothelial cells lacking Bmx showed impaired phosphorylation of extracellular signal-regulated kinase (Erk) upon VEGF stimulation, indicating that Bmx contributes to the transduction of vascular endothelial growth factor signals. In transgenic mice overexpressing Bmx in epidermal keratinocytes, tumors induced by a two-stage chemical skin carcinogenesis treatment showed increased growth and angiogenesis. Our findings therefore indicate that Bmx activity contributes to tumor angiogenesis and growth.

  1. Angiogenesis-associated crosstalk between collagens, CXC chemokines, and thrombospondin domain-containing proteins.

    Science.gov (United States)

    Rivera, Corban G; Bader, Joel S; Popel, Aleksander S

    2011-08-01

    Excessive vascularization is a hallmark of many diseases including cancer, rheumatoid arthritis, diabetic nephropathy, pathologic obesity, age-related macular degeneration, and asthma. Compounds that inhibit angiogenesis represent potential therapeutics for many diseases. Karagiannis and Popel [Proc. Natl. Acad. Sci. USA 105(37):13775-13780, 2008] used a bioinformatics approach to identify more than 100 peptides with sequence homology to known angiogenesis inhibitors. The peptides could be grouped into families by the conserved domain of the proteins they were derived from. The families included type IV collagen fibrils, CXC chemokine ligands, and type I thrombospondin domain-containing proteins. The relationships between these families have received relatively little attention. To investigate these relationships, we approached the problem by placing the families of proteins in the context of the human interactome including >120,000 physical interactions among proteins, genes, and transcripts. We built on a graph theoretic approach to identify proteins that may represent conduits of crosstalk between protein families. We validated these findings by statistical analysis and analysis of a time series gene expression data set taken during angiogenesis. We identified six proteins at the center of the angiogenesis-associated network including three syndecans, MMP9, CD44, and versican. These findings shed light on the complex signaling networks that govern angiogenesis phenomena.

  2. Evaluation of Angiogenesis Using Micro-Computed Tomography in a Xenograft Mouse Model of Lung Cancer

    Directory of Open Access Journals (Sweden)

    Rajkumar Savai

    2009-01-01

    Full Text Available Quantitative evaluation of lung tumor angiogenesis using immunohistochemical techniques has been limited by difficulties in generating reproducible data. To analyze intrapulmonary tumor angiogenesis, we used high-resolution micro-computed tomography (micro-CT of lung tumors of mice inoculated with mouse Lewis lung carcinoma (LLC1 or human adenocarcinoma (A549 cell lines. The lung vasculature was filled with the radiopaque silicone rubber, Microfil, through the jugular vein (in vivo application or pulmonary artery (ex vivo application. In addition, human adenocarcinoma lung tumor-bearing mice treated site-specifically with humanized monoclonal antibody (bevacizumab against vascular endothelial growth factor. Quantitative analysis of lung tumor microvessels imaged with micro-CT showed that more vessels (mainly small, <0.02 mm2 were filled using the in vivo (5.4% compared with the ex vivo (2.1% method. Furthermore, bevacizumab-treated lung tumor-bearing mice showed significantly reduced lung tumor volume and lung tumor angiogenesis compared with untreated mice as assessed by micro-CT. Interestingly, microvascularization of mainly the smaller vessels (<0.02 mm2 was reduced after bevacizumab treatment. This observation with micro-CT was nicely correlated with immunohistochemical measurement of microvessels. Therefore, micro-CT is a novel method for investigating lung tumor angiogenesis, and this might be considered as an additional complementary tool for precise quantification of angiogenesis.

  3. 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.

  4. Heparanase and Syndecan-4 Are Involved in Low Molecular Weight Fucoidan-Induced Angiogenesis

    Directory of Open Access Journals (Sweden)

    Oualid Haddad

    2015-10-01

    Full Text Available Induction of angiogenesis is a potential treatment for chronic ischemia. Low molecular weight fucoidan (LMWF, the sulfated polysaccharide from brown seaweeds, has been shown to promote revascularization in a rat limb ischemia, increasing angiogenesis in vivo. We investigated the potential role of two heparan sulfate (HS metabolism enzymes, exostosin-2 (EXT2 and heparanase (HPSE, and of two HS-membrane proteoglycans, syndecan-1 and -4 (SDC-1 and SDC-4, in LMWF induced angiogenesis. Our results showed that LMWF increases human vascular endothelial cell (HUVEC migration and angiogenesis in vitro. We report that the expression and activity of the HS-degrading HPSE was increased after LMWF treatment. The phenotypic tests of LMWF-treated and EXT2- or HPSE-siRNA-transfected cells indicated that EXT2 or HPSE expression significantly affect the proangiogenic potential of LMWF. In addition, LMWF increased SDC-1, but decreased SDC-4 expressions. The effect of LMWF depends on SDC-4 expression. Silencing EXT2 or HPSE leads to an increased expression of SDC-4, providing the evidence that EXT2 and HPSE regulate the SDC-4 expression. Altogether, these data indicate that EXT2, HPSE, and SDC-4 are involved in the proangiogenic effects of LMWF, suggesting that the HS metabolism changes linked to LMWF-induced angiogenesis offer the opportunity for new therapeutic strategies of ischemic diseases.

  5. Endothelial cell Toll-like receptor 4 regulates fibrosis associated angiogenesis in liver

    Science.gov (United States)

    Jagavelu, K; Routray, C; Shergill, U; O’Hara, SP; Faubion, W; Shah, VH

    2010-01-01

    Angiogenesis defines the growth of new blood vessels from pre-existing vascular endothelial networks and corresponds with the wound healing process that is typified by the process of liver fibrosis. Liver fibrosis is also associated with increased endotoxin within the gut lumen and its associated portal circulation. However, the interrelationship of gut endotoxin and its receptor, Toll-like receptor 4 (TLR4), with liver fibrosis and associated angiogenesis remains incompletely defined. RESULT Here we provide evidence, using complementary genetic, molecular, and pharmacologic approaches that the pattern recognition receptor that recognizes endotoxin, TLR4, expressed on liver endothelial cells (LEC), regulates angiogenic responses both in vitro and in vivo. Mechanistic studies reveal a key role for a cognate TLR4 effector protein, MyD88 in this process which culminates in extracellular protease production that regulates LEC invasive capacity, a key step in angiogenesis. Furthermore TLR4 dependent angiogenesis in vivo corresponds with fibrosis in complementary liver models of fibrosis. CONCLUSION These studies provide evidence that the TLR4 pathway in LEC regulates angiogenesis through its MyD88 effector protein by regulating extracellular protease production and that this process is linked to the development of liver fibrosis. PMID:20564354

  6. 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.

  7. Adiponectin promotes VEGF-A-dependent angiogenesis in human chondrosarcoma through PI3K, Akt, mTOR, and HIF-α pathway

    OpenAIRE

    Lee, Hsiang-Ping; Lin, Chih-Yang; Shih, Jhao-Sheng; Fong, Yi-Chin; Wang, Shih-Wei; Li, Te-Mao; Tang, Chih-Hsin

    2015-01-01

    Chondrosarcoma is a type of highly malignant tumor with a potent capacity to invade locally and cause distant metastasis. Adiponectin is a protein hormone secreted predominantly by differentiated adipocytes. On the other hand, angiogenesis is a critical step in tumor growth and metastasis. However, the relationship of adiponectin with vascular endothelial growth factor-A (VEGF-A) expression and angiogenesis in human chondrosarcoma is mostly unknown. In this study we first demonstrated that th...

  8. Vascular Endothelial Growth Factor, diagnostic and therapeutic aspects

    NARCIS (Netherlands)

    Kusumanto, Yoka Hadiani

    2006-01-01

    This thesis focuses on the diagnostic and therapeutic potential of Vascular Endothelial Growth Factor, an angiogenic growth factor. Since the recognition of VEGF’s pivotal role in physiological and pathological angiogenesis research has evolved from cell culture and animal experiments to application

  9. Vascular remodeling underlies rebleeding in hemophilic arthropathy.

    Science.gov (United States)

    Bhat, Vikas; Olmer, Merissa; Joshi, Shweta; Durden, Donald L; Cramer, Thomas J; Barnes, Richard Fw; Ball, Scott T; Hughes, Tudor H; Silva, Mauricio; Luck, James V; Moore, Randy E; Mosnier, Laurent O; von Drygalski, Annette

    2015-11-01

    Hemophilic arthropathy is a debilitating condition that can develop as a consequence of frequent joint bleeding despite adequate clotting factor replacement. The mechanisms leading to repeated spontaneous bleeding are unknown. We investigated synovial, vascular, stromal, and cartilage changes in response to a single induced hemarthrosis in the FVIII-deficient mouse. We found soft-tissue hyperproliferation with marked induction of neoangiogenesis and evolving abnormal vascular architecture. While soft-tissue changes were rapidly reversible, abnormal vascularity persisted for months and, surprisingly, was also seen in uninjured joints. Vascular changes in FVIII-deficient mice involved pronounced remodeling with expression of α-Smooth Muscle Actin (SMA), Endoglin (CD105), and vascular endothelial growth factor, as well as alterations of joint perfusion as determined by in vivo imaging. Vascular architecture changes and pronounced expression of α-SMA appeared unique to hemophilia, as these were not found in joint tissue obtained from mouse models of rheumatoid arthritis and osteoarthritis and from patients with the same conditions. Evidence that vascular changes in hemophilia were significantly associated with bleeding and joint deterioration was obtained prospectively by dynamic in vivo imaging with musculoskeletal ultrasound and power Doppler of 156 joints (elbows, knees, and ankles) in a cohort of 26 patients with hemophilia at baseline and during painful episodes. These observations support the hypothesis that vascular remodeling contributes significantly to bleed propagation and development of hemophilic arthropathy. Based on these findings, the development of molecular targets for angiogenesis inhibition may be considered in this disease.

  10. Complex role of matrix metalloproteinases in angiogenesis

    Institute of Scientific and Technical Information of China (English)

    SANGQINGXIANGAMY

    1998-01-01

    Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) play a significant role in regulating angiogenesis,the process of new blood vessel formation.Interstitial collagenase (MMP-1),72kDa gelatinase A/type IV collagenase (MMP-2),and 92 kDA gelatinase B/type IV collagenase (MMP-9) dissolve extracellular matrix (ECM) and may initiate and promote angiogenesis.TIMP-1,TIMP-2,TIMP-3,and possibly,TIMP-4 inhibit neovascularization.A new paradign is emerging that matrilysin (MMP-7),MMP-9,and metalloelastase (MMP-12) may block angiogenesis by converting plasminogen to angiostatin,which is one of the most potent angiogenesis antagonists.MMPs and TIMPs play a complex role in regulating angiogenesis.An understanding of the biochemical and cellular pathways and mechanisms of angiogenesis will provide important information to allow the control of angiogenesis,e.g.the stimulation of angiogenesis for coronary collateral circulation formation;while the inhibition for treating arthritis and cancer.

  11. Organoarsenic Roxarsone Promotes Angiogenesis In Vivo.

    Science.gov (United States)

    Zhang, Yumei; Wang, Yujing; Lu, Qianqian; Xin, Wenfang; Cui, Weibo; Zhu, Jiaqiao

    2016-04-01

    Roxarsone, an organoarsenic feed additive, is widely used worldwide to promote animal growth. It has been found to exhibit a higher angiogenic index than As(III) at lower concentrations and to promote angiogenic phenotype in human endothelial cell in vitro. Little research has focused on the potential angiogenic effect of roxarsone in vitro or in vivo. Here, we investigated the pro-angiogenic effect of roxarsone in vivo. The effects of 0.1-10.0 μM roxarsone were tested in the rat endothelial cell Matrigel plug assay, chicken chorioallantoic membrane (CAM) model and MCF-7 cell xenograft tumour model; 10 ng/mL vascular endothelial growth factor (VEGF) was used as a positive control and PBS as a negative control. Roxarsone significantly increased the volume, weight and haemoglobin content of the Matrigel plugs compared to PBS group (p roxarsone exerted the most significant effects. H&E staining and CD31 immunochemistry revealed obviously more new vessels or capillary-like structures in the plugs of the roxarsone and VEGF groups. Roxarsone significantly increased the numbers of primary/secondary vessels and area of vessels in the CAM assay and obviously increased tumour weight and volume in the xenograft model compared to PBS (p roxarsone groups, with less necrosis apparent in the VEGF-treated tumours. The growth of endothelial cells and VEGF level was obviously affected at blockade of VEGF and its receptor Flt-1/Flk-1 by SU5416 or its antibody in vitro. This study demonstrates roxarsone promotes angiogenesis in vivo, and a VEGF/VEGFR mechanism may be involved.

  12. Anatomical and microstructural imaging of angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Kiessling, Fabian [University of Aachen (RWTH), Experimental Molecular Imaging, Aachen (Germany); Razansky, Daniel [Technical University of Munich and Helmholtz Center Munich, Institute for Biological and Medical Imaging, Munich (Germany); Alves, Frauke [University Medical Center, Department of Haematology and Oncology, Goettingen (Germany); Max-Planck-Institute for Experimental Medicine, Department of Molecular Biology of Neuronal Signals, Goettingen (Germany)

    2010-08-15

    This article reviews and discusses different options for visualizing the microarchitecture of vessels ex vivo and in vivo with respect to reliability, practicability and availability. The investigation of angiogenesis by standard histological methods, like microvessel density counts, is limited since the three-dimensional (3-D) architecture and the functionality of vessels cannot be considered properly. Coregistration of immunostained images of vessels may be performed but is time consuming and often not sufficiently accurate. Confocal fluorescence microscopy is an alternative, but only enables 3-D stacks of less than 500 nm in thickness. Multiphoton microscopy and other advanced technologies, such as optical coherence tomography and optical frequency domain imaging, provide a deeper view into tissues and allow for in vivo imaging of microvessels, which is a precondition for longitudinal studies. Besides these microscopic techniques, the vascularization in larger tissue samples can be investigated using corrosion casts in combination with scanning electron microscopy, or microcomputed tomography ({mu}CT). Furthermore, recent improvements in {mu}CT technology open up new perspectives for in vivo scans with high resolution and tolerable X-ray doses. Also 3-D contrast-enhanced high-frequency ultrasound has been shown to be sensitive for angiogenic vessels and even distinguishing between mature and immature vessels appears feasible. Microvessel architecture can also be visualized by MRI. Here, T1-weighted angiography techniques after injection of blood pool contrast agents appear preferable. Optoacoustic tomographic imaging has more recently shown promise for high-resolution in vivo mapping of the microvasculature in rodents using intrinsic haemoglobin-based contrast and exogenous contrast agents. (orig.)

