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Sample records for vascular factors angiogenesis

  1. Vascular grading of angiogenesis

    DEFF Research Database (Denmark)

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

    2000-01-01

    years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers...

  2. Vascular grading of angiogenesis

    DEFF Research Database (Denmark)

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

    2000-01-01

    The study aimed to evaluate the prognostic value of angiogenesis by vascular grading of primary breast tumours, and to evaluate the prognostic impact of adding the vascular grade to the Nottingham Prognostic Index (NPI). The investigation included 836 patients. The median follow-up time was 11...... years and 4 months. The microvessels were immunohistochemically stained by antibodies against CD34. Angiogenesis was graded semiquantitatively by subjective scoring into three groups according to the expected number of microvessels in the most vascular tumour area. The vascular grading between observers...... 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...

  3. A novel compound, NP-184, inhibits the vascular endothelial growth factor induced angiogenesis.

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    Lin, Kuan-Ting; Lien, Jin-Cherng; Chung, Ching-Hu; Kuo, Sheng-Chu; Huang, Tur-Fu

    2010-03-25

    Angiogenesis is observed in many diseases, such as tumor progression, diabetes and rheumatoid arthritis; it is a process that involves proliferation, migration, differentiation and tube formation of endothelial cells. Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis by induction of these endothelial functions. Thus, inhibition of these critical angiogenic steps is a practical therapeutic strategy for those diseases. NP-184 is a substituted benzimidazole analogue which exhibits a potent anti-thrombotic activity. In this report, NP-184 inhibited the viability of human umbilical vascular endothelial cells (HUVEC) in a concentration-dependent manner, and caused cell apoptosis as examined by cell-cycle analysis and Annexin V staining with flow cytometry. NP-184 also concentration-dependently inhibited the HUVEC migration, tube formation on Matrigel, and rat aortic ring sprouting stimulated by VEGF. Regarding the intracellular signal transduction, NP-184 concentration-dependently interfered with the activation of AKT, ERK and the nuclear translocation of NF-kappaB. In vivo study showed that NP-184 dose-dependently reduced angiogenesis in Matrigel plug assay. These results indicate that NP-184 is a potential candidate for developing the treatment of angiogenesis related-diseases.

  4. 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.

  5. Leptin and vascular endothelial growth factor regulate angiogenesis in tooth germs.

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    Ide, Shinji; Tokuyama, Reiko; Davaadorj, Purevsuren; Shimozuma, Masashi; Kumasaka, Shuku; Tatehara, Seiko; Satomura, Kazuhito

    2011-03-01

    Leptin, a 16 kDa non-glycolated polypeptide of 146 amino acids produced by the ob gene, has a variety of physiological roles not only in lipid metabolism, hematopoiesis, thermogenesis and ovarian function, but also in angiogenesis. This study focuses to investigate the possibility that leptin, as an angiogenic factor, may regulate the angiogenesis during tooth development. We firstly studied the expression of leptin and vascular endothelial growth factor (VEGF) during tooth development immunohistochemically. This investigation revealed that leptin is expressed in ameloblasts, odontoblasts, dental papilla cells and stratum intermedium cells. This expression pattern was similar to that of VEGF, one of the most potent angiogenic factors. Interestingly, more leptin-positive cells were observed in the upper third portion of dental papilla, which is closest to odontoblastic layer, compared to middle and lower thirds. Moreover, in the dental papilla, more CD31 and/or CD34-positive vascular endothelial cells were observed in the vicinity of ameloblasts and odontoblasts expressing leptin and VEGF. These findings strongly suggest that ameloblasts, odontoblasts and dental papilla cells induce the angiogenesis in tooth germs by secretion of leptin as well as VEGF.

  6. Inhibition of vascular endothelial growth factor (VEGF)-induced endothelial proliferation, arterial relaxation, vascular permeability and angiogenesis by dobesilate.

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    Angulo, Javier; Peiró, Concepción; Romacho, Tania; Fernández, Argentina; Cuevas, Begoña; González-Corrochano, Rocío; Giménez-Gallego, Guillermo; de Tejada, Iñigo Sáenz; Sánchez-Ferrer, Carlos F; Cuevas, Pedro

    2011-09-30

    Vascular endothelial growth factor (VEGF) is a key factor in angiogenesis and vascular permeability which is associated with many pathological processes. 2,5-hydroxybenzene sulfonate (DHBS; dobesilate) is a small molecule with anti-angiogenic activity that has been described as an inhibitor of fibroblast growth factors (FGF). The aim of the present study was to evaluate the effects of DHBS on VEGF-induced actions. The effects of DHBS were evaluated on VEGF-induced proliferation in human umbilical vein endothelial cells (HUVEC) and rat aorta relaxation, as well as on in vivo VEGF-induced skin vascular permeability and neovascularization in rats. DHBS at 50 and 100 μM concentration significantly inhibited the proliferation of HUVEC induced by VEGF (10 ng/ml), without significantly affecting HUVEC proliferation in the absence of VEGF. Rapid VEGF-induced activation of Akt in HUVEC was also prevented by DHBS (100 μM). Additionally, DHBS (2 μM) specifically inhibited the relaxation of rat aorta induced by VEGF (0.1 to 30 ng/ml), but not endothelium-dependent relaxation to acetylcholine (1 nM to 10 μM). The in vivo enhancement of vascular permeability caused by VEGF injection (50 μl at 10 ng/ml) in rat skin was also inhibited by DHBS co-administration (200 μM) (74.8±3.8% inhibition of dye extravasation). Administration of DHBS (200 mg/kg/day; i.p.) also reduced VEGF-induced angiogenesis in vivo. DHBS inhibits main responses elicited in vitro and in vivo by VEGF. As a dual antagonist of VEGF and FGF activities, DHBS could be of therapeutic interest in the treatment of diseases related to VEGF/FGF overproduction and excessive angiogenesis. Copyright © 2011 Elsevier B.V. All rights reserved.

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

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    Jingshan Zhao

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

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

    Science.gov (United States)

    Zhao, Jingshan; Niu, Honglin; Li, Aiying; Nie, Lei

    2016-01-01

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

  9. 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.

  10. Clopidogrel inhibits angiogenesis of gastric ulcer healing via downregulation of vascular endothelial growth factor receptor 2.

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    Luo, Jiing-Chyuan; Peng, Yen-Ling; Chen, Tseng-Shing; Huo, Teh-Ia; Hou, Ming-Chih; Huang, Hui-Chun; Lin, Han-Chieh; Lee, Fa-Yauh

    2016-09-01

    Although clopidogrel does not cause gastric mucosal injury, it does not prevent peptic ulcer recurrence in high-risk patients. We explored whether clopidogrel delays gastric ulcer healing via inhibiting angiogenesis and to elucidate the possible mechanisms. Gastric ulcers were induced in Sprague Dawley rats, and ulcer healing and angiogenesis of ulcer margin were compared between clopidogrel-treated rats and controls. The expressions of the proangiogenic growth factors and their receptors including basic fibroblast growth factor (bFGF), bFGF receptor (FGFR), vascular endothelial growth factor (VEGF), VEGFR1, VEGFR2, platelet-derived growth factor (PDGF)A, PDGFB, PDGFR A, PDGFR B, and phosphorylated form of mitogenic activated protein kinase pathways over the ulcer margin were compared via western blot and reverse transcription polymerase chain reaction. In vitro, human umbilical vein endothelial cells (HUVECs) were used to elucidate how clopidogrel inhibited growth factors-stimulated HUVEC proliferation. The ulcer sizes were significantly larger and the angiogenesis of ulcer margin was significantly diminished in the clopidogrel (2 and 10 mg/kg/d) treated groups. Ulcer induction markedly increased the expression of phosphorylated form of extracellular signal-regulated kinase (pERK), FGFR2, VEGF, VEGFR2, and PDGFRA when compared with those of normal mucosa. Clopidogrel treatment significantly decreased pERK, FGFR2, VEGF, VEGFR2, and PDGFRA expression at the ulcer margin when compared with those of the respective control group. In vitro, clopidogrel (10(-6)M) inhibited VEGF-stimulated (20 ng/mL) HUVEC proliferation, at least, via downregulation of VEGFR2 and pERK. Clopidogrel inhibits the angiogenesis of gastric ulcer healing at least partially by the inhibition of the VEGF-VEGFR2-ERK signal transduction pathway. Copyright © 2015. Published by Elsevier B.V.

  11. Vascular endothelial growth factor and basic fibroblast growth factor differentially modulate early postnatal coronary angiogenesis.

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    Tomanek, R J; Sandra, A; Zheng, W; Brock, T; Bjercke, R J; Holifield, J S

    2001-06-08

    The roles of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF [FGF-2]) in early postnatal regulation of coronary angiogenesis were investigated by administering neutralizing antibodies to these growth factors between postnatal days 5 and 12. Immunohistochemistry and Western blotting both revealed decreases in VEGF protein in the hearts of rats treated with either antibody. In contrast, bFGF mRNA increased in both treated groups, whereas VEGF mRNA was unchanged. Using stereological assessment of perfusion-fixed hearts, we found that both anti-VEGF and anti-bFGF inhibited the rapid and marked capillary growth that occurs during this time period and that the effects of the two neutralizing antibodies are not additive. Arteriolar growth, as indicated by a lower length density, was inhibited by anti-bFGF, but not anti-VEGF. When both anti-VEGF and anti-bFGF were administered, arteriolar length density was not significantly lower, but the population of small arterioles (<15 microm) was markedly reduced, whereas the percentage of large arterioles (26 to 50 microm) more than doubled. Thus, inhibition of both growth factors negated or limited the formation of small arterioles and facilitated an expansion of the largest arterioles. These in vivo data are the first to document that during the early neonatal period, (1) both VEGF and bFGF modulate capillary growth, (2) bFGF facilitates arteriolar growth, and (3) the two growth factors interact to establish the normal hierarchy of the arteriolar tree.

  12. Overexpression of clusterin promotes angiogenesis via the vascular endothelial growth factor in primary ovarian cancer.

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    Fu, Yanxia; Lai, Yingrong; Wang, Qiongjuan; Liu, Xingyang; He, Weipeng; Zhang, Haihong; Fan, Chunyang; Yang, Guofen

    2013-06-01

    Clusterin (CLU), a multifunctional glycoprotein, is ubiquitously produced in mammalian tissues. CLU has been shown to play significant roles in many of the biological behaviours of human tumors, such as cell proliferation, apoptosis, chemoresistance and angiogenesis. However, the relationship of CLU expression with angiogenesis in ovarian cancer has not been studied. A total of 275 epithelial ovarian tumors were obtained from archives of paraffin‑embedded tissues. Immunohistochemical (IHC) staining for CLU and vascular endothelial growth factor (VEGF) was performed on a tissue microarray (TMA) including 181 primary ovarian epithelial cancer, 40 borderline ovarian tumors and 54 ovarian cancer mesenteric metastasis samples. Of the 174 cases, overexpression of CLU and VEGF were detected in 107 (61.5%) and 109 (62.9%) cases of primary ovarian carcinoma, respectively. Of the 107 cases of primary ovarian carcinoma with overexpression of CLU, expression of VEGF was increased in 82 (75.2%) cases. However, in another 67 cases without CLU overexpression, overexpression of VEGF was observed in only 27 (24.8%) cases (Povarian cancer appears to be correlated with increased tumor angiogenesis, consistent with the established role of CLU as an oncogene in the biology of ovarian cancer. In the treatment of ovarian cancer, these two markers may be used in the selection of patients for targeted therapy.

  13. Apatinib-loaded nanoparticles suppress vascular endothelial growth factor-induced angiogenesis and experimental corneal neovascularization.