  13. Angiogenesis in tissue-engineered small intestine.

    Science.gov (United States)

    Gardner-Thorpe, James; Grikscheit, Tracy C; Ito, Hiromichi; Perez, Alexander; Ashley, Stanley W; Vacanti, Joseph P; Whang, Edward E

    2003-12-01

    Tissue-engineered intestine offers promise as a potential novel therapy for short bowel syndrome. In this study we characterized the microvasculature and angiogenic growth factor profile of the engineered intestine. Twenty-three tissue-engineered small intestinal grafts were harvested from Lewis rat recipients 1 to 8 weeks after implantation. Architectural similarity to native bowel obtained from juvenile rats was assessed with hematoxylin and eosin-stained sections. Capillary density, measured after immunohistochemical staining for CD34, was expressed as number of capillaries per 1000 nuclei. Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) tissue levels were measured by ELISA and normalized to total protein. Over the 8-week period cysts increased in volume (0.5 cm(3) at week 1 versus 12.6 cm(3) at week 8) and mass (1.30 +/- 0.29 versus 9.74 +/- 0.3 g; mean +/- SEM). Muscular and mucosal layers increased in thickness, but capillary density remained constant (82.95 +/- 4.81 capillaries per 1000 nuclei). The VEGF level was significantly higher in juvenile rat bowel than in engineered cyst (147.6 +/- 23.9 versus 42.3 +/- 3.4 pg/mg; p < 0.001). Tissue bFGF levels were also higher (315 +/- 65.48 versus 162.3 +/- 15.09 pg/mg; p < 0.05). The mechanism driving angiogenesis differs in engineered intestine and in normal bowel. VEGF and bFGF delivery may prove useful for bioengineering of intestine.

  14. Angiogenesis in vestibular schwannomas: expression of extracellular matrix factors MMP-2, MMP-9, and TIMP-1

    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 t...... targets the angiogenic process by investigation of tumor expression of MMP-2, MMP-9, and tissue inhibitors of metalloproteinase (TIMP)-1. A possible correlation with gender, patient age, symptom duration, tumor size, and the absolute and relative growth rate is explored....

  15. vascular hemiplegia

    OpenAIRE

    Voto Bernales, Jorge; Facultad de Medicina, Universidad Nacional Mayor de San Marcos, Lima, Perú

    2014-01-01

    The vascular hemiplegia is the functional disorder of a lateral half of the body produced by alterations of cerebral vessels. Should review the concepts of this common condition, with the dual aim of expanding its nosographic value and considering the hemiplegic patient as worthy of the highest professional care La hemiplejia vascular, es el trastorno funcional de una mitad lateral del cuerpo producido por alteraciones de los vasos cerebrales. Conviene revisar los conceptos sobre esta frec...

  16. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine.

    Energy Technology Data Exchange (ETDEWEB)

    Martino, Mikael M.; Brkic, Sime; Bovo, Emmanuela; Burger, Maximilian; Schaefer, Dirk J.; Wolff, Thomas; Gurke, Lorenz; Briquez, Priscilla S.; Larsson, Hans M.; Gianni-Barrera, Roberto; Hubbell, Jeffrey A.; Banfi, Andrea

    2015-04-01

    Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF) is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localization of angiogenic signals in the extracellular matrix (ECM) is crucial to ensure the proper assembly and maturation of new vascular structures. Here, we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of ECM to optimize the signaling microenvironment of vascular growth factors.

  17. Extracellular matrix and growth factor engineering for controlled angiogenesis in regenerative medicine

    Directory of Open Access Journals (Sweden)

    Mikaël M Martino

    2015-04-01

    Full Text Available Blood vessel growth plays a key role in regenerative medicine, both to restore blood supply to ischemic tissues and to ensure rapid vascularization of clinical-size tissue-engineered grafts. For example, vascular endothelial growth factor (VEGF is the master regulator of physiological blood vessel growth and is one of the main molecular targets of therapeutic angiogenesis approaches. However, angiogenesis is a complex process and there is a need to develop rational therapeutic strategies based on a firm understanding of basic vascular biology principles, as evidenced by the disappointing results of initial clinical trials of angiogenic factor delivery. In particular, the spatial localization of angiogenic signals in the extracellular matrix is crucial to ensure the proper assembly and maturation of new vascular structures. Here we discuss the therapeutic implications of matrix interactions of angiogenic factors, with a special emphasis on VEGF, as well as provide an overview of current approaches, based on protein and biomaterial engineering that mimic the regulatory functions of extracellular matrix to optimize the signaling microenvironment of vascular growth factors.

  18. Non-small-cell lung carcinoma tumor growth without morphological evidence of neo-angiogenesis.

    Science.gov (United States)

    Pezzella, F; Pastorino, U; Tagliabue, E; Andreola, S; Sozzi, G; Gasparini, G; Menard, S; Gatter, K C; Harris, A L; Fox, S; Buyse, M; Pilotti, S; Pierotti, M; Rilke, F

    1997-11-01

    Neoplastic growth is usually dependent on blood supply, and it is commonly accepted that this is provided by the formation of new vessels. However, tumors may be able to grow without neovascularization if they find a suitable vascular bed available. We have investigated the pattern of vascularization in a series of 500 primary stage I non-small-cell lung carcinomas. Immunostaining of endothelial cells has highlighted four distinct patterns of vascularization. Three patterns (which we called basal, papillary, and diffuse) have in common the destruction of normal lung and the production of newly formed vessels and stroma. The fourth pattern, which we called alveolar or putative nonangiogenic, was observed in 16% (80/500) of the cases and is characterized by lack of parenchymal destruction and absence of both tumor associated stroma and new vessels. The only vessels present were the ones in the alveolar septa, and their presence highlighted, through the whole tumor, the lung alveoli filled up by the neoplastic cells. This observation suggests that, if an appropriate vascular bed is available, a tumor can exploit it and grows without inducing neo-angiogenesis. This could have implications for strategies aimed at inhibiting tumor growth by vascular targeting or inhibition of angiogenesis.

  19. 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.

  20. Inhibitory Effects of Quercetin on Angiogenesis of Experimental Mammary Carcinoma

    Institute of Scientific and Technical Information of China (English)

    Lingquan Kong; Kainan Wu; Hui Lin

    2005-01-01

    OBJECTIVE To explore the inhibitory effects of quercetin on angiogenesis of experimental mammary carcinoma.METHODS A 7,12-dimethylbenzanthracene (DMBA)-induced animal model of mammary carcinoma was established in rats. Seventy-nine female Sprague-Dawly rats were randomized into 4 groups namely, DMBA, DMBA with tamoxifen (TAM), DMBA with quercetin and control agents identified as group A, B, C and D respectively. Treatment was for 28 weeks. Samples of breast tissues were collected for histopathological observation and microvessel density (MVD) estimation by light microscopy. The expression of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and the protein product of H-ras were examined by immunohistochemical staining.tumor diameter of group A (76.2%, 2.37cm) were significantly higher than that in group B (40.9%, 1.82cm), C (45.5%, 1.71cm) and D (0%, 0cm) (P<0.05). There was no significant difference between groups B and C (P >0.05), which indicated that quercetin inhibited the incidence and growth of ing for VEGF, bFGF and the H-ras protein product showed significant differences between groups A and B, as well as groups A and C (P < 0.05), but no significant difference between groups B and C (P>0.05).CONCLUSION Quercetin can reduce the DMBA- induced mammary carcinoma incidence and tumor growth.The following mechanisms may be recausing inhibition of proliferation of the tumor cells and tumor angiogenesis.as VEGF and bFGF, so that angiogenesis in the mammary carcinomas is suppressed, with decreased mammary MVD in the rats receiving quercetin treatment.

  1. Galectin-3 induces pulmonary artery endothelial cell morphogenesis and angiogenesis

    Institute of Scientific and Technical Information of China (English)

    ZHANG Li; LI Yu-mei; WANG Xiao-yan; ZHU Da-ling

    2016-01-01

    AIM:Increasing evidence suggests that carbohydrate-binding proteins play an essential role in tumor growth and metastasis .Ga-lectin-3, a multifunctional protein of an expanding family of β-galactoside-binding animal lectins , is the major nonintegrin cellular laminin-binding protein , and is implicated in a variety of biologic events , such as inflammation and angiogenesis .Because galectin-3 expression was shown to participate in mediating tumor angiogenesis and initiate signaling cascades in several diseases .We hypothe-sized that galectin-3 may promote pulmonary vascular endothelial neovascularization .METHODS:Hypoxic and MCT rat model of pul-monary artery remodeling was used .The mRNA and protein levels of galectin-3 in rats were measured by in situ hybrization and West-ern blot analysis.Endothelial cell (EC) proliferation, migration and tube formation were measured using MTT , cell scratch and Matri-gel assays, respectively.Protein expression was quantitated by Western blot analysis .LC 3A/B staining was detected with cellular im-munofluorescence staining .RESULTS:We found that galectin-3 was localized on the intima and adventitial wall .Galectin-3 was in-creased after rat hypoxia and MCT administration .Galectin-3 promoted EC proliferation , migration and tube formation , while its roles were reversed by RNA interference.Galectin-3 induced Atg 5, Beclin-1, LAMP-2, and LC 3A/B expression increases.Galectin-3 al-so increased LC 3A/B staining in ECs.Akt/mTOR and GSK-3βsignaling pathways were activated after galectin-3 treated ECs using its specific phosphorylation antibodies , while blocked it with LY294002 inhibited cell autophagy and EC dynamic alterations induced by galectin-3.CONCLUSION:These findings demonstrate that galectin-3 can induce an Akt signaling cascade leading to cell autoph-agy, and then the differentiation and angiogenesis of pulmonary artery endothelial cells .

  2. Ig-like domain 6 of VCAM-1 is a potential therapeutic target in TNFα-induced angiogenesis.

    Science.gov (United States)

    Kim, Taek-Keun; Park, Chang Sik; Na, Hee-Jun; Lee, Kangseung; Yoon, Aerin; Chung, Junho; Lee, Sukmook

    2017-02-17

    Tumor necrosis factor alpha (TNFα)-induced angiogenesis plays important roles in the progression of various diseases, including cancer, wet age-related macular degeneration, and rheumatoid arthritis. However, the relevance and role of vascular cell adhesion molecule-1 (VCAM-1) in angiogenesis have not yet been clearly elucidated. In this study, VCAM-1 knockdown shows VCAM-1 involvement in TNFα-induced angiogenesis. Through competitive blocking experiments with VCAM-1 Ig-like domain 6 (VCAM-1-D6) protein, we identified VCAM-1-D6 as a key domain regulating TNFα-induced vascular tube formation. We demonstrated that a monoclonal antibody specific to VCAM-1-D6 suppressed TNFα-induced endothelial cell migration and tube formation and TNFα-induced vessel sprouting in rat aortas. We also found that the antibody insignificantly affected endothelial cell viability, morphology and activation. Finally, the antibody specifically blocked VCAM-1-mediated cell-cell contacts by directly inhibiting VCAM-1-D6-mediated interaction between VCAM-1 molecules. These findings suggest that VCAM-1-D6 may be a potential novel therapeutic target in TNFα-induced angiogenesis and that antibody-based modulation of VCAM-1-D6 may be an effective strategy to suppress TNFα-induced angiogenesis.

  3. A novel role for platelet secretion in angiogenesis: mediating bone marrow-derived cell mobilization and homing.

    Science.gov (United States)

    Feng, Weiyi; Madajka, Maria; Kerr, Bethany A; Mahabeleshwar, Ganapati H; Whiteheart, Sidney W; Byzova, Tatiana V

    2011-04-07

    Angiogenesis alleviates hypoxic stress in ischemic tissues or during tumor progression. In addition to endothelial cell proliferation and migration, the angiogenic process requires bone marrow-derived cell (BMDC) recruitment to sites of neovascularization. However, the mechanism of communication between hypoxic tissues and the BM remains unknown. Using 2 models of hypoxia-induced angiogenesis (ischemic hindlimb surgery and subcutaneous tumor growth), we show that platelet infusion promotes BMDC mobilization into the circulation, BMDC recruitment into growing neovasculature, tumor vascularization, and blood flow restoration in ischemic limbs, whereas platelet depletion inhibits these effects. Thus, platelets are required for BMDC recruitment into ischemia-induced vasculature. Secretion of platelet α-granules, but neither dense granules nor platelet aggregation is crucial for BMDC homing and subsequent angiogenesis, as determined using VAMP-8(-/-), Pearl, and integrin Beta 3(-/-) platelets. Finally, platelets sequester tumor-derived promoters of angiogenesis and BMDC mobilization, which are counterbalanced by the antiangiogenic factor thrombospondin-1. A lack of thrombospondin-1 in platelets leads to an imbalance in proangiogenic and antiangiogenic factors and accelerates tumor growth and vascularization. Our data demonstrate that platelets stimulate BMDC homing in a VAMP-8-dependent manner, revealing a previously unknown role for platelets as key mediators between hypoxic tissues and the bone marrow during angiogenesis.

  4. Independent prognostic value of angiogenesis and the level of plasminogen activator inhibitor type 1 in breast cancer patients

    DEFF Research Database (Denmark)

    Hansen, S.; Overgaard, Jens; Rose, C.

    2003-01-01

    Tumour angiogenesis and the levels of plasminogen activator inhibitor type 1 (PAI-1) are both informative prognostic markers in breast cancer. In cell cultures and in animal model systems, PAI-1 has a proangiogenic effect. To evaluate the interrelationship of angiogenesis and the PAI-1 level in b...... and the Chalkley count are independent prognostic markers for recurrence-free survival in patients with primary breast cancer, suggesting that the prognostic impact of PAI-1 is not only based on its involvement in angiogenesis.......Tumour angiogenesis and the levels of plasminogen activator inhibitor type 1 (PAI-1) are both informative prognostic markers in breast cancer. In cell cultures and in animal model systems, PAI-1 has a proangiogenic effect. To evaluate the interrelationship of angiogenesis and the PAI-1 level...... in breast cancer, we have evaluated the prognostic value of those factors in a total of 228 patients with primary, unilateral, invasive breast cancer, evaluated at a median follow-up time of 12 years. Microvessels were immunohistochemically stained by antibodies against CD34 and quantitated by the Chalkley...

  5. Overexpression of Wnt5a Promotes Angiogenesis in NSCLC

    Directory of Open Access Journals (Sweden)

    Lingli Yao

    2014-01-01

    Full Text Available To evaluate Wnt5a expression and its role in angiogenesis of non-small-cell lung cancer (NSCLC, immunohistochemistry and CD31/PAS double staining were performed to examine the Wnt5a expression and we analyze the relationships between Wnt5a and microvessel density (MVD, vasculogenic mimicry (VM, and some related proteins. About 61.95% of cases of 205 NSCLC specimens exhibited high expression of Wnt5a. Wnt5a expression level was upregulated in the majority of NSCLC tissues, especially in squamous cell carcinoma, while its expression level in adenocarcinoma was the lowest. Wnt5a was also found more frequently expressed in male patients than in female patients. Except for histological classification and gender, little association was found between Wnt5a and clinicopathological features. Moreover, Wnt5a was significantly correlated with prognosis. Overall, Wnt5a-positive expression in patients with NSCLC indicated shorter survival time. As for vascularization in NSCLC, Wnt5a showed close association with VM and MVD. In addition, Wnt5a was positively related with β-catenin-nu, VE-cadherin, MMP2, and MMP9. The results demonstrated that overexpression of Wnt5a may play an important role in NSCLC angiogenesis and it may function via canonical Wnt signal pathway. This study will provide evidence for further research on NSCLC and also will provide new possible target for NSCLC diagnosis and therapeutic strategies.

  6. Notch Signaling in Vascular Smooth Muscle Cells.

    Science.gov (United States)

    Baeten, J T; Lilly, B

    2017-01-01

    The Notch signaling pathway is a highly conserved pathway involved in cell fate determination in embryonic development and also functions in the regulation of physiological processes in several systems. It plays an especially important role in vascular development and physiology by influencing angiogenesis, vessel patterning, arterial/venous specification, and vascular smooth muscle biology. Aberrant or dysregulated Notch signaling is the cause of or a contributing factor to many vascular disorders, including inherited vascular diseases, such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, associated with degeneration of the smooth muscle layer in cerebral arteries. Like most signaling pathways, the Notch signaling axis is influenced by complex interactions with mediators of other signaling pathways. This complexity is also compounded by different members of the Notch family having both overlapping and unique functions. Thus, it is vital to fully understand the roles and interactions of each Notch family member in order to effectively and specifically target their exact contributions to vascular disease. In this chapter, we will review the Notch signaling pathway in vascular smooth muscle cells as it relates to vascular development and human disease.

  7. Angiogenesis in Acute Myeloid Leukemia and Opportunities for Novel Therapies

    Directory of Open Access Journals (Sweden)

    Angelica Trujillo

    2012-01-01

    Full Text Available Acute myeloid leukemia (AML arises from neoplastic transformation of hematopoietic stem and progenitor cells, and relapsed disease remains one of the greater challenges in treating this hematologic malignancy. This paper focuses on angiogenic aspects of AML including the significance and prognostic value of bone marrow microvessel density and circulating cytokine levels. We show three general mechanisms whereby AML exploits angiogenic pathways, including direct induction of angiogenesis, paracrine regulation, and autocrine stimulation. We also present early evidence that leukemia cells contribute directly to vascular endothelia. Novel treatment strategies are proposed, and a review of relevant antiangiogenic clinical trials is presented. By understanding how blood vessels can serve as a reservoir for refractory and relapsed AML, new diagnostics and promising treatment strategies can be developed.

  8. Heparanase—A Link between Coagulation, Angiogenesis, and Cancer

    Directory of Open Access Journals (Sweden)

    Yona Nadir

    2012-01-01

    Full Text Available Heparanase that was cloned from and is abundant in the placenta is implicated in cell invasion, tumor metastasis, and angiogenesis. Recently we have demonstrated that heparanase may also affect the hemostatic system in a non-enzymatic manner. Heparanase was shown to up-regulate tissue factor (TF expression and interact with tissue factor pathway inhibitor (TFPI on the cell surface, leading to dissociation of TFPI from the cell membrane of endothelial and tumor cells, resulting in increased cell surface coagulation activity. More recently, we have shown that heparanase directly enhances TF activity, resulting in increased factor Xa production and activation of the coagulation system. Data indicate increased levels and possible involvement of heparanase in vascular complications in pregnancy. Taking into account the prometastatic and proangiogenic functions of heparanase, overexpression in human malignancies, and abundance in platelets and placenta, its involvement in the coagulation machinery is an intriguing novel arena for further research.

  9. Vascular Endothelial Growth Factor Receptor Type 1 Signaling Prevents Delayed Wound Healing in Diabetes by Attenuating the Production of IL-1β by Recruited Macrophages.

    Science.gov (United States)

    Okizaki, Shin-Ichiro; Ito, Yoshiya; Hosono, Kanako; Oba, Kazuhito; Ohkubo, Hirotoki; Kojo, Ken; Nishizawa, Nobuyuki; Shibuya, Masabumi; Shichiri, Masayoshi; Majima, Masataka

    2016-06-01

    The persistence of proinflammatory macrophages, which are recruited to the granulation tissue, impairs the healing of diabetic wounds. Herein, we examined the role of vascular endothelial growth factor receptor type 1 (VEGFR1) signaling in streptozotocin (STZ)-induced diabetic wound healing. Angiogenesis, lymphangiogenesis, and the healing of full-thickness skin wounds were impaired in STZ-treated wild-type (WT) mice compared with vehicle-treated WT mice, with attenuated recruitment of VEGFR1-positive macrophages expressing vascular endothelial growth factor (VEGF)-A, VEGF-C, and VEGF-D to the wound granulation tissue. These phenomena were even more prevalent in STZ-treated VEGFR1 tyrosine kinase knockout mice (VEGFR1 TK(-/-) mice). STZ-treated WT mice, but not STZ-treated VEGFR1 TK(-/-) mice, showed accelerated wound healing when treated with placenta growth factor. Compared with that of STZ-treated WT mice, the wound granulation tissue of STZ-treated VEGFR1 TK(-/-) mice contained more VEGFR1-positive cells expressing IL-1β [a classic (M1) activated macrophage marker] and fewer VEGFR1-positive cells expressing the mannose receptor [CD206; an alternatively activated (M2) macrophage marker]. Treatment of STZ-treated VEGFR1 TK(-/-) mice with an IL-1β-neutralizing antibody restored impaired wound healing and angiogenesis/lymphangiogenesis and induced macrophages in the wound granulation tissue to switch to an M2 phenotype. Taken together, these results suggest that VEGFR1 signaling plays a role in regulating the balance between macrophage phenotypes in STZ-induced diabetic wounds, prevents impaired diabetic wound healing, and promotes angiogenesis/lymphangiogenesis.

  10. Different role of COX-2 and angiogenesis in canine inflammatory and non-inflammatory mammary cancer.

    Science.gov (United States)

    Clemente, Mónica; Sánchez-Archidona, Ana Rodríguez; Sardón, David; Díez, Lucía; Martín-Ruiz, Asunción; Caceres, Sara; Sassi, Francesco; Dolores Pérez-Alenza, M; Illera, Juan C; Dunner, Susana; Peña, Laura

    2013-08-01

    Human inflammatory breast cancer (IBC) and canine inflammatory mammary cancer (IMC) are the most aggressive and fatal types of mammary cancer, and both have a very poor prognosis and low survival rate. Human IBC is characterised by exacerbated angiogenesis, lymphangiogenesis, and lymphangiotropism. Lymphangiotropism is also characteristic of IMC, but microvascular density (MVD) and lymphangiogenesis have not been previously studied in canine IMC. In this study immunohistochemical expression of several angiogenesis-related factors (cyclooxygenase [COX]-2, vascular endothelial growth factors A and D [VEGF-A, VEGF-D], and vascular endothelial growth factor receptor 3 [VEGFR-3]), MVD, lymphatic proliferation index (LPI), and Ki-67 tumour proliferation index (PI) were studied in 21 canine IMC samples, 20 canine high-grade malignant non-IMC mammary tumours (MMTs), and four normal mammary gland samples (NMGs). All mammary neoplasms were histologically categorised as grade III. COX-2 values were also analysed by RT-PCR in seven IMCs, six MMTs and four NMGs. The expressions of COX-2, VEGF-A, and VEGF-D were significantly higher in IMC, MVD and LPI tumours, but not PI. In MMTs, COX-2 immunoexpression was significantly associated with VEGF-A, while in IMCs COX-2 was associated with VEGF-D (lymphangiogenic factor), its receptor VEGFR-3, and LPI. These results suggested that lymphangiogenic pathway stimulation isa specific role of COX-2 in IMC angiogenesis, which justifies the use of COX-2-based targeted palliative therapies in dogs. The exacerbated angiogenesis and lymphangiogenesis and the increased expression of angiogenesis-related factors further support canine IMC as a natural model for the study of human IBC.

  11. 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. 

  12. Hypoxia inducible factor: It’s role in angiogenesis and tumor

    Directory of Open Access Journals (Sweden)

    Mozhgan Jahani

    2016-02-01

    Full Text Available Angiogenesis, as the process of new vessel formation from pre-existing vessels is dependent on a delicate equilibrium between endogenous angiogenic and antiangiogenic factors. However, under pathological conditions, this tight regulation becomes lost which can result in the formation of the different diseases such as cancer. Angiogenesis is a complex process that includes many gene products that are produced by different cells. Each of the processes influenced by specific genes that their expression can be regulated by hypoxi inducible factor-1 (HIF-1. Hypoxia, the imbalance between the oxygen in need and the oxygen available, usually occurs in tumors and ischemic cardiovascular diseases. In order to overcome this challenge, tumors regulate and control the expression of genes related to angiogenesis, cell cycle and metabolism using hypoxia-inducible factor 1 (HIF-1. HIF-1 was first recognized as a transcription factor involved in hypoxia-induced erythropoietin expression. As angiogenesis pathway molecules are being described, this factor has been characterized as a key transcription regulator for these molecules. In this review article, after discussing HIF-1 structure and characterization, the role of this important factor in angiogenesis and cancer as a pathological case and finally, the clinical applications has been evaluated. Articles related to the key words of hypoxia, HIF-1 and angiogenesis were searched from valid databases such as Springer Link, google scholar, Pubmed and Sciencedirect. Then, the articles related to the role of hypoxia and HIF-1 in activation of genes that are involved in angiogenesis and cancer were searched and selected for this study. Studies show that, HIF-1 activation of genes including vascular endothelial growth factor (VEGF, angiopoietin-1 (Ang-1 and angiopoietin-2 (Ang-2, etc., induced angiogenesis in the tumor cells. Furthermore, the activation of genes such as insulin-like growth factor 2 (IGF2

  13. The development of the vascular system: a historical overview.

    Science.gov (United States)

    Ribatti, Domenico; Nico, Beatrice; Crivellato, Enrico

    2015-01-01

    Development of the vascular system involves a complex sequence of inductive and differentiating signals leading to vasculogenesis and/or angiogenesis. Dissecting and exploring this process in its multifaceted morphological and molecular aspects has represented a basic contribution and a fascinating adventure in the history of biology. Vasculogenesis, that is de novo formation of vascular channels, initiates early during embryo development and prevails at the beginning of embryo patterning and organ formation. Angiogenesis, the process of shaping new vessels from preexisting blood vessels, mainly operates during postnatal life. In this historical introduction, we try to retrace the early steps of scientific speculation on vascular development and to recapitulate the principal paths leading to our present appreciation of blood vessel formation.

  14. Clinical Decision Support for Vascular Disease in Community Family Practice

    Science.gov (United States)

    Keshavjee, K; Holbrook, AM; Lau, E; Esporlas-Jewer, I; Troyan, S

    2006-01-01

    The COMPETE III Vascular Disease Tracker (C3VT) is a personalized, Web-based, clinical decision support tool that provides patients and physicians access to a patient’s 16 individual vascular risk markers, specific advice for each marker and links to best practices in vascular disease management. It utilizes the chronic care model1 so that physicians can better manage patients with chronic diseases. Over 1100 patients have been enrolled into the COMPETE III study to date.

  15. Regulation of angiogenesis, mural cell recruitment and adventitial macrophage behavior by Toll-like receptors.

    Science.gov (United States)

    Aplin, Alfred C; Ligresti, Giovanni; Fogel, Eric; Zorzi, Penelope; Smith, Kelly; Nicosia, Roberto F

    2014-01-01

    The angiogenic response to injury can be studied by culturing rat or mouse aortic explants in collagen gels. Gene expression studies show that aortic angiogenesis is preceded by an immune reaction with overexpression of Toll-like receptors (TLRs) and TLR-inducible genes. TLR1, 3, and 6 are transiently upregulated at 24 h whereas TLR2, 4, and 8 expression peaks at 24 h but remains elevated during angiogenesis and vascular regression. Expression of TLR5, 7 and 9 steadily increases over time and is highest during vascular regression. Studies with isolated cells show that TLRs are expressed at higher levels in aortic macrophages compared to endothelial or mural cells with the exception of TLR2 and TLR9 which are more abundant in the aortic endothelium. LPS and other TLR ligands dose dependently stimulate angiogenesis and vascular endothelial growth factor production. TLR9 ligands also influence the behavior of nonendothelial cell types by blocking mural cell recruitment and inducing formation of multinucleated giant cells by macrophages. TLR9-induced mural cell depletion is associated with reduced expression of the mural cell recruiting factor PDGFB. The spontaneous angiogenic response of the aortic rings to injury is reduced in cultures from mice deficient in myeloid differentiation primary response 88 (MyD88), a key adapter molecule of TLRs, and following treatment with an inhibitor of the NFκB pathway. These results suggest that the TLR system participates in the angiogenic response of the vessel wall to injury and may play an important role in the regulation of inflammatory angiogenesis in reactive and pathologic processes.

  16. Inhibiting angiogenesis with human single-chain variable fragment antibody targeting VEGF.

    Science.gov (United States)

    Hosseini, Hossien; Rajabibazl, Masoumeh; Ebrahimizadeh, Walead; Dehbidi, Gholamreza Rafiei

    2015-01-01

    Vascular endothelial growth factor (VEGF) is a highly specific angiogenesis factor which has crucial roles in the angiogenesis of tumors. Anti-angiogenesis agents can inhibit growth and metastasis of tumor cells. Single-chain variable fragments (scFv) have the same affinity as whole antibodies and smaller size, thus result in more tissue permeability and higher production yield. In this research we aim to isolate a human scFv antibody against VEGF that inhibits angiogenesis. For that, we have used human scFv phage library to isolate a specific scFv antibody against binding site of VEGF. The human scFv phage library was amplified according to the manufacture protocol and panned against recombinant VEGF. ScFv antibody was isolated after five rounds of panning. Phage ELISA was used for detection of the highest affinity binder (HR6). Soluble HR6 scFv was expressed in non-suppressor strain of Escherichia coli HB2151 and purified using Ni-NTA chromatography. In vivo and in vitro function of the HR6 scFv was analyzed by chorioallantoic membrane assay and endothelial cell proliferation assay on VEGF stimulated HUVECs. Result of the cross reactivity showed that HR6 scFv specifically bounds to VEGF. The affinity was calculated to be 1.8×10(-7)M. HR6 could stop HUVEC proliferation in a dose dependent manner and anti-angiogenesis activity was observed using 10μg of HR6 in chorioallantoic membrane assay. In this work, we demonstrate that a HR6 scFv selected from human library phage display specifically blocks VEGF signaling, furthermore, this scFv has an anti-angiogenesis effect and because of its small size has more tissue diffusion. The HR6 antibody was isolated form a human library thus, it is not immunogenic for humans and could serve as a potential therapeutic agent in cancer.