    Science.gov (United States)

    Lee, Jung Eun; Kim, Koung Li; Kim, Danbi; Yeo, Yeongju; Han, Hyounkoo; Kim, Myung Goo; Kim, Sun Hwa; Kim, Hyuncheol; Jeong, Ji Hoon; Suh, Wonhee

    2017-01-01

    Pathological angiogenesis is one of the major symptoms of severe ocular diseases, including corneal neovascularization. The blockade of vascular endothelial growth factor (VEGF) action has been recognized as an efficient strategy for treating corneal neovascularization. In this study, we aimed to investigate whether nanoparticle-based delivery of apatinib, a novel and selective inhibitor of VEGF receptor 2, inhibits VEGF-mediated angiogenesis and suppresses experimental corneal neovascularization. Water-insoluble apatinib was encapsulated in nanoparticles composed of human serum albumin (HSA)-conjugated polyethylene glycol (PEG). In vitro angiogenesis assays showed that apatinib-loaded HSA-PEG (Apa-HSA-PEG) nanoparticles potently inhibited VEGF-induced tube formation, scratch wounding migration, and proliferation of human endothelial cells. In a rat model of alkali burn injury-induced corneal neovascularization, a subconjunctival injection of Apa-HSA-PEG nanoparticles induced a significant decrease in neovascularization compared to that observed with an injection of free apatinib solution or phosphate-buffered saline. An in vivo distribution study using HSA-PEG nanoparticles loaded with fluorescent hydrophobic model drugs revealed the presence of a substantial number of nanoparticles in the corneal stroma within 24 h after injection. These in vitro and in vivo results demonstrate that apatinib-loaded nanoparticles may be promising for the prevention and treatment of corneal neovascularization-related ocular disorders.

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

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    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. Copyright © 2014 Elsevier Inc. All rights reserved.

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

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    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.

  16. Angiogenesis, Cancer, and Vascular Aging

    OpenAIRE

    Junji Moriya; Tohru Minamino

    2017-01-01

    Several lines of evidence have revealed that the angiogenic response to ischemic injury declines with age, which might account for the increased morbidity and mortality of cardiovascular disease (CVD) among the elderly. While impairment of angiogenesis with aging leads to delayed wound healing or exacerbation of atherosclerotic ischemic diseases, it also inhibits the progression of cancer. Age-related changes of angiogenesis have been considered to at least partly result from vascular aging o...

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

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

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    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.

  19. Induction of angiogenesis and modulation of vascular endothelial growth factor receptor-2 by simvastatin after traumatic brain injury.

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    Wu, Hongtao; Jiang, Hao; Lu, Dunyue; Qu, Changsheng; Xiong, Ye; Zhou, Dong; Chopp, Michael; Mahmood, Asim

    2011-05-01

    Our previous studies demonstrated that simvastatin reduced neuronal death, increased neurogenesis, and promoted functional recovery after traumatic brain injury (TBI). To investigate the effect of simvastatin on angiogenesis after TBI and the related signaling pathways. Saline or simvastatin (1 mg/kg) was administered orally to rats starting at day 1 after TBI or sham surgery and then daily for 14 days. Rats were sacrificed at 3 and 14 days after treatment. Brain sections and tissues were prepared for immunohistochemical staining, enzyme-linked immunosorbent assay, and Western blot analysis. Cultured rat brain microvascular endothelial cells were subjected to oxygen-glucose deprivation followed by immunocytochemical staining with phallotoxins and vascular endothelial growth factor receptor-2 (VEGFR-2). Western blot analysis was carried out to examine the simvastatin-induced activation of the v-akt murine thymoma viral oncogene homolog (Akt) signaling pathway. The expression of VEGFR-2 was detected by enzyme-linked immunosorbent assay. Simvastatin significantly increased the length of vascular perimeter, promoted the proliferation of endothelial cells, and improved the sensorimotor function after TBI. Simvastatin stimulated endothelial cell tube formation after oxygen-glucose deprivation in vitro. VEGFR-2 expression in both brain tissues and cultured rat brain microvascular endothelial cells was enhanced after simvastatin treatment, which may be modulated by activation of Akt. Akt-dependent endothelial nitric oxide synthase phosphorylation was also induced by simvastatin in vivo and in vitro. Simvastatin augments TBI-induced angiogenesis in the lesion boundary zone and hippocampus and improves functional recovery. Simvastatin also promotes angiogenesis in vitro. These beneficial effects on angiogenesis may be related to simvastatin-induced activation of the VEGFR-2/Akt/endothelial nitric oxide synthase signaling pathway.

  20. Interplay between vascular endothelial growth factor-A and extracellular matrix in angiogenesis: molecular and cellular mechanisms

    OpenAIRE

    Traub, Stephanie

    2011-01-01

    The induction of angiogenesis by stimulation of physiological vessel growth using pro- angiogenic growth factors is currently under intense investigation in medical research. It is well accepted, that angiogenesis is a rate-limiting step in skin regeneration, as it ensures supply of novel tissue with nutrients and oxygen. Chronic wounds are characterized by a lack of angiogenesis and thus represent a major target for the induction of angiogenesis by therapeutic means. For the delivery of VEGF...

  1. Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats.

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    Coch, Laura; Mejias, Marc; Berzigotti, Annalisa; Garcia-Pras, Ester; Gallego, Javier; Bosch, Jaime; Mendez, Raul; Fernandez, Mercedes

    2014-08-01

    Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the contribution and therapeutic impact of the endogenous angioinhibitor vasohibin-1 in portal hypertension and cirrhosis. The spatiotemporal expression profiling of vasohibin-1 and its relationship with vascular endothelial growth factor (VEGF), angiogenesis, and fibrogenesis was determined through the analysis of human cirrhotic liver specimens, widely accepted in vivo animal models of portal hypertension and cirrhosis, and in vitro angiogenesis assays. Effects of vasohibin-1 overexpression by adenoviral-mediated gene transfer on angiogenesis, fibrogenesis, and portal hypertension-associated hemodynamic alterations were also studied in rats. We found that vasohibin-1 and VEGF are up-regulated, in mesentery and liver, in cirrhotic and precirrhotic portal hypertensive rats and cirrhosis patients. Our results are consistent with vasohibin-1/VEGF cascades being spatially and temporally coordinated through a negative-feedback loop driving pathological angiogenesis. Paradoxically, further overexpression of vasohibin-1 by adenoviral gene transfer exerts multifold beneficial effects in portal hypertension and cirrhosis: reduction of pathologic angiogenesis, attenuation of liver fibrogenesis partly mediated through inhibition of hepatic stellate cell activation, and significant decreases in portocollateralization, splanchnic blood flow, portohepatic resistance, and portal pressure. The explanation for this apparent contradiction is that, unlike endogenous vasohibin-1, the ectopic overexpression is not regulated by VEGF and therefore disrupts the negative-feedback loop, thus generating constant, but lower levels of VEGF synthesis sufficient to maintain vascular

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

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

    2015-02-28

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

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

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    Schlieve, Christopher R; Mojica, Salvador Garcia; Holoyda, Kathleen A; Hou, Xiaogang; Fowler, Kathryn L; Grikscheit, Tracy C

    2016-01-01

    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. 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. 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. 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 cell therapies for intestinal

  4. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188.

    Science.gov (United States)

    Maes, Christa; Carmeliet, Peter; Moermans, Karen; Stockmans, Ingrid; Smets, Nico; Collen, Désiré; Bouillon, Roger; Carmeliet, Geert

    2002-02-01

    Vascular endothelial growth factor (VEGF)-mediated angiogenesis is an important part of bone formation. To clarify the role of VEGF isoforms in endochondral bone formation, we examined long bone development in mice expressing exclusively the VEGF120 isoform (VEGF120/120 mice). Neonatal VEGF120/120 long bones showed a completely disturbed vascular pattern, concomitant with a 35% decrease in trabecular bone volume, reduced bone growth and a 34% enlargement of the hypertrophic chondrocyte zone of the growth plate. Surprisingly, embryonic hindlimbs at a stage preceding capillary invasion exhibited a delay in bone collar formation and hypertrophic cartilage calcification. Expression levels of marker genes of osteoblast and hypertrophic chondrocyte differentiation were significantly decreased in VEGF120/120 bones. Furthermore, inhibition of all VEGF isoforms in cultures of embryonic cartilaginous metatarsals, through the administration of a soluble receptor chimeric protein (mFlt-1/Fc), retarded the onset and progression of ossification, suggesting that osteoblast and/or hypertrophic chondrocyte development were impaired. The initial invasion by osteoclasts and endothelial cells into VEGF120/120 bones was retarded, associated with decreased expression of matrix metalloproteinase-9. Our findings indicate that expression of VEGF164 and/or VEGF188 is important for normal endochondral bone development, not only to mediate bone vascularization but also to allow normal differentiation of hypertrophic chondrocytes, osteoblasts, endothelial cells and osteoclasts.

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

    Directory of Open Access Journals (Sweden)

    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.

  6. 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

  7. Combined angiopoietin-1 and vascular endothelial growth factor gene transfer restores cavernous angiogenesis and erectile function in a rat model of hypercholesterolemia.

    Science.gov (United States)

    Ryu, Ji-Kan; Cho, Chung-Hyun; Shin, Hwa-Yean; Song, Sun U; Oh, Seung-Min; Lee, Minhyung; Piao, Shuguang; Han, Jee-Young; Kim, In-Hoo; Koh, Gou Young; Suh, Jun-Kyu

    2006-04-01

    Hypercholesterolemia-related endothelial cell dysfunction and decreased endothelium-derived nitric oxide formation may account for impaired angiogenesis and subsequent erectile dysfunction. Angiopoietin-1 (Ang1) is a critical angiogenic factor for vascular maturation and enhances vascular endothelial growth factor (VEGF)-induced angiogenesis in a complementary manner. We hypothesized that combined adenovirus-delivered human Ang1 (ad-Ang1) and VEGF165 (ad-VEGF165) gene transfer might promote angiogenesis cooperatively in a rat model of hypercholesterolemic erectile dysfunction and result in a recovery of erectile function. Ad-Ang1 and ad-VEGF165 were injected either alone or in combination into the corpus cavernosum of the penis. Combined gene transfer of both ad-Ang1 and ad-VEGF165 significantly increased cavernous angiogenesis, eNOS phosphorylation, and cGMP expression compared with that in the groups treated with either therapy alone. Erectile function, as evaluated by electrical stimulation of the cavernous nerve 2 and 8 weeks after treatment, was completely restored in the combined treatment group, whereas intracavernous injection of either ad-Ang1 or ad-VEGF165 alone elicited partial improvement. The results indicate that combined application of angiogenic factors may enhance cavernous angiogenesis cooperatively by reinforcing the endothelium both structurally and functionally, which results in an additive effect on erectile function in hypercholesterolemic rats.

  8. 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; Germain, Stéphane

    2016-01-01

    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. Significance The results from the present study show that fibroblast growth factor-2 (FGF-2) priming is more

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

    Science.gov (United States)

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

    2013-01-01

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

  10. 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.

  11. 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

  12. Anti-Cancer Activity of an Osthole Derivative, NBM-T-BMX-OS01: Targeting Vascular Endothelial Growth Factor Receptor Signaling and Angiogenesis

    Science.gov (United States)

    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. PMID:24312323

  13. 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.

  14. 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.

  15. Role of caveolin-1/vascular endothelial growth factor pathway in basic fibroblast growth factor-induced angiogenesis and neurogenesis after treadmill training following focal cerebral ischemia in rats.