  17. 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

  18. Primary xenografts of human prostate tissue as a model to study angiogenesis induced by reactive stroma.

    Directory of Open Access Journals (Sweden)

    Viviana P Montecinos

    Full Text Available Characterization of the mechanism(s of androgen-driven human angiogenesis could have significant implications for modeling new forms of anti-angiogenic therapies for CaP and for developing targeted adjuvant therapies to improve efficacy of androgen-deprivation therapy. However, models of angiogenesis by human endothelial cells localized within an intact human prostate tissue architecture are until now extremely limited. This report characterizes the burst of angiogenesis by endogenous human blood vessels in primary xenografts of fresh surgical specimens of benign prostate or prostate cancer (CaP tissue that occurs between Days 6-14 after transplantation into SCID mice pre-implanted with testosterone pellets. The wave of human angiogenesis was preceded by androgen-mediated up-regulation of VEGF-A expression in the stromal compartment. The neo-vessel network anastomosed to the host mouse vascular system between Days 6-10 post-transplantation, the angiogenic response ceased by Day 15, and by Day 30 the vasculature had matured and stabilized, as indicated by a lack of leakage of serum components into the interstitial tissue space and by association of nascent endothelial cells with mural cells/pericytes. The angiogenic wave was concurrent with the appearance of a reactive stroma phenotype, as determined by staining for α-SMA, Vimentin, Tenascin, Calponin, Desmin and Masson's trichrome, but the reactive stroma phenotype appeared to be largely independent of androgen availability. Transplantation-induced angiogenesis by endogenous human endothelial cells present in primary xenografts of benign and malignant human prostate tissue was preceded by induction of androgen-driven expression of VEGF by the prostate stroma, and was concurrent with and the appearance of a reactive stroma phenotype. Androgen-modulated expression of VEGF-A appeared to be a causal regulator of angiogenesis, and possibly of stromal activation, in human prostate xenografts.

  19. Endogenous LXA4 circuits are determinants of pathological angiogenesis in response to chronic injury.

    Science.gov (United States)

    Leedom, Alexander J; Sullivan, Aaron B; Dong, Baiyan; Lau, Denise; Gronert, Karsten

    2010-01-01

    Inflammation and angiogenesis are intimately linked, and their dysregulation leads to pathological angiogenesis in human diseases. 15-lipoxygenase (15-LOX) and lipoxin A(4) receptors (ALX) constitute a LXA(4) circuit that is a key feature of inflammatory resolution. LXA(4) analogs have been shown to regulate vascular endothelial growth factor (VEGF)-A-induced angiogenic response in vitro. 15-LOX and ALX are highly expressed in the avascular and immune-privileged cornea. However, the role of this endogenous LXA(4) circuit in pathological neovascularization has not been determined. We report that suture-induced chronic injury in the cornea triggered polymorphonuclear leukocytes (PMN) infiltration, pathological neovascularization, and up-regulation of mediators of inflammatory angiogenesis, namely VEGF-A and the VEGF-3 receptor (FLT4). Up-regulation of the VEGF circuit and neovascularization correlated with selective changes in both 15-LOX (Alox15) and ALX (Fpr-rs2) expression and a temporally defined increase in basal 15-LOX activity. More importantly, genetic deletion of 15-LOX or 5-LOX, key and obligatory enzymes in the formation of LXA(4), respectively, led to exacerbated inflammatory neovascularization coincident with increased VEGF-A and FLT4 expression. Direct topical treatment with LXA(4), but not its metabolic precursor 15-hydroxyeicosatetraenoic acid, reduced expression of VEGF-A and FLT4 and inflammatory angiogenesis and rescued 15-LOX knockout mice from exacerbated angiogenesis. In summary, our findings and the prominent expression of 15-LOX and ALX in epithelial cells and macrophages place the LXA(4) circuit as an endogenous regulator of pathological angiogenesis.

  20. Marker development

    Energy Technology Data Exchange (ETDEWEB)

    Adams, M.R.

    1987-05-01

    This report is to discuss the marker development for radioactive waste disposal sites. The markers must be designed to last 10,000 years, and place no undue burdens on the future generations. Barriers cannot be constructed that preclude human intrusion. Design specifications for surface markers will be discussed, also marker pictograms will also be covered.

  1. Vascular Disease Foundation

    Science.gov (United States)

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  2. What Is Vascular Disease?

    Science.gov (United States)

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  3. Vascular emergencies.

    Science.gov (United States)

    Semashko, D C

    1997-01-01

    This article reviews the initial assessment and emergent management of several common as well as uncommon vascular emergencies. Aortic dissection, aneurysms, and arterial occlusive disease are familiar but challenging clinical entities. Less frequently encountered conditions are also discussed including an aortic enteric fistula, mesenteric venous thrombosis, phlegmasia alba dolens, and subclavian vein thrombosis.

  4. Notch in Pathological Angiogenesis and Lymphangiogenesis

    Science.gov (United States)

    2013-05-01

    Branching of Dopaminergic Axons. Journal of Neuroscience, 29(38): 11973-11981. BOOK CHAPTERS 1. Uh, M.K., Kandel , J., Kitajewski, J. Evaluating Tumor Angiogenesis. 2nd ed. 980. New York: Springer, 2013. 341-51. Print.

  5. Galectins in angiogenesis: consequences for gestation.

    Science.gov (United States)

    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.

  6. Therapeutic Angiogenesis for Treating Cardiovascular Diseases

    Directory of Open Access Journals (Sweden)

    Lorenzo Deveza, Jeffrey Choi, Fan Yang

    2012-01-01

    Full Text Available Cardiovascular disease is the leading cause of death worldwide and is often associated with partial or full occlusion of the blood vessel network in the affected organs. Restoring blood supply is critical for the successful treatment of cardiovascular diseases. Therapeutic angiogenesis provides a valuable tool for treating cardiovascular diseases by stimulating the growth of new blood vessels from pre-existing vessels. In this review, we discuss strategies developed for therapeutic angiogenesis using single or combinations of biological signals, cells and polymeric biomaterials. Compared to direct delivery of growth factors or cells alone, polymeric biomaterials provide a three-dimensional drug-releasing depot that is capable of facilitating temporally and spatially controlled release. Biomimetic signals can also be incorporated into polymeric scaffolds to allow environmentally-responsive or cell-triggered release of biological signals for targeted angiogenesis. Recent progress in exploiting genetically engineered stem cells and endogenous cell homing mechanisms for therapeutic angiogenesis is also discussed.

  7. Serum Level of Vascular Endothelial Growth Factor in Patients with Different Clinical SubtypeS of Oral Lichen Planus

    Directory of Open Access Journals (Sweden)

    Maryam Mardani

    2012-12-01

    Full Text Available Background: Oral lichen planus is a chronic inflammatory disease with a poorly understood etiology. The role of angiogenesis in the development of different chronic inflammatory diseases is of great concern. Vascular endothelial growth factor (VEGF is an important regulator of angiogenesis. We aimed to evaluate the serum level of VEGF in patients with oral lichen planus compared with normal individuals and consider its clinical significance.Methods: In this case-control study, 36 serum samples from patients diagnosed with oral lichen planus admitted to the Oral Medicine Department of the School of Dentistry at Shiraz University of Medical Sciences (14 men, 22 women, mean [±SD] age: 38.8 [±6.07] years and 23 serum samples from healthy individuals (9 men, 14 women, mean [±SD] age: 38.7 [±4.9] years were collected. VEGF concentration was measured using the ELISA method. The Mann-Whitney test was used for statistical analysis.Results: The serum VEGF level was significantly higher in patients with oral lichen planus compared with the healthy controls (112.97 [±63.2] vs. 66.21 [±56.2] ngr/ml, P<0.001. A similar difference was also observed between the two types of oral lichen planus, being more pronounced in the erosive form (P<0.001.Conclusion: Serum VEGF can be used as a useful and suitable marker to scrutinize the disease activity.

  8. Tnactivation of PTEN is associated with increased angiogenesis and VEGF overexpression in gastric cancer

    Institute of Scientific and Technical Information of China (English)

    Ye-Jiang Zhou; Yu-Xia Xiong; Xiao-Ting Wu; De Shi; Wei Fan; Tong Zhou; Yue-Chun Li; Xiong Huang

    2004-01-01

    AIM: To investigate the expression of PTEN/MMAC1/TEP1and vascular endothelial growth factor (VEGF), their roles in biologic behavior and angiogenesis and their association in gastric cancer.METHODS: Immunohistochemical staining was used to evaluate the expression of PTEN, VEGF and microvascular density (MVD) on paraffin-embedded sections in 70 patients with primary gastric cancer and 24 patients with chronic superficial gastritis (CSG). Expression of PTEN, VEGF and MVD were compared with clinicopathological features of gastric cancer. The relationship between expression of PTEN, VEGF and MVD as well as the relationship between PTEN and VEGF expression in caner cells were investigated.RESULTS: PTEN expression significantly decreased (t= 3.98,P<0.01) whereas both VEGF expression and MVD significant increased (t = 4.29 and 4.41, respectively, both P<0.01)in gastric cancer group compared with CSG group. PTEN expression was significantly down-regulated (t = 1.95,P<0.05) whereas VEGF expression (t = 2.37, P<0.05) and MVD (t = 3.28, P<0.01) was significantly up-regulated in advanced gastric cancer compared with early-stage gastric cancer. PTEN expression in gastric cancer showed a negative association with lymph node metastasis (t= 3.91, P<0.01),invasion depth (t= 1.95, P<0.05) and age (t= 4.69, P<0.01).MVD in PTEN-negative gastric cancer was significantly higher than that in PTEN-positive gastric cancer (t = 3.69,P<0.01), and there was a negative correlation between PTEN expression and MVD (γ = -0.363, P<0.05). VEGF expression was positively associated with invasion depth (especially with serosa invasion, t = 4.69, P<0.01), lymph node metastasis (t= 2.31, P<0.05) and TNM stage (t= 3.04,P<0.01). MVD in VEGF-positive gastric cancer was significantly higher than that in VEGF-negative gastric cancer (t = 4.62,P<0.01), and there was a positive correlation between VEGF expression of and MVD (γ = 0.512, P<0.05). VEGF expression in PTEN

  9. Neomycin inhibits angiogenin-induced angiogenesis

    OpenAIRE

    1998-01-01

    A class of angiogenesis inhibitor has emerged from our mechanistic study of the action of angiogenin, a potent angiogenic factor. Neomycin, an aminoglycoside antibiotic, inhibits nuclear translocation of human angiogenin in human endothelial cells, an essential step for angiogenin-induced angiogenesis. The phospholipase C-inhibiting activity of neomycin appears to be involved, because U-73122, another phospholipase C inhibitor, has a similar effect. In contrast, genistein, oxophenylarsine, an...

  10. Piperine, a dietary phytochemical, inhibits angiogenesis

    OpenAIRE

    2012-01-01

    Angiogenesis plays an important role in tumor progression. Piperine, a major alkaloid constituent of black pepper, has diverse physiological actions including killing of cancer cells; however, the effect of piperine on angiogenesis is not known. Here we show that piperine inhibited the proliferation and G1/S transition of human umbilical vein endothelial cells (HUVECs) without causing cell death. Piperine also inhibited HUVEC migration and tubule formation in vitro, as well as collagen-induce...

  11. In Vivo Imaging Study of Angiogenesis in a Channelized Porous Scaffold

    Directory of Open Access Journals (Sweden)

    Margherita Tamplenizza

    2015-05-01

    Full Text Available The main scientific issue hindering the development of tissue engineering technologies is the lack of proper vascularization. Among the various approaches developed for boosting vascularization, scaffold design has attracted increasing interest over the last few years. The aim of this article is to illustrate a scaffold design strategy for enhancing vascularization based on sacrificial microfabrication of embedded microchannels. This approach was combined with an innovative poly(ether urethane urea (PEUtU porous scaffold to provide an alternative graft substitute material for the treatment of tissue defects. Fluorescent and chemiluminescent imaging combined with computed tomography were used to study the behavior of the scaffold composition within living subjects by analyzing angiogenesis and inflammation processes and observing the variation in x-ray absorption, respectively. For this purpose, an IntegriSense 680 probe was used in vivo for the localization and quantification of integrin αvβ3, due to its critical involvement in angiogenesis, and a XenoLight RediJect Inflammation Probe for the study of the decline in inflammation progression during healing. Overall, the collected data suggest the advantages of embedding a synthetic vascular network into a PEUtU porous matrix to enhance in vivo tissue integration, maturation, and regeneration. Moreover, our imaging approach proved to be an efficient and versatile tool for scaffold in vivo testing.

  12. In vivo imaging study of angiogenesis in a channelized porous scaffold.

    Science.gov (United States)

    Tamplenizza, Margherita; Tocchio, Alessandro; Gerges, Irini; Martello, Federico; Martelli, Cristina; Ottobrini, Luisa; Lucignani, Giovanni; Milani, Paolo; Lenardi, Cristina

    2015-01-01

    The main scientific issue hindering the development of tissue engineering technologies is the lack of proper vascularization. Among the various approaches developed for boosting vascularization, scaffold design has attracted increasing interest over the last few years. The aim of this article is to illustrate a scaffold design strategy for enhancing vascularization based on sacrificial microfabrication of embedded microchannels. This approach was combined with an innovative poly(ether urethane urea) (PEUtU) porous scaffold to provide an alternative graft substitute material for the treatment of tissue defects. Fluorescent and chemiluminescent imaging combined with computed tomography were used to study the behavior of the scaffold composition within living subjects by analyzing angiogenesis and inflammation processes and observing the variation in x-ray absorption, respectively. For this purpose, an IntegriSense 680 probe was used in vivo for the localization and quantification of integrin αvβ3, due to its critical involvement in angiogenesis, and a XenoLight RediJect Inflammation Probe for the study of the decline in inflammation progression during healing. Overall, the collected data suggest the advantages of embedding a synthetic vascular network into a PEUtU porous matrix to enhance in vivo tissue integration, maturation, and regeneration. Moreover, our imaging approach proved to be an efficient and versatile tool for scaffold in vivo testing.

  13. Nogo-A regulates vascular network architecture in the postnatal brain.

    Science.gov (United States)

    Wälchli, Thomas; Ulmann-Schuler, Alexandra; Hintermüller, Christoph; Meyer, Eric; Stampanoni, Marco; Carmeliet, Peter; Emmert, Maximilian Y; Bozinov, Oliver; Regli, Luca; Schwab, Martin E; Vogel, Johannes; Hoerstrup, Simon P

    2017-02-01

    Recently, we discovered a new role for the well-known axonal growth inhibitory molecule Nogo-A as a negative regulator of angiogenesis in the developing central nervous system. However, how Nogo-A affected the three-dimensional (3D) central nervous system (CNS) vascular network architecture remained unknown. Here, using vascular corrosion casting, hierarchical, synchrotron radiation μCT-based network imaging and computer-aided network analysis, we found that genetic ablation of Nogo-A significantly increased the three-dimensional vascular volume fraction in the postnatal day 10 (P10) mouse brain. More detailed analysis of the cerebral cortex revealed that this effect was mainly due to an increased number of capillaries and capillary branchpoints. Interestingly, other vascular parameters such as vessel diameter, -length, -tortuosity, and -volume were comparable between both genotypes for non-capillary vessels and capillaries. Taken together, our three-dimensional data showing more vessel segments and branchpoints at unchanged vessel morphology suggest that stimulated angiogenesis upon Nogo-A gene deletion results in the insertion of complete capillary micro-networks and not just single vessels into existing vascular networks. These findings significantly enhance our understanding of how angiogenesis, vascular remodeling, and three-dimensional vessel network architecture are regulated during central nervous system development. Nogo-A may therefore be a potential novel target for angiogenesis-dependent central nervous system pathologies such as brain tumors or stroke.

  14. Studies on tumor induced angiogenesis.

    Science.gov (United States)

    Ambrus, J L; Ambrus, C M; Forgach, P; Stadler, S; Halpern, J; Sayyid, S; Niswander, P; Toumbis, C

    1992-01-01

    Methods were developed to test angiogenic response to human tumor implants and various biologic agents in the cornea of rabbits and non-human primates (Macaca arctoides). Crude PDGF preparations were found to have significant angiogenic effect. Purified, recombinant PDGF preparations were also effective inhibitors (e.g. pentoxifylline (Px) (which also were found to release PgI2 and t-PA) inhibited human tumor implant induced angiogenesis and reduced spontaneous metastases in 3 transplantable murine tumors (Furth-Columbia Wilms' tumor in Furth-Wistar rats, C-1300 neuroblastoma in A/J mice and HM-Kim mammary carcinoma in Wistar rats) but not in the NIH adenocarcinoma in Balb/c mice. Sodium diethyldithiocarbamate (DDTC), a metal complexing agent with special affinity to copper and anti-thyroid as well as, immune stimulating activity was shown to be anti-angiogenic and to potentiate the effect of Px. The anti-fibrinolytic agents epsilon amino caproic acid (EACA) and tranaxamic acid (t-AMCHA) were anti-angiogenic. DDTC and Px were synergistic from this point of view.

  15. Angiogenesis is a link between atherosclerosis and tumorigenesis: role of LOX-1.

    Science.gov (United States)

    Jiang, Junlin; Yan, Meiling; Mehta, Jawahar L; Hu, Changping

    2011-10-01

    Angiogenesis is defined as the formation of new blood vessels sprouting from pre-existing vessels. It plays an important role not only in physiological situations such as embryonic vascular development and wound healing, but also in pathological conditions including atherogenesis and evolution and spread of certain tumors. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a receptor for oxidized low density lipoprotein (ox-LDL), is mainly expressed in endothelial cells. It has diverse physiological functions and it could be a link between atherogenesis and tumorigenesis. The risk factors for atherosclerosis like hypertension, diabetes mellitus and hyperlipidemia are associated with LOX-1. Dyslipidemia and obesity are also being recognized as risk factor for certain tumors. LOX-1 is also found to be important for maintaining the transformed state in developmentally diverse cancer cell lines and for tumor growth. There is emerging evidence that LOX-1 plays an important role in the angiogenesis process. In this review, we outline the roles of angiogenesis in atherogenesis and tumorigenesis, and describe the role of LOX-1 as a potential molecular target for blocking angiogenesis.

  16. Tumor angiogenesis in the absence of fibronectin or its cognate integrin receptors.

    Directory of Open Access Journals (Sweden)

    Patrick A Murphy

    Full Text Available Binding of α5β1 and αvβ3/β5 integrin receptors on the endothelium to their fibronectin substrate in the extracellular matrix has been targeted as a possible means of blocking tumor angiogenesis and tumor growth. However, clinical trials of blocking antibodies and peptides have been disappointing despite promising preclinical results, leading to questions about the mechanism of the inhibitors and the reasons for their failure. Here, using tissue-specific and inducible genetics to delete the α5 and αv receptors in the endothelium or their fibronectin substrate, either in the endothelium or globally, we show that both are dispensable for tumor growth, in transplanted tumors as well as spontaneous and angiogenesis-dependent RIP-Tag-driven pancreatic adenocarcinomas. In the nearly complete absence of fibronectin, no differences in vascular density or the deposition of basement membrane laminins, ColIV, Nid1, Nid2, or the TGFβ binding matrix proteins, fibrillin-1 and -2, could be observed. Our results reveal that fibronectin and the endothelial fibronectin receptor subunits, α5 and αv, are dispensable for tumor angiogenesis, suggesting that the inhibition of angiogenesis induced by antibodies or small molecules may occur through a dominant negative effect, rather than a simple functional block.

  17. Macrophage Wnt-Calcineurin-Flt1 signaling regulates mouse wound angiogenesis and repair.

    Science.gov (United States)

    Stefater, James A; Rao, Sujata; Bezold, Katie; Aplin, Alfred C; Nicosia, Roberto F; Pollard, Jeffrey W; Ferrara, Napoleone; Lang, Richard A

    2013-03-28

    The treatment of festering wounds is one of the most important aspects of medical care. Macrophages are important components of wound repair, both in fending off infection and in coordinating tissue repair. Here we show that macrophages use a Wnt-Calcineurin-Flt1 signaling pathway to suppress wound vasculature and delay repair. Conditional mutants deficient in both Wntless/GPR177, the secretory transporter of Wnt ligands, and CNB1, the essential component of the nuclear factor of activated T cells dephosporylation complex, displayed enhanced angiogenesis and accelerated repair. Furthermore, in myeloid-like cells, we show that noncanonical Wnt activates Flt1, a naturally occurring inhibitor of vascular endothelial growth factor-A-mediated angiogenesis, but only when calcineurin function is intact. Then, as expected, conditional deletion of Flt1 in macrophages resulted in enhanced wound angiogenesis and repair. These results are consistent with the published link between enhanced angiogenesis and enhanced repair, and establish novel therapeutic approaches for treatment of wounds.

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

    Directory of Open Access Journals (Sweden)

    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.

  19. Topical simvastatin accelerates wound healing in diabetes by enhancing angiogenesis and lymphangiogenesis.

    Science.gov (United States)

    Asai, Jun; Takenaka, Hideya; Hirakawa, Satoshi; Sakabe, Jun-ichi; Hagura, Asami; Kishimoto, Saburo; Maruyama, Kazuichi; Kajiya, Kentaro; Kinoshita, Shigeru; Tokura, Yoshiki; Katoh, Norito

    2012-12-01

    Impaired wound healing is a major complication of diabetes. Recent studies have reported reduced lymphangiogenesis and angiogenesis during diabetic wound healing, which are thought to be new therapeutic targets. Statins have effects beyond cholesterol reduction and can stimulate angiogenesis when used systemically. However, the effects of topically applied statins on wound healing have not been well investigated. The present study tested the hypothesis that topical application of simvastatin would promote lymphangiogenesis and angiogenesis during wound healing in genetically diabetic mice. A full-thickness skin wound was generated on the back of the diabetic mice and treated with simvastatin or vehicle topically. Simvastatin administration resulted in significant acceleration of wound recovery, which was notable for increases in both angiogenesis and lymphangiogenesis. Furthermore, simvastatin promoted infiltration of macrophages, which produced vascular endothelial growth factor C in granulation tissues. In vitro, simvastatin directly promoted capillary morphogenesis and exerted an antiapoptotic effect on lymphatic endothelial cells. These results suggest that the favorable effects of simvastatin on lymphangiogenesis are due to both a direct influence on lymphatics and indirect effects via macrophages homing to the wound. In conclusion, a simple strategy of topically applied simvastatin may have significant therapeutic potential for enhanced wound healing in patients with impaired microcirculation such as that in diabetes.

  20. Role of heparin and non heparin binding serpins in coagulation and angiogenesis: A complex interplay.

    Science.gov (United States)

    Bhakuni, Teena; Ali, Mohammad Farhan; Ahmad, Irshad; Bano, Shadabi; Ansari, Shoyab; Jairajpuri, Mohamad Aman

    2016-08-15

    Pro-coagulant, anti-coagulant and fibrinolytic pathways are responsible for maintaining hemostatic balance under physiological conditions. Any deviation from these pathways would result in hypercoagulability leading to life threatening diseases like myocardial infarction, stroke, portal vein thrombosis, deep vein thrombosis (DVT) and pulmonary embolism (PE). Angiogenesis is the process of sprouting of new blood vessels from pre-existing ones and plays a critical role in vascular repair, diabetic retinopathy, chronic inflammation and cancer progression. Serpins; a superfamily of protease inhibitors, play a key role in regulating both angiogenesis and coagulation. They are characterized by the presence of highly conserved secondary structure comprising of 3 β-sheets and 7-9 α-helices. Inhibitory role of serpins is modulated by binding to cofactors, specially heparin and heparan sulfate proteoglycans (HSPGs) present on cell surfaces and extracellular matrix. Heparin and HSPGs are the mainstay of anti-coagulant therapy and also have therapeutic potential as anti-angiogenic inhibitors. Many of the heparin binding serpins that regulate coagulation cascade are also potent inhibitors of angiogenesis. Understanding the molecular mechanism of the switch between their specific anti-coagulant and anti-angiogenic role during inflammation, stress and regular hemostasis is important. In this review, we have tried to integrate the role of different serpins, their interaction with cofactors and their interplay in regulating coagulation and angiogenesis.

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

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Jinqiao, E-mail: jinqiao1977@163.com [Institute of Pediatrics, Children' s Hospital of Fudan University (China); Sha, Bin [Department of Neonatology, Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China); Zhou, Wenhao, E-mail: zhou_wenhao@yahoo.com.cn [Department of Neonatology, Children' s Hospital of Fudan University, 399 Wanyuan Road, Shanghai 201102 (China); Yang, Yi [Institute of Pediatrics, Children' s Hospital of Fudan University (China)

    2010-03-26

    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.

  2. Angiogenesis in atherosclerotic plaque obtained from carotid endarterectomy: association between symptomatology and plaque morphology.

    Science.gov (United States)

    Hiyama, Takami; Tanaka, Toshihide; Endo, Shinichi; Komine, Kazumasa; Kudo, Tadashi; Kobayashi, Hiroo; Shiokawa, Yoshiaki

    2010-01-01

    Carotid plaque with hemorrhage leads to cerebral embolism and ischemic stroke. Plaque angiogenesis and angiogenetic factors such as vascular endothelial growth factor (VEGF) are critical in the progression of atherosclerotic carotid plaque and intraplaque hemorrhage. The correlation between plaque angiogenesis and presence of clinical symptoms was studied in 41 specimens obtained during carotid endarterectomy from 20 symptomatic and 21 asymptomatic patients treated for carotid artery stenosis. Histological findings using hematoxylin-eosin and immunohistochemical staining against von Willebrand factor and VEGF were examined. Intraplaque hemorrhage, calcification, necrosis, and invasion of foam cells were frequently observed in the carotid plaques from symptomatic patients compared with asymptomatic patients. Higher microvessel density was found in the carotid plaques with necrosis and invasion of foam cells compared with plaques without necrosis and/or foam cell invasion, and higher expression of VEGF was found from symptomatic patients compared with asymptomatic patents. These results suggest that plaque angiogenesis and higher level of VEGF expression may enhance the progression of ischemic symptoms in patients with carotid artery stenosis. Invasive macrophages in the plaque of symptomatic patients increase levels of VEGF and might enhance plaque angiogenesis and atherosclerosis progression.

  3. Fibrocyte-like cells from intrauterine growth restriction placentas have a reduced ability to stimulate angiogenesis.

    Science.gov (United States)

    Riddell, Meghan R; Winkler-Lowen, Bonnie; Jiang, Yanyan; Guilbert, Larry J; Davidge, Sandra T

    2013-09-01

    Intrauterine growth restriction (IUGR) is a common complication of pregnancy whereby the fetus fails to achieve its genetic growth potential. Malformation of the placental vasculature is observed in IUGR and may be due to the development of the placenta in a chronically hypoxic environment. Recently, we identified that the predominant stromal cells in the angiogenic zones of the placenta are fibrocyte-like cells. The conditioned medium from fibrocyte-like cells (FcCM) has been shown to stimulate angiogenesis in vitro. Thus, we hypothesized that FcCM from IUGR cells would have a reduced ability to stimulate angiogenesis and that chronic hypoxia would decrease the ability of both normal and IUGR fibrocyte-like cells to stimulate angiogenesis. IUGR FcCM had a reduced ability to stimulate endothelial tubule-like structure formation and an increased ability to stimulate endothelial migration compared with normal FcCM. However, normal and IUGR FcCM produced in chronic hypoxia did not alter endothelial proliferation, migration, or tubule-like structure formation. IUGR FcCM was found to have reduced levels of the pro-angiogenic cytokine IL-8 and increased levels of the anti-angiogenic factors activin-A and pigment epithelium-derived growth factor. Thus, alterations in the ability of IUGR fibrocyte-like cells to stimulate angiogenesis may contribute to the development of vascular malformation in IUGR, but in vitro these changes cannot be attributed to a chronically hypoxic environment.

  4. Angiogenesis in Interstitial Lung Diseases: a pathogenetic hallmark or a bystander?

    Directory of Open Access Journals (Sweden)

    Anevlavis Stavros

    2006-05-01

    Full Text Available Abstract The past ten years parallels have been drawn between the biology of cancer and pulmonary fibrosis. The unremitting recruitment and maintenance of the altered fibroblast phenotype with generation and proliferation of immortal myofibroblasts is reminiscent with the transformation of cancer cells. A hallmark of tumorigenesis is the production of new blood vessels to facilitate tumor growth and mediate organ-specific metastases. On the other hand several chronic fibroproliferative disorders including fibrotic lung diseases are associated with aberrant angiogenesis. Angiogenesis, the process of new blood vessel formation is under strict regulation determined by a dual, yet opposing balance of angiogenic and angiostatic factors that promote or inhibit neovascularization, respectively. While numerous studies have examined so far the interplay between aberrant vascular and matrix remodeling the relative role of angiogenesis in the initiation and/or progression of the fibrotic cascade still remains elusive and controversial. The current article reviews data concerning the pathogenetic role of angiogenesis in the most prevalent and studied members of ILD disease-group such as IIPs and sarcoidosis, presents some of the future perspectives and formulates questions for potential further research.