    Science.gov (United States)

    Pang, Qiongyi; Zhang, Huimei; Chen, Zhenzhen; Wu, Yudan; Bai, Min; Liu, Yidian; Zhao, Yun; Tu, Fengxia; Liu, Chan; Chen, Xiang

    2017-05-15

    Exercise is known to aid functional recovery following ischemia, though the mechanisms responsible for the beneficial effects of exercise on recovery from ischemic stroke are not fully understood. Basic fibroblast growth factor (bFGF) contributes to angiogenesis and promotes neurologic functional recovery after stroke. The present study aimed to investigate the possible mechanisms whereby treadmill exercise ameliorated impaired angiogenesis and neurogenesis following transient cerebral ischemia in middle cerebral artery occlusion (MCAO) rats. Treadmill exercise was started 2days after ischemia-reperfusion in MCAO rats and continued until 7 or 28days after MCAO, after which the animals were sacrificed. Changes in neurological deficit, infarction volume, neuronal morphology, expression levels of bFGF, caveolin-1, and vascular endothelial growth factor (VEGF), and angiogenesis and neurogenesis in the ischemic penumbra were examined by reverse transcription-polymerase chain reaction, western blots, and/or double immunofluorescence. The results suggested that treadmill exercise promoted the expression of bFGF, improved neurological recovery, and reduced infarct volume compared with non-exercised rats, and also enhanced the expression of caveolin-1, VEGF, VEGF receptor 2(FIK-1)/CD34, and Brdu/nestin staining. Small interfering RNA targeting bFGF blocked the protective effects of bFGF. In addition, 4weeks of post-stroke recovery still ameliorated ischemia-induced damage without bFGF shRNA. These findings suggest a novel mechanism underlying the beneficial effects of bFGF following stroke, and indicate that treadmill exercise may aid stroke recovery by regulating the caveolin-1/VEGF pathway in the ischemic zone. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. [Recombinant AAV1 mediated vascular endothelial growth factor gene expression promotes angiogenesis and improves neural function: experiment with rats].

    Science.gov (United States)

    Li, Shi-fang; Meng, Qing-hai; Yao, Wei-cheng; Hu, Guo-jie; Li, Gui-lin; Li, Zhao-jian; Wei, Jun-ji; Bo, Yong-li; Zhang, Zi-heng; Wang, Ren-zhi

    2009-01-20

    To investigate the therapeutic effect of vascular endothelial growth factor (VEGF) gene expression mediated by recombinant AAV1 (rAAV1) vector in brain ischemia and the mechanism thereof. Sixty-four SD rats were randomly divided into 2 equal groups and received intra-ventricular injection with rAAV1-VEGF or rAAV1-lacZ as controls. 21 days later the rats underwent transient middle cerebral artery occlusion (MCAO). Neurological severity score (NSS) was recorded 1, 2, 3, 7, 14, and 21 days after MCAO. 48 rats were sacrificed 21 days after MCAO and brains were taken out from 48 rats. Immune quantitative analysis was used to identify the quantity of VEGF expression. Immunohistochemistry was used to identify the site of VEGF expression. Immunofluorescence double labeling of von Willebrand factor (vWF) and 5-bromodeoxy-uridine (BrdU) was performed to detect the proliferation of endothelial cells. Fluorescein isothiocyanate (FITC)-dextran was infused into the caudal vein of 8 rats from each group and then the rats were killed with their brains taken out to evaluate the cerebral microvessel perfusion and microvessel density. The NSSs of the VEGF group 7, 14, and 21 days after MCAO were all significantly lower than those of the control group (all P < 0.05), and the VEGF165 protein expression quantity was 27 times as that of the control group (P < 0.05). Immunohistochemistry demonstrated that VEGF expression was distributed mainly in the caudate putamen, corpus callosum, choroid plexus, and hippocampus in the VEGF group, while no expression was detected in the control group. The microvessel density of the VEGF group was 157 +/- 13, significantly higher than that of the control group [(89 +/- 9), P < 0.05]. BrdU +/vWF + endothelial cells were detected in the area adjacent to the MCAO. The density of microvessel infused with FITC-dextran was (152,617 +/- 13,076) microm2/mm2 in the VEGF group, significantly higher than that of the control group [(91,658 +/- 6577) microm2/mm2 P

  17. 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.

  18. Grifola frondosa (maitake mushroom) water extract inhibits vascular endothelial growth factor-induced angiogenesis through inhibition of reactive oxygen species and extracellular signal-regulated kinase phosphorylation.

    Science.gov (United States)

    Lee, Jong-Suk; Park, Byung Chul; Ko, Yu Jin; Choi, Mi Kyoung; Choi, Han Gon; Yong, Chul Soon; Lee, Jae-Sung; Kim, Jung-Ae

    2008-12-01

    Grifola frondosa, a large edible mushroom also known as maitake, has been used as a health food for centuries in China and Japan. In the present study, we examined anti-angiogenic activity of a water extract of the fruiting body of G. frondosa (GFW). An in vivo angiogenesis assay using chick chorioallantoic membrane revealed that GFW (1-100 microg/mL) dose-dependently inhibited vascular endothelial growth factor (VEGF)-induced angiogenesis. In addition, GFW inhibited VEGF-induced proliferation, chemotactic migration, and capillary-like tube formation of human umbilical vein endothelial cells (HUVECs) in a concentration-dependent manner. Upon stimulation by VEGF, HUVECs rapidly increased reactive oxygen species production, which was significantly blocked by the treatment with GFW. Moreover, phosphorylation of extracellular signal-regulated kinase 1/2, a downstream signaling molecule following VEGF receptor activation, was also inhibited by GFW. The results indicate that GFW effectively inhibit angiogenesis by blocking VEGF signaling and suggest that G. frondosa fruiting body may be a valuable medicinal food for treatment of angiogenesis-associated human diseases.

  19. 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.

  20. 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

    compared to both colorectal liver metastases (p=0.10) and normal liver tissue (p=0.06). In neuroendocrine tumors, gene-expression was highly variable of VEGF (530-fold), integrin alphaV (23-fold) and integrin beta3 (106-fold). Quantitative gene-expression levels of the key angiogenesis molecules VEGF......, 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 (pbeta3 there was also a borderline significant lower level of mRNA in neuroendocrine tumors...

  1. MSCs transfected with hepatocyte growth factor or vascular endothelial growth factor improve cardiac function in the infarcted porcine heart by increasing angiogenesis and reducing fibrosis.

    Science.gov (United States)

    Lu, Fanglin; Zhao, Xianxian; Wu, Jun; Cui, Yong; Mao, Yanjun; Chen, Kebiao; Yuan, Yang; Gong, Dejun; Xu, Zhiyun; Huang, Shengdong

    2013-09-10

    Cell transplantation and gene therapy have been demonstrated to have beneficial effects after a myocardial infarction (MI). Here, we used a large animal model of MI to investigate the beneficial effects of mesenchymal stem cells (MSCs) transfected with hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) genes. A porcine MI model was created by balloon occlusion of the distal left anterior descending artery for 90 min followed by reperfusion. At 1 week after MI, the pigs were infused via the coronary vein with saline (n=8), MSCs + AdNull(n=8), MSC+VEGF(n=10), or MSC+HGF(n=10). Cardiac function and myocardial perfusion were evaluated by using echocardiography and gated cardiac perfusion imaging before and 4 weeks after transplantation. Morphometric and histological analyses were performed. All cell-implanted groups had better cardiac function than the saline control group. There were further functional improvements in the MSC+HGF group, accompanied by smaller infarct sizes, increased cell survival, and less collagen deposition. Blood vessel densities in the damaged area and cardiac perfusion were significantly greater in the MSC+AdNull group than in the saline control group, and further increased in the MSC+VEGF/HGF groups. Tissue fibrosis was significantly less extensive in the MSC and MSC+VEGF groups than in the saline control group and was most reduced in the MSC+HGF group. MSCs (alone or transfected with VEGF/HGF) delivered into the infarcted porcine heart via the coronary vein improved cardiac function and perfusion, probably by increasing angiogenesis and reducing fibrosis. MSC+HGF was superior to MSC+VEGF, possibly owing to its enhanced antifibrotic effect. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  2. Hypoxia-inducible factor-1α, vascular endothelial growth factor, inducible nitric oxide synthase, and endothelin-1 expression correlates with angiogenesis in congenital heart disease

    Directory of Open Access Journals (Sweden)

    Hsin-Ling Yin

    2016-07-01

    Full Text Available In Taiwan, the average prevalence of congenital heart disease (CHD is 13.08/1000 live births. Most children with CHD die before the age of 5 years; therefore, identifying treatment methods to extend the life of CHD patients is an important issue in clinical practice. The objective of this study is to evaluate the roles of hypoxia-inducible factor-1α (HIF-1α, vascular endothelial growth factor (VEGF, inducible nitric oxide synthase (iNOS, endothelin-1 (ET-1, and CD34 in CHD autopsy cases in comparison with autopsy cases without CHD. The study included 19 autopsy cases, which were divided into the following four groups: acyanotic CHD (n = 11, cyanotic CHD (n = 3, CHD associated with chromosomal abnormalities (n = 3, and complex CHD (n = 2. Heart specimens obtained from 10 autopsy cases without CHD were included as controls. Our results indicated that high percentages of HIF-1α (100%, VEGF (89.5%, iNOS (78.9%, and ET-1 (84.2% expressions were observed in CHD autopsy cases and this was found to be significant. HIF-1α induced by hypoxia could play a potential role in relating downstream gene expressions in CHD patients. Upregulation of VEGF by HIF-1α could play an important role in triggering angiogenesis to protect myocardial cell survival in a hypoxic microenvironment. Therefore, HIF-1α could be a significant prognosis marker in CHD and be a prospective candidate in the development of target therapy in cardiovascular diseases.

  3. A cystine-knot miniprotein from tomato fruit inhibits endothelial cell migration and angiogenesis by affecting vascular endothelial growth factor receptor (VEGFR) activation and nitric oxide production.

    Science.gov (United States)

    Treggiari, Davide; Zoccatelli, Gianni; Molesini, Barbara; Degan, Maurizio; Rotino, Giuseppe Leonardo; Sala, Tea; Cavallini, Chiara; MacRae, Calum A; Minuz, Pietro; Pandolfini, Tiziana

    2015-11-01

    Cystine-knot miniproteins are bioactive molecules with a broad range of potential therapeutic applications. Recently, it was demonstrated that two tomato cystine-knot miniproteins (TCMPs) exhibit in vitro antiangiogenic activity on human umbilical vein cells. The aim of the present study was to investigate the effects of a fruit-specific cystine-knot miniprotein of tomato on in vitro endothelial cell migration and in vivo angiogenesis using a zebrafish model. The cystine-knot protein purified from tomato fruits using gel filtration LC and RP-HPLC inhibited cell migration when tested at 200 nM using the wound healing assay, and reduced nitric oxide formation probed by 4-amino-5-methylamino-27-difluorofluoscescin diacetate. RT-PCR and Western blot analyses demonstrated that vascular endothelium growth factor A dependent signaling was the target of TCMP bioactivity. Angiogenesis was inhibited in vivo in zebrafish embryos treated with 500 nM TCMP. Our results demonstrate that cystine-knot miniproteins present in mature tomato fruits are endowed with antiangiogenic activity in vitro and in vivo. These molecules may confer beneficial effects to tomato dietary intake, along with lycopene and other antioxidants. Further investigation is warranted to explore the potential of these compounds as model scaffolds for the development of new drugs. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  4. 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.

  5. The role of microRNAs on angiogenesis and vascular pressure in ...

    African Journals Online (AJOL)

    Results: Data reveal that miRNAs interfere with angiogenesis during early pregnancy by dysregulating pro-angiogenic factors (such as placental growth factor, vascular endothelial growth factor, fibroblast growth factor, transforming growth factor and insulin-like growth factor) and their receptors including Fms-like tyrosine ...

  6. 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

    Science.gov (United States)

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

    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 inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-α -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways. PMID:25874616

  7. 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.