  5. Synthesis of specific nanoparticles for targeting tumor angiogenesis using electron-beam irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Deshayes, Stephanie, E-mail: stephanie.deshayes@u-bordeaux2.f [Universite de Bordeaux, UMR CNRS 5084, CNAB, Chimie Bio-Organique, 33076 Bordeaux (France); Ecole Polytechnique, CEA, UMR CNRS 7642, Laboratoire des Solides Irradies, 91128 Palaiseau (France); Maurizot, Victor [Universite de Bordeaux, UMR CNRS 5084, CNAB, Chimie Bio-Organique, 33076 Bordeaux (France); Clochard, Marie-Claude; Berthelot, Thomas; Baudin, Cecile [Ecole Polytechnique, CEA, UMR CNRS 7642, Laboratoire des Solides Irradies, 91128 Palaiseau (France); Deleris, Gerard [Universite de Bordeaux, UMR CNRS 5084, CNAB, Chimie Bio-Organique, 33076 Bordeaux (France)

    2010-03-15

    Angiogenesis plays a critical role in both growth and metastasis of tumors. Vascular endothelial growth factor (VEGF) is an endogenous mediator of tumor angiogenesis. Blocking associations of the VEGF with its corresponding receptors (KDR) have become critical for anti-tumor therapy. A cyclo-peptide (CBO-P11), derived from VEGF, able to inhibit the interaction between the growth factor and its receptor, was synthesized in our laboratory to provide a target for angiogenesis. We have prepared biocompatible poly(vinylidene fluoride) (PVDF) nanoparticles in order to obtain long blood circulating systems. Electron-beam (EB) irradiation was used to activate the PVDF nanoparticles. From electron paramagnetic resonance (EPR) measurements, we studied the radical stability in order to optimize the radio-grafting of acrylic acid (AA). Further functionalization of PVDF-g-PAA nanoparticles with the cyclo-peptide via a spacer arm was also possible by performing coupling reactions. High resolution magic angle spinning nuclear magnetic resonance (HRMAS NMR) and MALDI mass spectrometry allowed us to follow each chemical step of this peptide immobilization. We designed a new nanodevice suggesting a great potential for targeting angiogenesis. 7727-21-1

  6. Plasma treatment effect on angiogenesis in wound healing process evaluated in vivo using angiographic optical coherence tomography

    Science.gov (United States)

    Kim, D. W.; Park, T. J.; Jang, S. J.; You, S. J.; Oh, W. Y.

    2016-12-01

    Non-thermal atmospheric pressure plasma holds promise for promoting wound healing. However, plasma-induced angiogenesis, which is important to better understand the underlying physics of plasma treatment effect on wound healing, remains largely unknown. We therefore evaluated the effect of non-thermal plasma on angiogenesis during wound healing through longitudinal monitoring over 30 days using non-invasive angiographic optical coherence tomography imaging in vivo. We demonstrate that the plasma-treated vascular wound area of mouse ear was noticeably decreased as compared to that of control during the early days in the wound healing process. We also observed that the vascular area density was increased in the plasma affected region near the wound as compared to the plasma unaffected region. The difference in the vascular wound area and the vascular area density peaked around day 3. This indicates that the plasma treatment induced additional angiogenic effects in the wound healing process especially during the early days. This non-invasive optical angiographic approach for in vivo time-lapse imaging provides further insights into elucidating plasma-induced angiogenesis in the wound healing process and its application in the biomedical plasma evaluation.

  7. 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.

  8. EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN PRIMARY NON-SMALL CELL LUNG CARCINOMA

    Institute of Scientific and Technical Information of China (English)

    ZHANG Lijian; YANG Guoli; XIE Yuquan; XU Weiguo

    1999-01-01

    Objective: Tumor growth depends on angiogenesis.The aim of this paper is to clarify the relationship between the expression of vascular endothelial growth factor (VEGF)/vascular permeability factor (VPF) and the angiogenesis, or growth, or invasion and prognostic value in Non-Small Cell Lung Cancer (NSCLC).Methods: Microvessei quantification and expression of VEGF was performed immunohistochemically, using multiclonal antibodies against endothelial protein factor Ⅷ-related antigen (F-Ⅷ antigen, or factor Ⅷ) for evaluating the angiogenesis; against VEGF antigen for the expression of VEGF. Results: A total of 53 patients with NSCLC after the radical resection were evaluated.The patients with high and low expression of VEGF were 33 and 20, respectively. A significant higher microvessel density (MVD) was observed in the tumors with high expression of VEGF compared with the tumors with low expression of it (12.17±2.57/mm2 vs 6.01±1.161/mm2, rank sum test, P<0.01). There were 29patients with lymphonodes metastasis in the high expression VEGF/VPF (29/33, 87.88%) group, and 9patients in the low (9/20, 45%) group. There was good correlation between MVD and expression of VEGF (chisquare tests, P<0.001). The overall 5 years survival for 53 patients was 20.75±5.78%; that of the high expression of the VEGF group was 3.03±2.98%; that of the low group was 36.36±13.94%, by Log rank test, P=0.0001.The difference between them had a high significance.There was good correlation between the survival and the expression of VEGF. By the COX's proportional hazard model analysis, the expression of VEGF and MVD was considered to be an independent marker of the prognosis in non-small cell lung cancer. Conclusion: the expression of VEGF has a significant correlation with MVD, growth, invasion, and lymph node metastasis. The increasing of the node metastasis and the size of tumor accompanied the increasing of VEGF/VPF. The cancer patient with higher VEGF and MVD expression might

  9. 白芨中萜类化合物通过诱导血管内皮细胞凋亡抑制血管生成%ANGIOGENESIS INHIBITION IN VASCULAR ENDOTHELIAL CELLS BY TERPENOID COMPOUNDS FROM Bletilla striata IS VIA APOPTOSIS PATHWAY

    Institute of Scientific and Technical Information of China (English)

    刘明志; 唐建洲; 张建社; 仇庆; 黄亚禹

    2008-01-01

    The inhibitive effects on angiogenesis and the potential mechanism by terpenoids from Bletilla striata were investigated in the study. Terpenoids were separated and purified from Bletilla striata by extraction and chromatography. The terpenoid and its crude extracts were used to treat on blood vessel of chick chorioallantoic membrane(CAM), as well as human umbilical vein endothelial cell(HUVEC). Our results demonstrated that the crude extracts containing the terpenoids could inhibit CAM angiogenesis and pure terpenoid sample could prohibit HUVEC proliferation and induce HUVEC undergoing apoptosis, which showed an apparent apoptotic characterizations, such as cell shrinking, blebbing of cell membrane, nucleus cracking, chromatin condensation and margination, apoptotic body formation and DNA degradation. Therefore, the inhibition on angiogenesis by terpenoids from Bletilla striata is depended on the induction of apoptosis to endothelial cells.%本文研究了白芨中的萜类化合物对血管生成的抑制作用,及其抑制血管生成的可能机制.采用萃取和色谱法从白芨中分离和纯化了该萜类化合物.通过鸡胚绒毛囊膜(CAM)和人脐静脉内皮细胞(HUVEC)研究了白芨中萜类化合物及其粗提物对血管及血管内皮细胞的抑制作用.结果表明,含该萜类的粗提物显著抑制鸡胚绒毛尿囊膜血管生成;该萜类纯品能明显抑制HUVEC增殖,且可诱导HUVEC凋亡,包括细胞体积缩小,细胞膜起泡,细胞核裂解,染色质浓缩和边集,出现凋亡小体,DNA降解.因此,白芨萜类化合物的抗血管生成作用与诱导血管内皮细胞凋亡有关.

  10. Catechol-Functionalized Hyaluronic Acid Hydrogels Enhance Angiogenesis and Osteogenesis of Human Adipose-Derived Stem Cells in Critical Tissue Defects.

    Science.gov (United States)

    Park, Hyun-Ji; Jin, Yoonhee; Shin, Jisoo; Yang, Kisuk; Lee, Changhyun; Yang, Hee Seok; Cho, Seung-Woo

    2016-06-13

    Over the last few decades, stem cell therapies have been highlighted for their potential to heal damaged tissue and aid in tissue reconstruction. However, materials used to deliver and support implanted cells often display limited efficacy, which has resulted in delaying translation of stem cell therapies into the clinic. In our previous work, we developed a mussel-inspired, catechol-functionalized hyaluronic acid (HA-CA) hydrogel that enabled effective cell transplantation due to its improved biocompatibility and strong tissue adhesiveness. The present study was performed to further expand the utility of HA-CA hydrogels for use in stem cell therapies to treat more clinically relevant tissue defect models. Specifically, we utilized HA-CA hydrogels to potentiate stem cell-mediated angiogenesis and osteogenesis in two tissue defect models: critical limb ischemia and critical-sized calvarial bone defect. HA-CA hydrogels were found to be less cytotoxic to human adipose-derived stem cells (hADSCs) in vitro compared to conventional photopolymerized HA hydrogels. HA-CA hydrogels also retained the angiogenic functionality of hADSCs and supported osteogenic differentiation of hADSCs. Because of their superior tissue adhesiveness, HA-CA hydrogels were able to mediate efficient engraftment of hADSCs into the defect regions. When compared to photopolymerized HA hydrogels, HA-CA hydrogels significantly enhanced hADSC-mediated therapeutic angiogenesis (promoted capillary/arteriole formation, improved vascular perfusion, attenuated ischemic muscle degeneration/fibrosis, and reduced limb amputation) and bone reconstruction (mineralized bone formation, enhanced osteogenic marker expression, and collagen deposition). This study proves the feasibility of using bioinspired HA-CA hydrogels as functional biomaterials for improved tissue regeneration in critical tissue defects.

  11. Low Molecular Weight Fucoidan Inhibits Tumor Angiogenesis through Downregulation of HIF-1/VEGF Signaling under Hypoxia

    Directory of Open Access Journals (Sweden)

    Meng-Chuan Chen

    2015-07-01

    Full Text Available Activation of hypoxia-induced hypoxia-inducible factors-1 (HIF-1 plays a critical role in promoting tumor angiogenesis, growth and metastasis. Low molecular weight fucoidan (LMWF is prepared from brown algae, and exhibits anticancer activity. However, whether LMWF attenuates hypoxia-induced angiogenesis in bladder cancer cells and the molecular mechanisms involved remain unclear. This is the first study to demonstrate that LMWF can inhibit hypoxia-stimulated H2O2 formation, HIF-1 accumulation and transcriptional activity vascular endothelial growth factor (VEGF secretion, and the migration and invasion in hypoxic human bladder cancer cells (T24 cells. LMWF also downregulated hypoxia-activated phosphorylation of PI3K/AKT/mTOR/p70S6K/4EBP-1 signaling in T24 cells. Blocking PI3K/AKT or mTOR activity strongly diminished hypoxia-induced HIF-1α expression and VEGF secretion in T24 cells, supporting the involvement of PI3K/AKT/mTOR in the induction of HIF-1α and VEGF. Additionally, LMWF significantly attenuated angiogenesis in vitro and in vivo evidenced by reduction of tube formation of hypoxic human umbilical vascular endothelial cells and blood capillary generation in the tumor. Similarly, administration of LMWF also inhibited the HIF-1α and VEGF expression in vivo, accompanied by a reduction of tumor growth. In summary, under hypoxia conditions, the antiangiogenic activity of LMWF in bladder cancer may be associated with suppressing HIF-1/VEGF-regulated signaling pathway.

  12. Matrix Metalloproteinases: Inflammatory Regulators of Cell Behaviors in Vascular Formation and Remodeling

    Directory of Open Access Journals (Sweden)

    Qishan Chen

    2013-01-01

    Full Text Available Abnormal angiogenesis and vascular remodeling contribute to pathogenesis of a number of disorders such as tumor, arthritis, atherosclerosis, restenosis, hypertension, and neurodegeneration. During angiogenesis and vascular remodeling, behaviors of stem/progenitor cells, endothelial cells (ECs, and vascular smooth muscle cells (VSMCs and its interaction with extracellular matrix (ECM play a critical role in the processes. Matrix metalloproteinases (MMPs, well-known inflammatory mediators are a family of zinc-dependent proteolytic enzymes that degrade various components of ECM and non-ECM molecules mediating tissue remodeling in both physiological and pathological processes. MMPs including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, and MT1-MMP, are stimulated and activated by various stimuli in vascular tissues. Once activated, MMPs degrade ECM proteins or other related signal molecules to promote recruitment of stem/progenitor cells and facilitate migration and invasion of ECs and VSMCs. Moreover, vascular cell proliferation and apoptosis can also be regulated by MMPs via proteolytically cleaving and modulating bioactive molecules and relevant signaling pathways. Regarding the importance of vascular cells in abnormal angiogenesis and vascular remodeling, regulation of vascular cell behaviors through modulating expression and activation of MMPs shows therapeutic potential.

  13. Molecular markers of extracellular matrix remodeling in glioblastoma vessels: microarray study of laser-captured glioblastoma vessels.

    Science.gov (United States)

    Pen, Ally; Moreno, Maria J; Martin, Joel; Stanimirovic, Danica B

    2007-04-15

    Glioblastoma multiforme (GBM) are the most malignant and vascularized brain tumors. The aberrant vascular phenotype of GBM could be exploited for diagnosis or therapeutic targeting. This study identified new molecular markers of GBM vessels, using a combination of laser capture microdissection (LCM) microscopy, RNA amplification, and microarray analyses to compare vessels from nonmalignant human brain and GBM tumors. Forty-two genes were differentially expressed in GBM vessels compared to nonmalignant brain vessels. Validation of differentially expressed genes was performed by literature mining, Q-PCR, and immunohistochemistry. Among the differentially expressed genes, only 64% were previously associated with vessels, angiogenesis, gliomas, and/or cancer. The upregulation of genes encoding secreted extracellular proteins IGFBP7 and SPARC was confirmed by Q-PCR in LCM-captured vessels. Whereas SPARC and IGFBP7 protein were absent in nonmalignant brain vessels, a distinct immunoreactivity patterns were observed in GBM sections whereby SPARC was strongly expressed in perivascular cells adjacent to GBM vessels while GBM endothelial cells were immunostained for IGFBP7. IGFBP7 immunoreactivity was also detected on the abluminal side of GBM vessels deposited between strands of vascular basal lamina. The study discerns unique molecular characteristics of GBM vessels compared with nonmalignant brain vessels that could potentially be used for diagnostic or therapeutic purposes.