    Directory of Open Access Journals (Sweden)

    Attila Varga

    Full Text Available 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 inhibitors would be of great value. To test this possibility, we screened our molecular library using recombinant kinase assays and identified the previously described compound VCC251801 with strong inhibitory effect on both VEGFR2 and PKD1. We further analyzed the effect of VCC251801 in the endothelium-derived EA.hy926 cell line and in different inflammatory cell types. In EA.hy926 cells, VCC251801 potently inhibited the intracellular activation and signaling of VEGFR2 and PKD1 which inhibition eventually resulted in diminished cell proliferation. In this model, our compound was also an efficient inhibitor of in vitro angiogenesis by interfering with endothelial cell migration and tube formation processes. Our results from functional assays in inflammatory cellular models such as neutrophils and mast cells suggested an anti-inflammatory effect of VCC251801. The neutrophil study showed that VCC251801 specifically blocked the immobilized immune-complex and the adhesion dependent TNF-α -fibrinogen stimulated neutrophil activation. Furthermore, similar results were found in mast cell degranulation assay where VCC251801 caused significant reduction of mast cell response. In summary, we described a novel function of a multiple kinase inhibitor which strongly inhibits the VEGFR2-PKD1 signaling and might be a novel inhibitor of pathological inflammatory pathways.

  8. Baculovirus-mediated vascular endothelial growth factor-D(ΔNΔC) gene transfer induces angiogenesis in rabbit skeletal muscle.

    Science.gov (United States)

    Heikura, Tommi; Nieminen, Tiina; Roschier, Miia M; Karvinen, Henna; Kaikkonen, Minna U; Mähönen, Anssi J; Lesch, Hanna P; Rissanen, Tuomas T; Laitinen, Olli H; Airenne, Kari J; Ylä-Herttuala, Seppo

    2012-01-01

    Occluded arteries and ischemic tissues cannot always be treated by angioplasty, stenting or by-pass-surgery. Under such circumstances, viral gene therapy may be useful in inducing increased blood supply to ischemic area. There is evidence of improved blood flow in ischemic skeletal muscle and myocardium in both animal and human studies using adenoviral vascular endothelial growth factor (VEGF) gene therapy. However, the expression is transient and repeated gene transfers with the same vector are inefficient due to immune responses. Different baculoviral vectors pseudotyped with or without vesicular stomatitis virus glycoprotein (VSV-G) and/or carrying woodchuck hepatitis virus post-transcriptional regulatory element (Wpre) were tested both in vitro and in vivo. VEGF-D(ΔNΔC) was used as therapeutic transgene and lacZ as a control. In vivo efficacy was evaluated as capillary enlargement and transgene expression in New Zealand White (NZW) rabbit skeletal muscle. A statistically significant capillary enlargement was detected 6 days after gene transfer in transduced areas compared to the control gene transfers with baculovirus and adenovirus encoding β-galactosidase (lacZ). Substantially improved gene transfer efficiency was achieved with a modified baculovirus pseudotyped with VSV-G and carrying Wpre. Dose escalation experiments revealed that either too large volume or too many virus particles caused inflammation and necrosis in the target tissue, whereas 10(9) plaque forming units injected in multiple aliquots resulted in transgene expression with only mild immune reactions. We show the first evidence of biologically significant baculoviral gene transfer in skeletal muscle of NZW rabbits using VEGF-D(ΔNΔC) as a therapeutic transgene. Copyright © 2012 John Wiley & Sons, Ltd.

  9. Huoxue Anxin Recipe () promotes myocardium angiogenesis of acute myocardial infarction rats by up-regulating miR-210 and vascular endothelial growth factor.

    Science.gov (United States)

    Wang, Jie; Zhang, Yun; Liu, Yong-Mei; Guo, Li-Li; Wu, Ping; Dong, Yu; Wu, Guang-Jun

    2016-09-01

    To investigate the microRNAs (miRNAs) expression profile of acute myocardial infarction (AMI) rats and the regulating effects of Huoxue Anxin Recipe (, HAR) on angiogenesis-related miRNAs and genes. Forty-five Wistar rats were randomly assigned to 3 groups according to a random number table: sham, AMI, and AMI+HAR groups (15 in each group). AMI rats were established by ligation of the left descending coronary artery. HAR was intragastrically administered to rats of the AMI+HAR group for successive 21 days since modeling, meanwhile the same volume of 0.9% normal saline was administered to rats of the sham and AMI groups. Doppler echocardiography was used for noninvasive cardiac function test. Hematoxylin and eosin staining was used to observe the histopathological change. miRNAs expression profile was detected by quantitative realtime polymerase chain reaction (qRT-PCR). The mRNA and protein expressions of vascular endothelial growth factor (VEGF), and a target gene of miR-210 was further detected by qRT-PCR and Western blot, respectively. The microvessels density of myocardium was evaluated by CD31 immunostaining. Compared with the sham group, ejection fraction (EF) and fractional shortening (FS) values were decreased significantly in the AMI group (Pinfarction area and the interstitial collagen deposition were increased obviously. As for the AMI+HAR group, EF and FS values were increased significantly (Pinfarction area was reduced and the interstitial collagen deposition were alleviated significantly. Total of 23 miRNAs in the AMI group expressed differently by at least 1.5 folds compared with those in the sham group; 5 miRNAs in the AMI+HAR group expressed differently by at least 1.5 folds compared with those in the AMI group. Among them, miR-210 was low in the AMI group and high in the AMI+HAR group. The relative mRNA and protein expressions of VEGF were decreased significantly in the AMI group (Pinfarction area, alleviate the interstitial fibrosis and improve

  10. The role of microRNAs on angiogenesis and vascular pressure in ...

    African Journals Online (AJOL)

    Harapan Harapan

    2015-04-28

    Apr 28, 2015 ... Abstract Background: In pre-clinical stage of preeclampsia, placental angiogenesis is impaired leading to hypoxic placenta and dysregulation of pro- and anti-angiogenetic factors. As a conse- quence, these cause elevated systemic vascular resistance, vasoconstriction and hypertension in clin- ical stage ...

  11. 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

  12. Friends Turned Foes: Angiogenic Growth Factors beyond Angiogenesis

    Directory of Open Access Journals (Sweden)

    Pratiek N. Matkar

    2017-10-01

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

  13. 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...

  14. Angiogenesis and Diabetes: Different Responses to Pro-Angiogenic Factors in the Chorioallantoic Membrane Assay

    OpenAIRE

    Di Marco, Giovana S; Alam, Antoine; Dol, Frédéric; Corvol, Pierre; Gasc, Jean-Marie; Larger, Etienne

    2008-01-01

    Hyperglycemia induces defects in angiogenesis without alteration in the expression of major vascular growth factors in the chicken chorioallantoic membrane (CAM) model. A direct negative effect of hyperglycemia on angiogenesis may participate in failures of “therapeutic angiogenesis” trials. Here, we tested the hypothesis that the response to pro-angiogenic molecules such as angiotensin-converting enzyme (ACE), endothelin-1 (ET-1), and vascular endothelial growth factor-A (VEGF) is altered by...

  15. Tylophorine, a phenanthraindolizidine alkaloid isolated from Tylophora indica exerts antiangiogenic and antitumor activity by targeting vascular endothelial growth factor receptor 2–mediated angiogenesis

    Science.gov (United States)

    2013-01-01

    Background Anti-angiogenesis targeting VEGFR2 has been considered as an important strategy for cancer therapy. Tylophorine is known to possess anti-inflammatory and antitumor activity, but its roles in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism is still unknown. Therefore, we examined its anti-angiogenic effects and mechanisms in vitro and in vivo. Methods We used tylophorine and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVEC) in vitro and Ehrlich ascites carcinoma (EAC) tumor in vivo. Results Tylophorine significantly inhibited a series of VEGF-induced angiogenesis processes including proliferation, migration, and tube formation of endothelial cells. Besides, it directly inhibited VEGFR2 tyrosine kinase activity and its downstream signaling pathways including Akt, Erk and ROS in endothelial cells. Using HUVECs we demonstrated that tylophorine inhibited VEGF-stimulated inflammatory responses including IL-6, IL-8, TNF-α, IFN-γ, MMP-2 and NO secretion. Tylophorine significantly inhibited neovascularization in sponge implant angiogenesis assay and also inhibited tumor angiogenesis and tumor growth in vivo. Molecular docking simulation indicated that tylophorine could form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit. Conclusion Tylophorine exerts anti-angiogenesis effects via VEGFR2 signaling pathway thus, may be a viable drug candidate in anti-angiogenesis and anti-cancer therapies. PMID:23895055

  16. Effect of glycation on basic fibroblast growth factor induced angiogenesis and activation of associated signal transduction pathways in vascular endothelial cells: possible relevance to wound healing in diabetes.

    Science.gov (United States)

    Duraisamy, Y; Slevin, M; Smith, N; Bailey, J; Zweit, J; Smith, C; Ahmed, N; Gaffney, J

    2001-01-01

    Ineffectual wound healing in hyperglycaemic patients suffering from diabetes mellitus is characterised by a reduction in capillary reformation (angiogenesis). Basic fibroblast growth factor (FGF-2) is secreted by fibroblasts, macrophages and in particular endothelial cells (EC) in response to tissue injury and is important in promotion of neovascularisation. Recently, glycation of FGF-2 has been shown to significantly reduce its activity in vitro. We have examined the kinetics of FGF-2 glycation and compared its ability with that of native FGF-2 to activate mitogenesis, capillary formation and associated signal transduction in bovine aortic EC (BAEC). FGF-2 was exposed to 0.25 M glucose-6-phosphate (G-6-P) for 24-72 h and the degree of glycation determined by matrix assisted laser desorption ionisation mass spectrometry. Native FGF-2 was heterogeneous with Mw in the range 15,153.6-17,903 Da. After 24 h incubation with G-6-P there was evidence of glycation, and the mass increase corresponded to addition of 2.7 mol of G-6-P residues; after 48 h, 4 mol sugar was added and this increased to 8.7 after 72 h. Dimerisation of FGF-2 was observed after 72 h of treatment. Induction of mitogenesis in BAEC was significantly reduced by 25%-40% after treatment for 48-96 h with glycated (24 h) FGF-2 (gFGF-2; 100 pg/ml-5 ng/ml; P mechanism behind impaired wound healing in patients with diabetes mellitus.

  17. Vascular tube formation and angiogenesis induced by polyvinylpyrrolidone-coated silver nanoparticles.

    Science.gov (United States)

    Kang, Kyeongah; Lim, Dae-Hyoun; Choi, In-Hong; Kang, Taegyeong; Lee, Kangtaek; Moon, Eun-Yi; Yang, Young; Lee, Myeong-Sok; Lim, Jong-Seok

    2011-09-10

    Silver nanoparticles (AgNPs) are one of the most commonly used nanomaterials due to their antibacterial properties. In this study, we examined the effects of polyvinylpyrrolidone (PVP)-coated AgNPs (average size 2.3nm) on angiogenesis in both an in vivo model and an in vitro endothelial cell line, SVEC4-10. Increased angiogenesis was detected around the injection site of AgNP-containing Matrigel in vivo. AgNPs also increased the infiltration of endothelial cells and the hemoglobin (Hb) content in AgNP-Matrigel plugs implanted into mice. AgNPs induced endothelial cell tube formation on growth factor-reduced Matrigel, production of reactive oxygen species (ROS), and production of angiogenic factors, such as vascular endothelial growth factor (VEGF) and nitric oxide (NO), in SVEC4-10 cells. In addition, AgNPs promoted the activation of FAK, Akt, ERK1/2, and p38, which are all involved in VEGF receptor (VEGFR)-mediated signaling. Finally, AgNP-treated tumors caused angiogenesis around tumors in B16F10 melanomas after they were injected into mice, and the Hb concentration in the tumors increased in a concentration-dependent manner with AgNP treatment. Thus, our study suggests that exposure to AgNPs can cause angiogenesis through the production of angiogenic factors. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  18. The role of vascular endothelial growth factor in ossification

    Science.gov (United States)

    Yang, Yan-Qi; Tan, Ying-Ying; Wong, Ricky; Wenden, Alex; Zhang, Lin-Kun; Rabie, A Bakr M

    2012-01-01

    Osteogenesis and angiogenesis are two closely correlated processes during bone growth, development, remodelling and repair. Vascular endothelial growth factor (VEGF) is an essential mediator during the process of angiogenesis. Based on an extensive literature search, which was carried out using the PubMed database and the keywords of osteogenesis, VEGF, endochondral ossification and intramembranous ossification, this manuscript reviews the role of VEGF in ossification, with emphasis on its effect in endochondral and intramembranous ossification. Osteogenesis and angiogenesis are closely correlated processes. VEGF acts as an essential mediator during these processes. It not only functions in bone angiogenesis but also in various aspects of bone development. PMID:22722639

  19. Oscillation of Angiogenesis and Vascular Dropout in Progressive Human Vascular Disease. [Vascular Pattern as Useful Read-Out of Complex Molecular Signaling

    Science.gov (United States)

    Parsons-Wingerter, Patricia

    2010-01-01

    When analyzed by VESsel GENeration Analysis (VESGEN) software, vascular patterns provide useful integrative read-outs of complex, interacting molecular signaling pathways. Using VESGEN, we recently discovered and published our innovative, surprising findings that angiogenesis oscillated with vascular dropout throughout progression of diabetic retinopathy, a blinding vascular disease. Our findings provide a potential paradigm shift in the current prevailing view on progression and treatment of this disease, and a new early-stage window of regenerative therapeutic opportunities. The findings also suggest that angiogenesis may oscillate with vascular disease in a homeostatic-like manner during early stages of other inflammatory progressive diseases such as cancer and coronary vascular disease.

  20. 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.

  1. Functional and molecular mapping of uncoupling between vascular permeability and loss of vascular maturation in ovarian carcinoma xenografts: the role of stroma cells in tumor angiogenesis.

    Science.gov (United States)

    Gilad, Assaf A; Israely, Tomer; Dafni, Hagit; Meir, Gila; Cohen, Batya; Neeman, Michal

    2005-11-01

    Maintaining homogeneous perfusion in tissues undergoing remodeling and vascular expansion requires tight orchestration of the signals leading to endothelial sprouting and subsequent recruitment of perivascular contractile cells and vascular maturation. This regulation, however, is frequently disrupted in tumors. We previously demonstrated the role of tumor-associated myofibroblasts in vascularization and exit from dormancy of human ovarian carcinoma xenografts in nude mice. The aim of this work was to determine the contribution of stroma- and tumor cell-derived angiogenic growth factors to the heterogeneity of vascular permeability and maturation in MLS human ovarian carcinoma tumors. We show by RT-PCR and by in situ hybridization that VEGF was expressed by the tumor cells, while angiopoietin-1 and -2 were expressed only by the infiltrating host stroma cells. Vascular maturation was detected in vivo by vasoreactivity to hypercapnia, measured by BOLD contrast MRI and validated by immunostaining of histologic sections to alpha-smooth muscle actin. Vascular permeability was measured in vivo by dynamic contrast-enhanced MRI using albumin-based contrast material and validated in histologic sections by fluorescent staining of the biotinylated contrast material. MRI as well as histologic correlation maps between vascular maturation and vascular permeability revealed a wide range of vascular phenotypes, in which the distribution of vascular maturation and vasoreactivity did not overlap spatially with reduced permeability. The large heterogeneity in the degree of vascular maturation and permeability is consistent with the differential expression pattern of VEGF and angiopoietins during tumor angiogenesis.

  2. Assessment of vascularity as an index of angiogenesis in periradicular granulomas. Comparison with oral carcinomas and normal tissue counterparts.

    Science.gov (United States)

    Davey, K J; Perrier, S; Ohe, G; Gilbert, A D; Bankfalvi, A; Saunders, W P; Schor, S L; Schor, A M

    2008-11-01

    To quantify vascularity in periradicular granulomas using different endothelial markers, and assess its value as an index of angiogenesis by comparing granulomas with healthy periodontal ligament (PDL). To use oral tumours, compared with adjacent normal mucosa, as positive controls. Paraffin-embedded sections were stained with antibodies to von Willebrand factor (vWF), a pan-endothelial marker, and CD105, a putative marker for angiogenic vessels. Vascularity was quantified by different methods reflecting vessel volume and density. Irrespective of the marker or method used, vascularity values were similar in periradicular granuloma and PDL. Both tissues were highly vascularized, with levels similar to those found in oral squamous cell carcinoma. Vascularity was significantly higher in the latter than in normal mucosa. Fewer vessels were positive for CD105 than for vWF in the normal mucosa, whereas similar numbers were found in the other tissues examined. A comparison of vascularity in oral tumours and normal oral mucosa provided evidence of angiogenesis in the former. Staining with CD105 added limited value to staining with vWF in these tissues. In contrast, a comparison of periradicular granuloma and PDL failed to demonstrate evidence of angiogenesis in the granuloma. As all vessels were similarly stained with vWF and CD105 in granuloma and PDL, a possible hypothesis is that all vessels are newly formed in these tissues. A more plausible alternative is that CD105 expression may reflect the metabolic activity or intrinsic characteristics of the tissues, rather than the presence of angiogenic vessels.

  3. 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.

  4. Vascular endothelial growth factor and vascular endothelial growth factor receptor-2 expression in mdx mouse brain.

    Science.gov (United States)

    Nico, Beatrice; Corsi, Patrizia; Vacca, Angelo; Roncali, Luisa; Ribatti, Domenico

    2002-10-25

    Recent data have demonstrated that vascular endothelial growth factor (VEGF) is expressed by subsets of neurons, coincident with angiogenesis within its developing cerebral cortex. In this study, with the aim of elucidating the mechanisms of vascular involvement during brain impairment in Duchenne muscular distrophy (DMD), we have correlated the vascular density with VEGF and VEGF receptor-2 (VEGFR-2) expression in the brain cortex of normal and mdx mouse, an animal model with a genetic defect in a region homologous with the human DMD gene. Results showed that in mdx mouse, tissue area occupied by microvessels positive to factor VIII related antigen and VEGFR-2 increased in parallel to the tissue area occupied by neurons positive to VEGF. Our data suggest that increased vascularity in the brain of mdx mouse may be due, at least in part, to proliferation of endothelial cells in response to VEGF secreted by neuronal cells.

  5. Chlamydia pneumoniae infection promotes vascular endothelial cell angiogenesis through an IQGAP1-related signaling pathway.

    Science.gov (United States)

    Wang, Beibei; Zhang, Lijun; Liu, Jingya; Ma, Lu; Wang, Haiwei; Zheng, Ningbo; Chen, Xiaoyu; Shen, Bingling; Xu, Zhelong; Zhang, Lijun

    2017-06-01

    Chlamydia pneumoniae (C. pneumoniae) infection plays a potential role in angiogenesis. However, it is still an enigma how C. pneumoniae is involved in this process. Therefore, we investigated the effect of C. pneumoniae infection on angiogenesis, and then explored the roles of IQGAP1-related signaling in C. pneumoniae infection-induced angiogenesis. C. pneumoniae infection significantly enhanced angiogenesis as assessed by the tube formation assay possibly by inducing vascular endothelial cell (VEC) migration in the wound healing and Transwell migration assays. Subsequently, immunoprecipitation, Western blot and tube formation assay results showed that the phosphorylation of both IQGAP1 and N-WASP was required for the angiogenesis induced by C. pneumoniae infection. Our co-immunoprecipitation study revealed that IQGAP1 physically associated with N-WASP after C. pneumoniae infection of VECs. Actin polymerization assay further showed that in C. pneumoniae-infected VECs, both IQGAP1 and N-WASP were recruited to filamentous actin, and shared some common compartments localized at the leading edge of lamellipodia, which was impaired after the depletion of IQGAP1 by using the small interference RNA. Moreover, the knockdown of IQGAP1 also significantly decreased N-WASP phosphorylation at Tyr256 induced by C. pneumoniae infection. We conclude that C. pneumoniae infection promotes VEC migration and angiogenesis presumably through the IQGAP1-related signaling pathway. Copyright © 2017 Elsevier GmbH. All rights reserved.

  6. Vascularization and Angiogenesis in Tissue Engineering: Beyond Creating Static Networks

    NARCIS (Netherlands)

    Rouwkema, Jeroen; Khademhosseini, A.

    2016-01-01

    Engineered tissues need a vascular network to supply cells with nutrients and oxygen after implantation. A network that can connect to the vasculature of the patient after implantation can be included during in vitro culture. For optimal integration, this network needs to be highly organized,

  7. Vascular endothelial growth factor from embryonic status to cardiovascular pathology

    OpenAIRE

    Mohsen Azimi-Nezhad

    2014-01-01

    Vascular endothelial growth factor (VEGF) is a multifunctional cytokine with distinct functions in angiogenesis, lymphangiogenesis, vascular permeability, and hematopoiesis. VEGF is a highly conserved, disulfide-bonded dimeric glycoprotein of 34 to 45 kDa produced by several cell types including fibroblasts, neutrophils, endothelial cells, and peripheral blood mononuclear cells, particularly T lymphocytes and macrophages. Six VEGF isoforms are generated as a result of alternative splicing fro...

  8. 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...

  9. Vascular endothelial growth factor overexpression in ischemic skeletal muscle enhances myoglobin expression in vivo

    NARCIS (Netherlands)

    van Weel, Vincent; Deckers, Martine M. L.; Grimbergen, Jos M.; van Leuven, Kees J. M.; Lardenoye, JanWillem H. P.; Schlingemann, Reinier O.; van Nieuw Amerongen, Geerten P.; van Bockel, J. Hajo; van Hinsbergh, Victor W. M.; Quax, Paul H. A.

    2004-01-01

    Therapeutic angiogenesis using vascular endothelial growth factor ( VEGF) is considered a promising new therapy for patients with arterial obstructive disease. Clinical improvements observed consist of improved muscle function and regression of rest pain or angina. However, direct evidence for

  10. Basic fibroblast growth factor induces VEGF expression in chondrosarcoma cells and subsequently promotes endothelial progenitor cell-primed angiogenesis.

    Science.gov (United States)

    Tzeng, Huey-En; Chen, Po-Chun; Lin, Kai-Wei; Lin, Chih-Yang; Tsai, Chun-Hao; Han, Shao-Min; Teng, Chieh-Lin; Hwang, Wen-Li; Wang, Shih-Wei; Tang, Chih-Hsin

    2015-07-01

    Chondrosarcoma, a common malignant tumour, develops in bone. Effective adjuvant therapy remains inadequate for treatment, meaning poor prognosis. It is imperative to explore novel remedies. Angiogenesis is a rate-limiting step in progression that explains neovessel formation for blood supply in the tumour microenvironment. Numerous studies indicate that EPCs (endothelial progenitor cells) promote angiogenesis and contribute to tumour growth. bFGF (basic fibroblast growth factor), a secreted cytokine, regulates biological activity, including angiogenesis, and correlates with tumorigenesis. However, the role of bFGF in angiogenesis-related tumour progression by recruiting EPCs in human chondrosarcoma is rarely discussed. In the present study, we found that bFGF induced VEGF (vascular endothelial growth factor) expression via the FGFR1 (fibroblast growth factor receptor 1)/c-Src/p38/NF-κB (nuclear factor κB) signalling pathway in chondrosarcoma cells, thereby triggering angiogenesis of endothelial progenitor cells. Our in vivo data revealed that tumour-secreted bFGF promotes angiogenesis in both mouse plug and chick CAM (chorioallantoic membrane) assays. Xenograft mouse model data, due to bFGF-regulated angiogenesis, showed the bFGF regulates angiogenesis-linked tumour growth. Finally, bFGF was highly expressed in chondrosarcoma patients compared with normal cartilage, positively correlating with VEGF expression and tumour stage. The present study reveals a novel therapeutic target for chondrosarcoma progression.