  14. Expression of vascular endo- thelial growth factor in rat uterus during peri- implantation

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    The first distinct mark of rodent implantation is the increased vascular permeability and significant angiogenesis at the sites of blastocyst implantation, but its mechanism is not clearly defined. Vascular endothelial growth factor (VEGF) is the key mediator for angiogenesis during embryogenesis and adult span and also serves as a vascular permeability factor. The aim of this study is to explore VEGF regulation mechanism and the possible role that VEGF plays in implantation by studying the VEGF expression and angio-genesis in the rat uterus during estrous cycle, ovarioecto-mized and peri-implantation stages using in situ message RNA hybridization and confocal laser scanning techniques. The results indicated that VEGF was regulated by ovarian steroid hormones. VEGF expression before implantation was localized at luminal epithelium, shifted to stroma as implan-tation initiated and extensively located at the decidualizing stroma region after implantation. Bandeiraea simplicifolia-1 (BS-1) agglutinin and antibody against von Willebrand fac-tor (vWF) were used to mark the endothelial cells and blood vessels. The results showed that the active angiogenesis oc-curred during the implantation process and this effect was probably mediated by VEGF. The results suggest that under the regulation of ovarian steroid hormones, VEGF plays an essential role in angiogenesis and increasing vascular perme-ability in endometrium, which are necessary for successful implantation.

  15. Molecular regulation of tumour angiogenesis by nitric oxide.

    Science.gov (United States)

    Ziche, Marina; Morbidelli, Lucia

    2009-12-01

    As tumors grow, their original vasculature can be insufficient to supply the growing tissue mass, and consequently local hypoxia develops. Thus neovascularisation is a key feature determining growth and metastasis of malignant tumors. This is, at least in part, mediated by humoral factors known to stimulate angiogenesis, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2). Among the multiple angiogenic modulators released by tumor and stromal cells, a key role is played by nitric oxide (NO). Beside its capacity to regulate permeability and blood flow, NO has been reported to exert angiogenic properties in various tumor models. The focus of this review will be the proangiogenic role of NO in the tumor microenvironment and its multiple mechanism of action on vascular endothelium. Particular attention will be devoted to the role of NO in regulating metalloproteinase activity on cultured microvascular endothelium and in the in vivo rabbit cornea assay. Finally, the potential clinical outcomes and expectations related to this topic will be discussed.

  16. Donepezil, an acetylcholinesterase inhibitor against Alzheimer's dementia, promotes angiogenesis in an ischemic hindlimb model.

    Science.gov (United States)

    Kakinuma, Yoshihiko; Furihata, Mutsuo; Akiyama, Tsuyoshi; Arikawa, Mikihiko; Handa, Takemi; Katare, Rajesh G; Sato, Takayuki

    2010-04-01

    Our recent studies have indicated that acetylcholine (ACh) protects cardiomyocytes from prolonged hypoxia through activation of the PI3K/Akt/HIF-1alpha/VEGF pathway and that cardiomyocyte-derived VEGF promotes angiogenesis in a paracrine fashion. These results suggest that a cholinergic system plays a role in modulating angiogenesis. Therefore, we assessed the hypothesis that the cholinergic modulator donepezil, an acetylcholinesterase inhibitor utilized in Alzheimer's disease, exhibits beneficial effects, especially on the acceleration of angiogenesis. We evaluated the effects of donepezil on angiogenic properties in vitro and in vivo, using an ischemic hindlimb model of alpha7 nicotinic receptor-deleted mice (alpha7 KO) and wild-type mice (WT). Donepezil activated angiogenic signals, i.e., HIF-1alpha and VEGF expression, and accelerated tube formation in human umbilical vein endothelial cells (HUVECs). ACh and nicotine upregulated signal transduction with acceleration of tube formation, suggesting that donepezil promotes a common angiogenesis pathway. Moreover, donepezil-treated WT exhibited rich capillaries with enhanced VEGF and PCNA endothelial expression, recovery from impaired tissue perfusion, prevention of ischemia-induced muscular atrophy with sustained surface skin temperature in the limb, and inhibition of apoptosis independent of the alpha7 receptor. Donepezil exerted comparably more effects in alpha7 KO in terms of angiogenesis, tissue perfusion, biochemical markers, and surface skin temperature. Donepezil concomitantly elevated VEGF expression in intracardiac endothelial cells of WT and alpha7 KO and further increased choline acetyltransferase (ChAT) protein expression, which is critical for ACh synthesis in endothelial cells. The present study concludes that donepezil can act as a therapeutic tool to accelerate angiogenesis in cardiovascular disease patients.

  17. Inhibition of VEGF-dependent angiogenesis by the anti-CD82 monoclonal antibody 4F9 through regulation of lipid raft microdomains.

    Science.gov (United States)

    Nomura, Sayaka; Iwata, Satoshi; Hatano, Ryo; Komiya, Eriko; Dang, Nam H; Iwao, Noriaki; Ohnuma, Kei; Morimoto, Chikao

    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.

  18. Marker chromosomes.

    Science.gov (United States)

    Rao, Kiran Prabhaker; Belogolovkin, Victoria

    2013-04-01

    Marker chromosomes are a morphologically heterogeneous group of structurally abnormal chromosomes that pose a significant challenge in prenatal diagnosis. Phenotypes associated with marker chromosomes are highly variable and range from normal to severely abnormal. Clinical outcomes are very difficult to predict when marker chromosomes are detected prenatally. In this review, we outline the classification, etiology, cytogenetic characterization, and clinical consequences of marker chromosomes, as well as practical approaches to prenatal diagnosis and genetic counseling.

  19. VASCULAR ENDOTHELIAL GROWTH FACTOR IN HEALTH AND DISEASE: A REVIEW

    Directory of Open Access Journals (Sweden)

    Niranjan Gopal

    2016-10-01

    Full Text Available BACKGROUND Vascular Endothelial Growth Factor (VEGF has been implicated as a key molecule, which regulates physiological angiogenesis. VEGF exerts its molecular actions through Receptor Tyrosine Kinases (RTKs VEGFR-1 and VEGFR-2, differ in signaling properties. VEGF plays a vital role in embryogenesis, growth and reproduction. VEGF as a mediator of pathological angiogenesis is associated with proliferation and micrometastasis of various tumours, ocular disorders involving neovascularisation, pre-eclampsia, etc. The pathogenesis of micro and macrovascular complications of diabetes mellitus and the role of VEGF is being studied extensively. Currently, several pharmacological interventions based on VEGF inhibitors and receptor antagonists have been tried to combat the pathological angiogenesis in a wide gamut of disorders. This review attempts to put together important properties, mechanism of action and the role of VEGF in common diseased states. CONCLUSION Effects of VEGF are widespread and have been implicated in several disease states. Therapeutic modalities targeting VEGF have been tried with success in recent years.

  20. Cancer gene therapy targeting angiogenesis: An updated review

    Institute of Scientific and Technical Information of China (English)

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

    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 antiangiogenesis 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.

  1. Murine experimental autoimmune encephalomyelitis is diminished by treatment with the angiogenesis inhibitors B20-4.1.1 and angiostatin (K1-3.

    Directory of Open Access Journals (Sweden)

    Carolyn J MacMillan

    Full Text Available Angiogenesis is the formation of new blood vessels form pre-existing vasculature whose contribution to inflammatory conditions of the Central Nervous System is being studied in order to generate novel therapeutic targets. This study is the first to investigate the impact of two particular angiogenesis inhibitors on murine Experimental Autoimmune Encephalomyelitis (EAE, an inflammatory disease that mimics aspects of the human disease Multiple Sclerosis. The inhibitors were chosen to reduce angiogenesis by complimentary means. Extrinsic factors were targeted with B20-4.1.1 through its ability to bind to murine Vascular Endothelial Growth Factor (VEGF. Vascular processes connected to angiogenesis were targeted directly with K(1-3, the first three kringle domains of angiostatin. Mice treated with B20-4.1.1 and K(1-3 from onset of signs had reduced clinical scores 18-21 days after EAE induction. Both agents suppressed spinal cord angiogenesis without effect on local VEGF expression. B20-4.1.1 reduced spinal cord vascular permeability while K(1-3 had no effect. T cell infiltration into the spinal cord at day 21 was unaffected by either treatment. B20-4.1.1 reduced peripheral T cell proliferation while K(1-3 had no effect. Lymphoid cells from treated mice produced reduced levels of the T helper-17 (Th-17 cell cytokine interleukin (IL-17 with no effect on the Th-1 cytokine interferon (IFN-γ or Th-2 cytokine IL-4. However, when both drugs were added in vitro to naive T cells or to antigen stimulated T cells from mice with untreated EAE they had no effect on proliferation or levels of IL-17 or IFN-γ. We conclude that these angiogenesis inhibitors mitigate EAE by both suppressing spinal cord angiogenesis and reducing peripheral T cell activation.

  2. In-vivo three-dimensional Doppler variance imaging for tumor angiogenesis on chorioallantoic membrane

    Science.gov (United States)

    Qi, Wenjuan; Liu, Gangjun; Chen, Zhongping

    2011-03-01

    Non-invasive tumor microvasculature visualization and characterization play significant roles in the detection of tumors and importantly, for aiding in the development of therapeutic strategies. The feasibility and effectiveness of a Doppler variance standard deviation imaging method for tumor angiogenesis on chorioallantoic membrane were tested in vivo on a rat glioma F98 tumor spheroid. Utilizing a high resolution Doppler Variance Optical Coherence Tomography (DVOCT) system with A-line rate of 20 kHz, three-dimensional mapping of a tumor with a total area of 3×2.5mm2 was completed within 15 seconds. The top-view image clearly visualized the complex vascular perfusion with the detection of capillaries as small as approximately 10μm. The results of the current study demonstrate the capability of the Doppler variance standard deviation imaging method as a non-invasive assessment of tumor angiogenesis, with the potential for its use in clinical settings.

  3. Cell proliferation along vascular islands during microvascular network growth

    Directory of Open Access Journals (Sweden)

    Kelly-Goss Molly R

    2012-06-01

    Full Text Available Abstract Background Observations in our laboratory provide evidence of vascular islands, defined as disconnected endothelial cell segments, in the adult microcirculation. The objective of this study was to determine if vascular islands are involved in angiogenesis during microvascular network growth. Results Mesenteric tissues, which allow visualization of entire microvascular networks at a single cell level, were harvested from unstimulated adult male Wistar rats and Wistar rats 3 and 10 days post angiogenesis stimulation by mast cell degranulation with compound 48/80. Tissues were immunolabeled for PECAM and BRDU. Identification of vessel lumens via injection of FITC-dextran confirmed that endothelial cell segments were disconnected from nearby patent networks. Stimulated networks displayed increases in vascular area, length density, and capillary sprouting. On day 3, the percentage of islands with at least one BRDU-positive cell increased compared to the unstimulated level and was equal to the percentage of capillary sprouts with at least one BRDU-positive cell. At day 10, the number of vascular islands per vascular area dramatically decreased compared to unstimulated and day 3 levels. Conclusions These results show that vascular islands have the ability to proliferate and suggest that they are able to incorporate into the microcirculation during the initial stages of microvascular network growth.

  4. Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

    Directory of Open Access Journals (Sweden)

    Maruo Kouji

    2009-10-01

    Full Text Available Abstract Background Human hemangiosarcoma (HSA tends to have a poor prognosis; its tumorigenesis has not been elucidated, as there is a dearth of HSA clinical specimens and no experimental model for HSA. However, the incidence of spontaneous HSA is relatively high in canines; therefore, canine HSA has been useful in the study of human HSA. Recently, the production of angiogenic growth factors and their receptors in human and canine HSA has been reported. Moreover, the growth-factor environment of HSA is very similar to that of pathophysiological angiogenesis, which some homeobox genes regulate in the transcription of angiogenic molecules. In the present study, we established 6 xenograft canine HSA tumors and detected the expression of growth factors, their receptors, and angiogenic homeobox genes. Methods Six primary canine HSAs were xenografted to nude mice subcutaneously and serially transplanted. Subsequently, the expressions of vascular endothelial growth factor (VEGF-A, basic fibroblast growth factors (bFGF, flt-1 and flk-1 (receptors of VEGF-A, FGFR-1, and angiogenic homeobox genes HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 were investigated in original and xenograft tumors by histopathology, immunostaining, and reverse transcription polymerase chain reaction (RT-PCR, using canine-specific primer sets. Results Histopathologically, xenograft tumors comprised a proliferation of neoplastic cells that were varied in shape, from spindle-shaped and polygonal to ovoid; some vascular-like structures and vascular clefts of channels were observed, similar to those in the original tumors. The expression of endothelial markers (CD31 and vWF was detected in xenograft tumors by immunohistochemistry and RT-PCR. Moreover, the expression of VEGF-A, bFGF, flt-1, flk-1, FGFR-1, HoxA9, HoxB3, HoxB7, HoxD3, Pbx1, and Meis1 was detected in xenograft tumors. Interestingly, expressions of bFGF tended to be higher in 3 of the xenograft HSA tumors than in the

  5. Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis.

    Science.gov (United States)

    Dunaway, Charlene M; Hwang, Yoonha; Lindsley, Craig W; Cook, Rebecca S; Wu, Jane Y; Boothby, Mark; Chen, Jin; Brantley-Sieders, Dana M

    2011-02-01

    Slit proteins induce cytoskeletal remodeling through interaction with roundabout (Robo) receptors, regulating migration of neurons and nonneuronal cells, including leukocytes, tumor cells, and endothelium. The role of Slit2 in vascular remodeling, however, remains controversial, with reports of both pro- and antiangiogenic activity. We report here that cooperation between Slit2 and ephrin-A1 regulates a balance between the pro- and antiangiogenic functions of Slit2. While Slit2 promotes angiogenesis in culture and in vivo as a single agent, Slit2 potently inhibits angiogenic remodeling in the presence of ephrin-A1. Slit2 stimulates angiogenesis through mTORC2-dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of ephrin-A1. Activated Rac or Akt partially rescues vascular assembly and motility in costimulated endothelium. Taken together, these data suggest that Slit2 differentially regulates angiogenesis in the context of ephrin-A1, providing a plausible mechanism for the pro- versus antiangiogenic functions of Slit2. Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms.

  6. Effects of netrin-1 and netrin-1 knockdown on human umbilical vein endothelial cells and angiogenesis of rat placenta.