  11. Vascular endothelial growth factor in children with cyanotic and acyanotic and congenital heart disease

    OpenAIRE

    Baghdady, Yasser; Hussein, Yasser; Shehata, Mohamed

    2010-01-01

    Introduction Vascular endothelial growth factor is a potent stimulator of angiogenesis. Children with cyanotic congenital heart disease often experience the development of widespread formation of collateral blood vessels, which may represent a form of abnormal angiogenesis resulting in increased morbidity and mortality. We undertook the present study to determine whether children with cyanotic congenital heart disease have elevated serum levels of vascular endothelial growth factor compared t...

  12. The role of microRNAs on angiogenesis and vascular pressure in preeclampsia: The evidence from systematic review

    Directory of Open Access Journals (Sweden)

    Harapan Harapan

    2015-10-01

    Conclusion: Data confirm that miRNAs are involved in pathobiology of preeclampsia including interference with angiogenesis during pre-clinical stage and induction of vascular resistance and vasoconstriction in clinical stage.

  13. Conjugation of gold nanoparticles and recombinant human endostatin modulates vascular normalization via interruption of anterior gradient 2-mediated angiogenesis.

    Science.gov (United States)

    Pan, Fan; Yang, Wende; Li, Wei; Yang, Xiao-Yan; Liu, Shuhao; Li, Xin; Zhao, Xiaoxu; Ding, Hui; Qin, Li; Pan, Yunlong

    2017-07-01

    Several studies have revealed the potential of normalizing tumor vessels in anti-angiogenic treatment. Recombinant human endostatin is an anti-angiogenic agent which has been applied in clinical tumor treatment. Our previous research indicated that gold nanoparticles could be a nanoparticle carrier for recombinant human endostatin delivery. The recombinant human endostatin-gold nanoparticle conjugates normalized vessels, which improved chemotherapy. However, the mechanism of recombinant human endostatin-gold nanoparticle-induced vascular normalization has not been explored. Anterior gradient 2 has been reported to be over-expressed in many malignant tumors and involved in tumor angiogenesis. To date, the precise efficacy of recombinant human endostatin-gold nanoparticles on anterior gradient 2-mediated angiogenesis or anterior gradient 2-related signaling cohort remained unknown. In this study, we aimed to explore whether recombinant human endostatin-gold nanoparticles could normalize vessels in metastatic colorectal cancer xenografts, and we further elucidated whether recombinant human endostatin-gold nanoparticles could interrupt anterior gradient 2-induced angiogenesis. In vivo, it was indicated that recombinant human endostatin-gold nanoparticles increased pericyte expression while inhibit vascular endothelial growth factor receptor 2 and anterior gradient 2 expression in metastatic colorectal cancer xenografts. In vitro, we uncovered that recombinant human endostatin-gold nanoparticles reduced cell migration and tube formation induced by anterior gradient 2 in human umbilical vein endothelial cells. Treatment with recombinant human endostatin-gold nanoparticles attenuated anterior gradient 2-mediated activation of MMP2, cMyc, VE-cadherin, phosphorylation of p38, and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in human umbilical vein endothelial cells. Our findings demonstrated recombinant human endostatin-gold nanoparticles might normalize

  14. 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.

  15. 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...... to exercise in skeletal muscle cells whereas disease is a more determining factor for the capillary network. In conclusion, the findings in the six studies that the PhD thesis is based on provide valuable information to further the understanding of the regulation of human skeletal muscle angiogenesis......, the findings of simultaneously enhanced pro-angiogenic and angiostatic factors in response to acute exercise before training points to that the angiogenic process is highly regulated even when capillary growth is required. The attenuated response in some of the pro-angiogenic factors after training...

  16. Vascular Function and Angiogenesis in Aging and Essential Hypertension

    DEFF Research Database (Denmark)

    Gliemann, Lasse

    Cardiovascular health in aged subjects and the effects of physical activity and resveratrol   Aging and inactivity are associated with decreased physical capacity and cardiovascular health, which ultimately, may affect quality of life. However, the findings of the present thesis support that even...... a relatively short period of exercise training improves a number of cardiovascular health parameters and increases exercise capacity in previously sedentary aged men. In contrast, our findings show that, although resveratrol has shown promising results in terms of improving cardiovascular health and physical...... capacity in animal models, this does not appear to be true in aged individuals. Moreover, resveratrol blunted a number of positive adaptations related to physical activity, including blood pressure, physical capacity and other cardiovascular health factors. Physical activity, resveratrol and endogenous...

  17. Type VIII collagen is elevated in diseases associated with angiogenesis and vascular remodeling

    DEFF Research Database (Denmark)

    Hansen, N. U. B.; Willumsen, N.; Bülow Sand, Jannie Marie

    2016-01-01

    Objectives Type VIII collagen is involved in angiogenesis and remodeling of arteries. We hypothesized that type VIII collagen was upregulated in diseases associated with vascular remodeling, e.g. pulmonary fibrosis and cancer. In this paper we present the development and validation of a competitive...... performance, and in relevant disease cohorts. The developed ELISA was applied for the assessment of type VIII collagen in serum from patients diagnosed with chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF) and various cancers. Results The C8-C ELISA was technically stable...

  18. 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.

  19. The analysis of feasibility and effectiveness of vascular targeting radiotherapy based on a model of tumor growth and angiogenesis

    Science.gov (United States)

    Ding, Yihong

    Targeting cytotoxic agents to tumor angiogenesis, instead of the tumor itself, is an attractive new approach in Radiation Oncology. Unlike tumor cells, endothelial cells are less likely to develop radio-resistance. Investigations have shown that radiation can cause a definite increase in cell permeability. Permeability changes in the tumor capillary endothelium can contribute to circulatory failure and serve as a site for clot formation. Therefore, radiation could initiate platelet aggregation and blood coagulation locally within the tumor vasculature, leading to tumor cell killing through depletion of oxygen and nutrients. In order to analyze the efficacy of a potential 90Y-labeled compound for vascular targeting radiotherapy and to evaluate the factors that may affect targets' absorbed dose, a tumor vasculature model including its angiogenesis process as a function of time and tumor growth are adopted and improved from the Liotta model. Its output is used to estimate targets' absorbed doses by Monte Carlo simulation. The results show that the effectiveness of vascular targeting therapy depends on the existence of available tumor endothelial cells and target expression. The alphavbeta3 antagonist model compound is less effective in the early stage tumors, which have very few vessels. Although a high administered dose, such as injecting of 2.1 mCi/kg to saturate all available binding sites, can destroy tumor endothelium network, the toxicity to bone marrow makes it impossible to inject such a dose. To a vascularized tumor, after giving one maximum allowable administered activity, 0.83 mCi/kg for the 90Y-labeled model compound, an average of 9.8%, 27.3%, 34.7% and 37.8% of endothelial cells would be killed when treatment starts at day 4, 7, 9 and 12 after tumor development, respectively. Therefore, recurrent treatment by vascular targeting therapy to well-vascularized tumor has the potential to slow down tumor growth or may even cause tumor regression at the primary

  20. Extracellular nonmitogenic angiogenesis factor and method of isolation thereof from wound fluid

    Science.gov (United States)

    Banda, M.J.; Werb, Z.; Knighton, D.R.; Hunt, T.K.

    1985-03-05

    A nonmitogenic angiogenesis factor is isolated from wound fluid by dialysis to include materials in the molecular size range of 2,000 to 14,000, lyophilization, and chromatography. The nonmitogenic angiogenesis factor is identified by activity by corneal implant assay and by cell migration assay. The angiogenesis factor is also characterized by inactivity by mitogenesis assay. 3 figs.

  1. HDAC4 Represses Vascular Endothelial Growth Factor Expression in Chondrosarcoma by Modulating RUNX2 Activity*

    OpenAIRE

    Sun, Xiaojuan; Wei, Lei; Chen, Qian; Terek, Richard M.

    2009-01-01

    Chondrosarcoma is a primary bone tumor with a dismal prognosis; most patients with this disease develop fatal pulmonary metastases, suggesting the need for a better systemic treatment. Anti-angiogenesis treatment may be useful, because angiogenesis is critical for both tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is the most potent pro-angiogenic factor and is regulated by pathways related to the normal physiologic response to hypoxia and genetic alterations related ...

  2. Vascular endothelial growth factors: A comparison between invertebrates and vertebrates.

    Science.gov (United States)

    Kipryushina, Yulia O; Yakovlev, Konstantin V; Odintsova, Nelly A

    2015-12-01

    This review aims to summarize recent data concerning the structure and role of the members of the vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor (VEGFR) families in the context of early development, organogenesis and regeneration, with a particular emphasis on the role of these factors in the development of invertebrates. Homologs of VEGF and/or VEGFR have been found in all Eumetazoa, in both Radiata and Bilateria, where they are expressed in the descendants of different germ layers and play a pivotal role in the development of animals with and without a vascular system. VEGF is a well-known angiogenesis regulator, but this factor also control cell migration during neurogenesis and the development of branching organs (the trachea) in invertebrate and vertebrate species. A possible explanation for the origin of Vegf/Vegfr in the animal kingdom and a pathway of Vegf/Vegfr evolution are discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

  3. Advances in neuroimaging techniques for the evaluation of tumor growth, vascular permeability, and angiogenesis in gliomas.

    Science.gov (United States)

    Gerstner, Elizabeth R; Sorensen, A Gregory; Jain, Rakesh K; Batchelor, Tracy T

    2008-12-01

    This review will summarize new neuroimaging techniques, particularly MRI and PET imaging, that can be used to assess brain tumor growth and angiogenesis. Glioma tumor vasculature is abnormal, and advances in MRI now permit visualization of the hemodynamic properties of gliomas including cerebral blood volume and blood flow, vascular permeability, and blood vessel diameter. New radiolabeled PET tracers have allowed more specific interrogation of glioma physiology such as hypoxia assessment or tumor proliferation rate. These two techniques are complementary and will likely yield important information on tumor response to therapy, particularly in the setting of antiangiogenic agents, which confound the interpretation of standard contrast-enhanced MRI scans. These techniques may allow development of patient-specific therapy to improve outcome in patients with gliomas.

  4. Omics meets hypothesis-driven research. Partnership for innovative discoveries in vascular biology and angiogenesis.

    Science.gov (United States)

    Rüegg, Curzio; Tissot, Jean-Daniel; Farmer, Pierre; Mariotti, Agnese

    2008-11-01

    The emergence of omics technologies allowing the global analysis of a given biological or molecular system, rather than the study of its individual components, has revolutionized biomedical research, including cardiovascular medicine research in the past decade. These developments raised the prospect that classical, hypothesis-driven, single gene-based approaches may soon become obsolete. The experience accumulated so far, however, indicates that omic technologies only represent tools similar to those classically used by scientists in the past and nowadays, to make hypothesis and build models, with the main difference that they generate large amounts of unbiased information. Thus, omics and classical hypothesis-driven research are rather complementary approaches with the potential to effectively synergize to boost research in many fields, including cardiovascular medicine. In this article we discuss some general aspects of omics approaches, and review contributions in three areas of vascular biology, thrombosis and haemostasis, atherosclerosis and angiogenesis, in which omics approaches have already been applied (vasculomics).