    Science.gov (United States)

    Xie, H; Zou, L; Zhu, J; Yang, Y

    2011-08-01

    Angiogenesis is an important process essential for the development of placenta. Netrin-1 was first discovered in nervous system and was later found to play roles in angiogenesis. In order to better understand the functional relevance of netrin-1 in placental angiogenesis, we investigated the effect of netrin-1 on human umbilical vein endothelial cells (HUVECs) and rat placenta by employing up-regulation and down-regulation strategies. HUVECs and rat placenta were treated with recombinant netrin-1, and netrin-1 expression in the cells and placenta was reduced by short hairpin RNA (shRNA) in vitro and in vivo. The inhibition efficiency was determined by real-time quantitative polymerase chain reaction (RT-PCR) and Western blotting. The expression of netrin-1 was immunohistochemically located. The results demonstrated that netrin-1 promoted viability, proliferation, migration and tube formation of HUVECs. A strong reduction in cell capability was observed in vitro after netrin-1 expression was inhibited with shRNA. Netrin-1 accelerated neovascularization of placenta in pregnant rats. Suppression of netrin-1 expression in placenta resulted in reduced vascular sprouting in vivo. These findings suggest that netrin-1 is essential for the proper functioning of HUVECs and angiogenesis of rat placenta, and it is involved in the development of placenta and fetus. The proangiogenic effect of netrin-1 might offer an alternative therapeutic approach for the treatment of vascular disease of placenta.

  7. Multilevel complexity of calcium signaling:Modeling angiogenesis

    Institute of Scientific and Technical Information of China (English)

    Luca; Munaron; Marco; Scianna

    2012-01-01

    Intracellular calcium signaling is a universal,evolutionary conserved and versatile regulator of cell biochemistry.The complexity of calcium signaling and related cell machinery can be investigated by the use of experimental strategies,as well as by computational approaches.Vascular endothelium is a fascinating model to study the specific properties and roles of calcium signals at multiple biological levels.During the past 20 years,live cell imaging,patch clamp and other techniques have allowed us to detect and interfere with calcium signaling in endothelial cells(ECs),providing a huge amount of information on the regulation of vascularization(angiogenesis) in normal and tumoral tissues.These data range from the spatiotemporal dynamics of calcium within different cell microcompartments to those in entire multicellular and organized EC networks.Beside experimental strategies,in silico endothelial models,specifically designed for simulating calcium signaling,are contributing to our knowledge of vascular physiol-ogy and pathology.They help to investigate and predict the quantitative features of proangiogenic events moving through subcellular,cellular and supracellular levels.This review focuses on some recent developments of computational approaches for proangiogenic endothelial calcium signaling.In particular,we discuss the creation of hybrid simulation environments,which combine and integrate discrete Cellular Potts Models.They are able to capture the phenomenological mechanisms of cell morphological reorganization,migration,and intercellular adhesion,with single-cell spatiotemporal models,based on reaction-diffusion equations that describe the agonist-induced intracellular calcium events.

  8. Reciprocal interactions between endothelial cells and macrophages in angiogenic vascular niches

    Energy Technology Data Exchange (ETDEWEB)

    Baer, Caroline; Squadrito, Mario Leonardo [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland); Iruela-Arispe, M. Luisa, E-mail: arispe@mcdb.ucla.edu [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland); Department of Molecular, Cell and Developmental Biology and Molecular Biology Institute, University of California, Los Angeles 90095, CA (United States); De Palma, Michele, E-mail: michele.depalma@epfl.ch [The Swiss Institute for Experimental Cancer Research (ISREC), School of Life Sciences, Swiss Federal Institute of Technology Lausanne (EPFL), 1015 Lausanne (Switzerland)

    2013-07-01

    The ability of macrophages to promote vascular growth has been associated with the secretion and local delivery of classic proangiogenic factors (e.g., VEGF-A and proteases). More recently, a series of studies have also revealed that physical contact of macrophages with growing blood vessels coordinates vascular fusion of emerging sprouts. Interestingly, the interactions between macrophages and vascular endothelial cells (ECs) appear to be bidirectional, such that activated ECs also support the expansion and differentiation of proangiogenic macrophages from myeloid progenitors. Here, we discuss recent findings suggesting that dynamic angiogenic vascular niches might also exist in vivo, e.g. in tumors, where sprouting blood vessels and immature myeloid cells like monocytes engage in heterotypic interactions that are required for angiogenesis. Finally, we provide an account of emerging mechanisms of cell-to-cell communication that rely on secreted microvesicles, such as exosomes, which can offer a vehicle for the rapid exchange of molecules and genetic information between macrophages and ECs engaged in angiogenesis. -- Highlights: • Macrophages promote angiogenesis by secreting proangiogenic factors. • Macrophages modulate angiogenesis via cell-to-cell contacts with endothelial cells. • Endothelial cells promote the differentiation of proangiogenic macrophages. • Macrophages and endothelial cells may cooperate to form angiogenic vascular niches.

  9. 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.

  10. 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.

  11. Ephrin-A3 and ephrin-A4 contribute to microglia-induced angiogenesis in brain endothelial cells.

    Science.gov (United States)

    Li, Ying; Liu, Dong-Xin; Li, Mei-Yang; Qin, Xiao-Xue; Fang, Wen-Gang; Zhao, Wei-Dong; Chen, Yu-Hua

    2014-10-01

    The association of microglia with brain vasculature during development and the reduced brain vascular complexity in microglia-deficient mice suggest the role of microglia in cerebrovascular angiogenesis. However, the underlying molecular mechanism remains unclear. Here, using an in vitro angiogenesis model, we found the culture supernatant of BV2 microglial cells significantly enhanced capillary-like tube formation and migration of brain microvascular endothelial cells (BMECs). The expression of angiogenic factors, ephrin-A3 and ephrin-A4, were specifically upregulated in BMECs exposed to BV2-derived culture supernatant. Knockdown of ephrin-A3 and ephrin-A4 in BMECs by siRNA significantly attenuated the enhanced angiogenesis and migration of BMECs induced by BV2 supernatant. Our further results indicated that the ability of BV2 supernatant to promote endothelial angiogenesis was caused by the soluble tumor necrosis factor α (TNF-α) released from BV2 microglial cells. Moreover, the upregulations of ephrin-A3 and ephrin-A4 in BMECs in response to BV2 supernatant were effectively abolished by neutralization antibody against TNF-α and TNF receptor 1, respectively. The present study provides evidence that microglia upregulates endothelial ephrin-A3 and ephrin-A4 to facilitate in vitro angiogenesis of brain endothelial cells, which is mediated by microglia-released TNF-α.

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

    Directory of Open Access Journals (Sweden)

    Partha S Bhattacharjee

    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.

  13. Epidermal Growth Factor Treatment of the Adult Brain Subventricular Zone Leads to Focal Microglia/Macrophage Accumulation and Angiogenesis

    Directory of Open Access Journals (Sweden)

    Olle R. Lindberg

    2014-04-01

    Full Text Available One of the major components of the subventricular zone (SVZ neurogenic niche is the specialized vasculature. The SVZ vasculature is thought to be important in regulating progenitor cell proliferation and migration. Epidermal growth factor (EGF is a mitogen with a wide range of effects. When stem and progenitor cells in the rat SVZ are treated with EGF, using intracerebroventricular infusion, dysplastic polyps are formed. Upon extended infusion, blood vessels are recruited into the polyps. In the current study we demonstrate how polyps develop through distinct stages leading up to angiogenesis. As polyps progress, microglia/macrophages accumulate in the polyp core concurrent with increasing cell death. Both microglia/macrophage accumulation and cell death peak during angiogenesis and subsequently decline following polyp vascularization. This model of inducible angiogenesis in the SVZ neurogenic niche suggests involvement of microglia/macrophages in acquired angiogenesis and can be used in detail to study angiogenesis in the adult brain.

  14. VEGF and colon cancer growth beyond angiogenesis: does VEGF directly mediate colon cancer growth via a non-angiogenic mechanism?

    Science.gov (United States)

    Ahluwalia, Amrita; Jones, Michael K; Matysiak-Budnik, Tamara; Tarnawski, Andrzej S

    2014-01-01

    In this article we review the role of vascular endothelial growth factor (VEGF) in colon cancer growth and the underlying mechanisms. Angiogenesis, the growth of new capillary blood vessels in the body, is critical for tissue injury healing and cancer growth. In 1971, Judah Folkman proposed the concept that tumor growth beyond 2 mm is critically dependent on angiogenesis. Tumors including colon cancers release angiogenic growth factors that stimulate blood vessels to grow into the tumors thus providing oxygen and nutrients that enable exponential growth. VEGF is the most potent angiogenic growth factor. Several studies have highlighted the role of VEGF in colon cancer, specifically in the stimulation of angiogenesis. This role of VEGF is strongly supported by studies showing that inhibition of VEGF using the blocking antibody, bevacizumab, results in decreased angiogenesis and abrogation of cancer growth. In the United States, bevacizumab in combination with chemotherapy is FDA approved for the treatment of metastatic colon cancer. However, the source of VEGF in colon cancer tissue, the mechanisms of VEGF generation in colon cancer cells and the molecular pathways involved in VEGF mediated angiogenesis in colon cancer are not fully known. The possibility that VEGF directly stimulates cancer cell growth in an autocrine manner has not been explored in depth.

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

    Directory of Open Access Journals (Sweden)

    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.

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

    Science.gov (United States)

    Yin, Cunping; Liang, Yuan; Zhang, Jian; Ruan, Guangping; Li, Zian; Pang, Rongqing; Pan, Xinghua

    2016-01-01

    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.

  17. Glycosaminoglycan-based hydrogels to modulate heterocellular communication in in vitro angiogenesis models

    Science.gov (United States)

    Chwalek, Karolina; Tsurkan, Mikhail V.; Freudenberg, Uwe; Werner, Carsten

    2014-03-01

    Angiogenesis, the outgrowth of blood vessels, is crucial in development, disease and regeneration. Studying angiogenesis in vitro remains challenging because the capillary morphogenesis of endothelial cells (ECs) is controlled by multiple exogenous signals. Therefore, a set of in situ-forming starPEG-heparin hydrogels was used to identify matrix parameters and cellular interactions that best support EC morphogenesis. We showed that a particular type of soft, matrix metalloproteinase-degradable hydrogel containing covalently bound integrin ligands and reversibly conjugated pro-angiogenic growth factors could boost the development of highly branched, interconnected, and lumenized endothelial capillary networks. Using these effective matrix conditions, 3D heterocellular interactions of ECs with different mural cells were demonstrated that enabled EC network modulation and maintenance of stable vascular capillaries over periods of about one month in vitro. The approach was also shown to permit in vitro tumor vascularization experiments with unprecedented levels of control over both ECs and tumor cells. In total, the introduced 3D hydrogel co-culture system could offer unique options for dissecting and adjusting biochemical, biophysical, and cell-cell triggers in tissue-related vascularization models.

  18. Study on Angiogenesis Factor of Human Osteosarcoma

    Institute of Scientific and Technical Information of China (English)

    2000-01-01

    Angiogenesis factor of human osteosarcoma was partially purified and its biological features were studied. The active peptide with 8000 to 10 000 u molecular weight in the conditioned medium obtained from the cultivation of human osteosarcoma cells were partially purified by ultrafiltration, chromatography and dialysis. The angiogenic effects of the fractions were assessed by proliferation assay of human umbilical vein and pig aorta thoracic endothelial cells. The results showed that the chromatography fractions of 4 to 6 could significantly promote the proliferation of the endothelial cells. It was suggested that the human osteosarcoma cells could synthesize and secrete angiogenesis factor with a molecular weight of 8000 to 10 000 u.

  19. In Vivo Models of Muscle Angiogenesis.

    Science.gov (United States)

    Egginton, Stuart

    2016-01-01

    Angiogenesis is an important determinant of tissue function, from delivery of oxygen and other substrates to removal of waste products, in health and disease (e.g., adaptive or pathological remodelling). The phenotype and functional responses of endothelial cells are conditioned by systemic humoral signals and local environmental factors, including the haemodynamic forces that act upon them. Here we describe some interventions that have been helpful in unraveling the integrative nature of the complex in vivo response, and quantitative assessment of angiogenesis in muscle.

  20. The Antiangiogenic Effects of a Vascular Endothelial Growth Factor Decoy Receptor Can Be Monitored in Vivo Using Contrast-Enhanced Ultrasound Imaging

    Directory of Open Access Journals (Sweden)

    Flemming Forsberg

    2014-03-01

    Full Text Available The development of antiangiogenic therapies has stimulated interest in noninvasive imaging methods to monitor response. We investigated whether the effects of a vascular endothelial growth factor decoy receptor (VEGF Trap, Regeneron Pharmaceuticals, Tarrytown, NY could be monitored in vivo using contrast-enhanced ultrasonography (CEUS. Twenty nude mice (in two groups were implanted with a human melanoma cell line (DB-1. The active group received VEGF Trap (4 × 25 mg/kg over 2 weeks, whereas the control group received an inactive protein. An ultrasound contrast agent was injected followed by power Doppler imaging (PDI and pulse inversion harmonic imaging (PIHI; regular and intermittent. Specimens were sectioned in the same planes as the images and stained for endothelial cells (CD31, cyclooxygenase-2 (COX-2, VEGF, and hypoxia (Glut1. Measures of tumor vascularity obtained with the different imaging modes were compared to immunohistochemical markers of angiogenesis. Mean tumor volume was smaller in the active group than in the control group (656 ± 225 vs 1,160 ± 605 mm3. Overall, PDI and VEGF correlated (r = .34; p = .037. Vascularity decreased from control to treated mice with intermittent PIHI, as did the expression of CD31 and COX-2 (p # .02, whereas VEGF increased (p = .05. CEUS appears to allow in vivo monitoring of the antiangiogenic effects of VEGF Trap in the DB-1 human melanoma xenograft model.

  1. Targeting oncogenic KRAS in non-small cell lung cancer cells by phenformin inhibits growth and angiogenesis

    OpenAIRE

    2015-01-01

    Tumors require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors. Many potential oncogenic mutations have been identified in tumor angiogenesis. Somatic mutations in the small GTPase KRAS are the most common activating lesions found in human cancer, and are generally associated with poor response to standard therapies. Biguanides, such as the diabetes therapeutics metformin and phenformin, have demonstrated anti-tumor activity both in vitro and...

  2. Targeting angiogenesis-dependent calcified neoplasms using combined polymer therapeutics.

    Directory of Open Access Journals (Sweden)

    Ehud Segal

    Full Text Available BACKGROUND: 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. METHODS AND FINDING: The anti-angiogenic and antitumor potency of HPMA co