  5. Angiogenesis and Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Ribatti, Domenico, E-mail: ribatti@anatomia.uniba.it; Annese, Tiziana; Longo, Vito [Department of Human Anatomy and Histology, University of Bari Medical School, Piazza G. Cesare, 11, Policlinico 70124, Bari (Italy)

    2010-02-25

    Angiogenesis occurs in pathological conditions, such as tumors, where a specific critical point in tumor progression is the transition from the avascular to the vascular phase. Tumor angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells, which are able to stimulate the growth of the host’s blood vessels. This article summarizes the literature concerning the relationship between angiogenesis and human melanoma progression. The recent applications of antiangiogenic agents which interfere with melanoma progression are also described.

  6. Fibroblast growth factor signaling pathway in endothelial cells is activated by BMPER to promote angiogenesis.

    Science.gov (United States)

    Esser, Jennifer S; Rahner, Susanne; Deckler, Meike; Bode, Christoph; Patterson, Cam; Moser, Martin

    2015-02-01

    Previously, we have identified bone morphogenetic protein endothelial cell precursor-derived regulator (BMPER) to increase the angiogenic activity of endothelial cells in a concentration-dependent manner. In this project, we now investigate how BMPER acts in concert with key molecules of angiogenesis to promote blood vessel formation. To assess the effect of BMPER on angiogenesis-related signaling pathways, we performed an angiogenesis antibody array with BMPER-stimulated endothelial cells. We detected increased basic fibroblast growth factor (bFGF/FGF-2) expression after BMPER stimulation and decreased expression of thrombospondin-1. Additionally, FGF receptor-1 expression, phosphorylation, FGF signaling pathway activity, and cell survival were increased. Consistently, silencing of BMPER by small interfering RNA decreased bFGF and FGF receptor-1 expression and increased thrombospondin-1 expression and cell apoptosis. Next, we investigated the interaction of BMPER and the FGF signaling pathway in endothelial cell function. BMPER stimulation increased endothelial cell angiogenic activity in migration, Matrigel, and spheroid assays. To block FGF signaling, an anti-bFGF antibody was used, which effectively inhibited the proangiogenic BMPER effect. Accordingly, BMPER-silenced endothelial cells under bFGF stimulation showed decreased angiogenic activity compared with bFGF control. We confirmed these findings in vivo by subcutaneous Matrigel injections with and without bFGF in C57BL/6_Bmper(+/-) mice. Aortic ring assays of C57BL/6_Bmper(+/-) mice confirmed a specific effect for bFGF but not for vascular endothelial growth factor. Taken together, the proangiogenic BMPER effect in endothelial cells is mediated by inhibition of antiangiogenic thrombospondin-1 and enhanced expression and activation of the FGF signaling pathway that is crucial in the promotion of angiogenesis. © 2014 American Heart Association, Inc.

  7. Angiogenesis in neuroblastoma.

    Science.gov (United States)

    Ribatti, Domenico; Marimpietri, Danilo; Pastorino, Fabio; Brignole, Chiara; Nico, Beatrice; Vacca, Angelo; Ponzoni, Mirco

    2004-12-01

    Angiogenesis is a biological process by which new capillaries are formed from preexisting vessels. It occurs in physiological and pathological conditions, such as tumors, where a specific turning point is the transition from the avascular to the vascular phase. Tumor angiogenesis depends mainly on the release by neoplastic cells of growth factors specific for endothelial cells able to stimulate the growth of the host's blood vessels. In neuroblastoma, the most common extracranial solid tumor of infancy and childhood, angiogenesis also appears to play an important role in determining tumor phenotype. The nature of the angiogenic balance in neuroblastoma is complex, and a spectrum of angiogenesis stimulators, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), and inhibitors, such as tissue inhibitors of matrix metalloproteinases (MMPs), have been detected in neuroblastoma tumors. Moreover, an increased production of MMP-2 and -9 has been also observed in advanced stages of tumor, favoring degradation of extracellular matrix and enhancing tumor dissemination. High tumor vascularity is correlated with widely disseminated disease, MYCN amplification, unfavorable histology, and poor outcome. In contrast, low tumor vascularity is associated with prognostically favorable features, such as a localized disease and favorable histology. It is becoming increasingly evident that agents that interfere with blood vessel formation also block tumor progression. Preclinical studies suggest that antiangiogenic strategies may be effective in the treatment of neuroblastoma. A major goal is the determination of whether inhibition of angiogenesis is a realistic way of inhibiting tumor cell dissemination and formation of metastasis in neuroblastoma.

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

    Directory of Open Access Journals (Sweden)

    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.

  9. α-Solanine reverses pulmonary vascular remodeling and vascular angiogenesis in experimental pulmonary artery hypertension.

    Science.gov (United States)

    Nie, Xiaowei; Dai, Youai; Tan, Jianxin; Chen, Yuan; Qin, Guowei; Mao, Wenjun; Zou, Jian; Chang, Yanhua; Wang, Qian; Chen, Jingyu

    2017-12-01

    Similar to cancer, pulmonary arterial hypertension (PAH) is characterized by vascular remodeling, which leads to obliteration of the small pulmonary arteriole, with marked proliferation of pulmonary artery smooth muscle cells (PASMC) and/or endothelial cells dysfunction. Aberrant expression of tumor suppressor genes is closely associated with susceptibility to PAH. We hypothesized that α-solanine, a glycoalkaloid found in members of the nightshade family known to have antitumor activity in different cancers, reverses experimental PAH by activating the tumor suppressor-axis inhibition protein 2 (AXIN2). We investigated the effects of α-solanine on PASMC proliferation and apoptosis by using 5-ethynyl-2'-deoxyuridine proliferation assay, proliferating cell nuclear antigen and Ki67 staining, TUNEL and Anexine V assays. Scratch wound healing and tube formation assays were also used to study migration of endothelial cells. In vitro, we demonstrated, using cultured human PASMC from PAH patients, that α-solanine reversed dysfunctional AXIN2, β-catenin and bone morphogenetic protein receptor type-2 signaling, whereas restored [Ca]i, IL-6 and IL-8, contributing to the decrease of PAH-PASMC proliferation and resistance to apoptosis. Meanwhile, α-solanine inhibits proliferation, migration and tube formation of PAH-pulmonary artery endothelial cells by inhibiting Akt/GSK-3α activation. In vivo, α-solanine administration decreases distal pulmonary arteries remodeling, mean pulmonary arteries pressure and right ventricular hypertrophy in both monocrotaline-induced and Sugen/hypoxia-induced PAH in mice. This study demonstrates that AXIN2/β-catenin axis and Akt pathway can be therapeutically targeted by α-solanine in PAH. α-Solanine could be used as a new therapeutic strategy for the treatment of PAH.

  10. Vascular endothelial growth factor A protein level and gene expression in intracranial meningiomas with brain edema

    DEFF Research Database (Denmark)

    Nassehi, Damoun; Dyrbye, Henrik; Andresen, Morten

    2011-01-01

    (VEGF) is an endothelial cell-specific mitogen and angiogen. VEGF-A protein, which is identical to vascular permeability factor, is a regulator of angiogenesis. In this study, 101 patients with meningiomas, and possible co-factors to PTBE, such as meningioma subtypes and tumor location, were examined...

  11. A Designed Angiopoietin-1 Variant, Dimeric CMP-Ang1 Activates Tie2 and Stimulates Angiogenesis and Vascular Stabilization in N-glycan Dependent Manner.

    Science.gov (United States)

    Oh, Nuri; Kim, Kangsan; Kim, Soo Jin; Park, Intae; Lee, Jung-Eun; Seo, Young Suk; An, Hyun Joo; Kim, Ho Min; Koh, Gou Young

    2015-10-19

    Angiopoietin-1 (Ang1), a potential growth factor for therapeutic angiogenesis and vascular stabilization, is known to specifically cluster and activate Tie2 in high oligomeric forms, which is a unique and essential process in this ligand-receptor interaction. However, highly oligomeric native Ang1 and Ang1 variants are difficult to produce, purify, and store in a stable and active form. To overcome these limitations, we developed a simple and active dimeric CMP-Ang1 by replacing the N-terminal of native Ang1 with the coiled-coil domain of cartilage matrix protein (CMP) bearing mutations in its cysteine residues. This dimeric CMP-Ang1 effectively increased the migration, survival, and tube formation of endothelial cells via Tie2 activation. Furthermore, dimeric CMP-Ang1 induced angiogenesis and suppressed vascular leakage in vivo. Despite its dimeric structure, the potencies of such Tie2-activation-induced effects were comparable to those of a previously engineered protein, COMP-Ang1. We also revealed that these effects of dimeric CMP-Ang1 were affected by specified N-glycosylation in its fibrinogen-like domain. Taken together, our results indicate that dimeric CMP-Ang1 is capable of activating Tie2 and stimulating angiogenesis in N-glycan dependent manner.

  12. Influences of placental growth factor on mouse retinal vascular development.

    Science.gov (United States)

    Kay, Vanessa R; Tayade, Chandrakant; Carmeliet, Peter; Croy, B Anne

    2017-09-01

    Placental growth factor (PGF) is important for wound-healing and vascular collaterogenesis. PGF deficiency is associated with preeclampsia, a hypertensive disease of human pregnancy. Offspring born to preeclamptic mothers display cognitive impairments and brain vascular and neurostructural deviations. Low PGF production during development may contribute to alterations in offspring cerebrovascular beds. Retina is a readily accessible part of the central nervous system with a well-described pattern of vascular development in mice. Impacts of PGF deficiency were addressed during mouse retinal vascularization. Retinal vessels were compared between Pgf-/- and congenic C57BL/6 (B6) mice. PGF deficiency altered neonatal retinal vascularization patterns. Some anatomic alterations persisted into adulthood, particularly in males. Greater arterial wall collagen IV expression was found in adult Pgf-/- females. Pregnancy (studied in adult females at gestational days 11.5 or 18.5) induced subtle changes upon the mother's retinal vasculature but these pregnancy-induced changes did not differ between genotypes. Significant sex-related differences occurred between adult male and female B6 although sexually dimorphic retinal vascular differences were absent in B6 neonates. Overall, PGF has a role in retinal vascular angiogenesis and vessel organization during development but does not affect retinal vessel adaptations in adult females during pregnancy. Developmental Dynamics 246:700-712, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  13. Human Cytomegalovirus Secretome Contains Factors That Induce Angiogenesis and Wound Healing

    Energy Technology Data Exchange (ETDEWEB)

    Dumortier, Jerome; Streblow, Daniel N.; Moses, Ashlee V.; Jacobs, Jon M.; Kreklywich, Craig N.; Camp, David G.; Smith, Richard D.; Orloff, Susan L.; Nelson, Jay

    2008-07-01

    Human cytomegalovirus (HCMV) is implicated in the acceleration of a number of vascular diseases including transplant vascular sclerosis (TVS), the lesion associated with chronic rejection (CR) of solid organ transplants. Although the virus persists in the allograft throughout the course of disease, few cells are directly infected by CMV. This observation is in contrast to the global effects that CMV has on the acceleration of TVS/CR, suggesting that CMV infection indirectly promotes the vascular disease process. Recent transcriptome analysis of CMV-infected heart allografts indicates that the virus induces cytokines and growth factors associated with angiogenesis (AG) and wound healing (WH), suggesting that CMV may accelerate TVS/CR through the induction and secretion of AG/WH factors from infected cells. We analyzed virus-free supernatants from HCMV-infected cells (HCMV secretomes) for growth factors, by mass spectrometry and immunoassays, and found that the HCMV secretome contains over 1,000 cellular proteins, many of which are involved in AG/WH. Importantly, functional assays demonstrated that CMV but not herpes simplex virus secretomes not only induce AG/WH but also promote neovessel stabilization and endothelial cell survival for 2 weeks. These findings suggest that CMV acceleration of TVS occurs through virus-induced growth factors and cytokines in the CMV secretome.

  14. Self-management of vascular risk factors

    OpenAIRE

    Sol-de Rijk, B.G.M.

    2009-01-01

    Summary The aim of this thesis was to provide insight into the potential of a self-management approach in treatment of vascular risk factors and to develop a self-management intervention. Furthermore to examine if this intervention, based on self-efficacy promoting theory, is effective in reducing vascular risk factors in patients with established vascular diseases. Patients with different manifestations of vascular diseases appeared to have high levels of self-efficacy concerning the self-ma...

  15. The role of vascular endothelial growth factor in inflammatory processes

    Directory of Open Access Journals (Sweden)

    Ewa Koczy-Baron

    2014-01-01

    Full Text Available The vascular endothelial growth factor (VEGF is produced by different types of cells and has a major role in both, physiological and pathological angiogenesis. On the one hand VEGF is a strong mitotic and chemotactic factor for the endothelial cells, stimulating thus formation of new vessels, while on the other, it enhances the vascular endothelium permeability of the existing blood vessels which contributes to development and persistence of the inflammatory conditions. In the latter its activity is by 50 000 times higher than that of histamine. VEGF facilitates formation of oedema and leukocyte migration from the circulation to the site of inflammation. VEGF is also important in remodeling of the extracellular matrix. Moreover, it has an important significance in regulation of the immunological response, therefore plays a role in autoaggressive phenomena as well as immediate- and delayed-type hypersensitivity. Its role in the pathogenesis of immunological and inflammatory diseases, including allergy, asthma and different skin disorders has been indicated.

  16. Deleted in Malignant Brain Tumors 1 is Present in the Vascular Extracellular Matrix and Promotes Angiogenesis

    DEFF Research Database (Denmark)

    Müller-Enbergs, Helmut; Hu, Jiong; Popp, Rüdiger

    2012-01-01

    into the extracellular matrix (ECM) by endothelial cells in vitro and in situ and the presence of DMBT1 in the ECM increased endothelial cell adherence. Endothelial cell-derived DMBT1 associated with galectin-3 (coprecipitation), and human recombinant DMBT1 bound EGF, vascular endothelial growth factor and Delta...

  17. 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.

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

    Directory of Open Access Journals (Sweden)

    s. Karami

    2016-09-01

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

  19. Control of angiogenesis by galectins involves the release of platelet-derived proangiogenic factors.

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    Julia Etulain

    Full Text Available Platelets contribute to vessel formation through the release of angiogenesis-modulating factors stored in their α-granules. Galectins, a family of lectins that bind β-galactoside residues, are up-regulated in inflammatory and cancerous tissues, trigger platelet activation and mediate vascularization processes. Here we aimed to elucidate whether the release of platelet-derived proangiogenic molecules could represent an alternative mechanism through which galectins promote neovascularization. We show that different members of the galectin family can selectively regulate the release of angiogenic molecules by human platelets. Whereas Galectin (Gal-1, -3, and -8 triggered vascular endothelial growth factor (VEGF release, only Gal-8 induced endostatin secretion. Release of VEGF induced by Gal-8 was partially prevented by COX-1, PKC, p38 and Src kinases inhibitors, whereas Gal-1-induced VEGF secretion was inhibited by PKC and ERK blockade, and Gal-3 triggered VEGF release selectively through a PKC-dependent pathway. Regarding endostatin, Gal-8 failed to stimulate its release in the presence of PKC, Src and ERK inhibitors, whereas aspirin or p38 inhibitor had no effect on endostatin release. Despite VEGF or endostatin secretion, platelet releasates generated by stimulation with each galectin stimulated angiogenic responses in vitro including endothelial cell proliferation and tubulogenesis. The platelet angiogenic activity was independent of VEGF and was attributed to the concerted action of other proangiogenic molecules distinctly released by each galectin. Thus, secretion of platelet-derived angiogenic molecules may represent an alternative mechanism by which galectins promote angiogenic responses and its selective blockade may lead to the development of therapeutic strategies for angiogenesis-related diseases.

  20. Hydrogen Sulfide Stimulates Ischemic Vascular Remodeling Through Nitric Oxide Synthase and Nitrite Reduction Activity Regulating Hypoxia‐Inducible Factor‐1α and Vascular Endothelial Growth Factor–Dependent Angiogenesis

    Science.gov (United States)

    Bir, Shyamal C.; Kolluru, Gopi K.; McCarthy, Paul; Shen, Xinggui; Pardue, Sibile; Pattillo, Christopher B.; Kevil, Christopher G.

    2012-01-01

    Background Hydrogen sulfide (H2S) therapy is recognized as a modulator of vascular function during tissue ischemia with the notion of potential interactions of nitric oxide (NO) metabolism. However, little is known about specific biochemical mechanisms or the importance of H2S activation of NO metabolism during ischemic tissue vascular remodeling. The goal of this study was to determine the effect of H2S on NO metabolism during chronic tissue ischemia and subsequent effects on ischemic vascular remodeling responses. Methods and Results The unilateral, permanent femoral artery ligation model of hind‐limb ischemia was performed in C57BL/6J wild‐type and endothelial NO synthase–knockout mice to evaluate exogenous H2S effects on NO bioavailability and ischemic revascularization. We found that H2S selectively restored chronic ischemic tissue function and viability by enhancing NO production involving both endothelial NO synthase and nitrite reduction mechanisms. Importantly, H2S increased ischemic tissue xanthine oxidase activity, hind‐limb blood flow, and angiogenesis, which were blunted by the xanthine oxidase inhibitor febuxostat. H2S treatment increased ischemic tissue and endothelial cell hypoxia‐inducible factor‐1α expression and activity and vascular endothelial growth factor protein expression and function in a NO‐dependent manner that was required for ischemic vascular remodeling. Conclusions These data demonstrate that H2S differentially regulates NO metabolism during chronic tissue ischemia, highlighting novel biochemical pathways to increase NO bioavailability for ischemic vascular remodeling. PMID:23316304

  1. Angiogenesis and lymphangiogenesis as prognostic factors after therapy in patients with cervical cancer.

    Science.gov (United States)

    Biedka, Marta; Makarewicz, Roman; Kopczyńska, Ewa; Marszałek, Andrzej; Goralewska, Alina; Kardymowicz, Hanna

    2012-01-01

    This retrospective study attempts to evaluate the influence of serum vascular endothelial growth factor C (VEGF-C), microvessel density (MVD) and lymphatic vessel density (LMVD) on the result of tumour treatment in women with cervical cancer. The research was carried out in a group of 58 patients scheduled for brachytherapy for cervical cancer. All women were patients of the Department and University Hospital of Oncology and Brachytherapy, Collegium Medicum in Bydgoszcz of Nicolaus Copernicus University in Toruń. VEGF-C was determined by means of a quantitative sandwich enzyme immunoassay using a human antibody VEGF-C ELISA produced by Bender MedSystem, enzyme-linked immunosorbent detecting the activity of human VEGF-C in body fluids. The measure for the intensity of angiogenesis and lymphangiogenesis in immunohistochemical reactions is the number of blood vessels within the tumour. Statistical analysis was done using Statistica 6.0 software (StatSoft, Inc. 2001). The Cox proportional hazards model was used for univariate and multivariate analyses. Univariate analysis of overall survival was performed as outlined by Kaplan and Meier. In all statistical analyses p < 0.05 (marked red) was taken as significant. In 51 patients who showed up for follow-up examination, the influence of the factors of angiogenesis, lymphangiogenesis, patients' age and the level of haemoglobin at the end of treatment were assessed. Selected variables, such as patients' age, lymph vessel density (LMVD), microvessel density (MVD) and the level of haemoglobin (Hb) before treatment were analysed by means of Cox logical regression as potential prognostic factors for lymph node invasion. The observed differences were statistically significant for haemoglobin level before treatment and the platelet number after treatment. The study revealed the following prognostic factors: lymph node status, FIGO stage, and kind of treatment. No statistically significant influence of angiogenic and

  2. Platelet-derived growth factor-DD targeting arrests pathological angiogenesis by modulating glycogen synthase kinase-3beta phosphorylation.

    Science.gov (United States)

    Kumar, Anil; Hou, Xu; Lee, Chunsik; Li, Yang; Maminishkis, Arvydas; Tang, Zhongshu; Zhang, Fan; Langer, Harald F; Arjunan, Pachiappan; Dong, Lijin; Wu, Zhijian; Zhu, Linda Y; Wang, Lianchun; Min, Wang; Colosi, Peter; Chavakis, Triantafyllos; Li, Xuri

    2010-05-14

    Platelet-derived growth factor-DD (PDGF-DD) is a recently discovered member of the PDGF family. The role of PDGF-DD in pathological angiogenesis and the underlying cellular and molecular mechanisms remain largely unexplored. In this study, using different animal models, we showed that PDGF-DD expression was up-regulated during pathological angiogenesis, and inhibition of PDGF-DD suppressed both choroidal and retinal neovascularization. We also demonstrated a novel mechanism mediating the function of PDGF-DD. PDGF-DD induced glycogen synthase kinase-3beta (GSK3beta) Ser(9) phosphorylation and Tyr(216) dephosphorylation in vitro and in vivo, leading to increased cell survival. Consistently, GSK3beta activity was required for the antiangiogenic effect of PDGF-DD targeting. Moreover, PDGF-DD regulated the expression of GSK3beta and many other genes important for angiogenesis and apoptosis. Thus, we identified PDGF-DD as an important target gene for antiangiogenic therapy due to its pleiotropic effects on vascular and non-vascular cells. PDGF-DD inhibition may offer new therapeutic options to treat neovascular diseases.

  3. Dobesilate is an angiogenesis inhibitor

    OpenAIRE

    Cuevas, P.; Sánchez, I.; Lozano, R.M.; Giménez-Gallego, Guillermo

    2005-01-01

    Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Antiangiogenic therapy is one of the most promising approaches to treat such diseases. Dobesilate is an oral agent for treatment of vascular complications of diabetic retinopathy. We have examined the possibility that this compound could interfere with the process of angiogenesis in a mouse gelatine sponge assay using acidic fibroblast growth factor (aFGF) as an inducer of neovascularization...

  4. CCN2/connective tissue growth factor is essential for pericyte adhesion and endothelial basement membrane formation during angiogenesis.

    Directory of Open Access Journals (Sweden)

    Faith Hall-Glenn

    Full Text Available CCN2/Connective Tissue Growth Factor (CTGF is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor β (TGFβ to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes.

  5. Tumor angiogenesis as an important prognostic factor in advanced non-small cell lung cancer (Stage IIIA).

    Science.gov (United States)

    Bačić, Ivan; Karlo, Robert; Zadro, Ana Šoštarić; Zadro, Zvonko; Skitarelić, Neven; Antabak, Anko

    2018-02-01

    The aim of the present study was to evaluate angiogenesis by determining the micro vascular density (MVD) and the expression of vascular endothelial growth factor (VEGF-A) in advanced non-small cell lung cancer (NSCLC) tumor samples, and to analyze their associations with clinical parameters and survival. Tumor tissue specimens of fifty patients (41 males and 9 females), who underwent radical surgical treatment for NSCLC in stage IIIA (T1-3N2) were collected for immunohistochemical analysis. MVD evaluation was performed using an anti-CD31 monoclonal antibody and VEGF-A expression using a polyclonal anti-VEGF-A antibody. The results were associated with two-year survival. Statistical analysis revealed significant associations in the level of angiogenesis (high MVD) and shorter survival of patients with NSCLC (P=0.0007). VEGF-A expression showed no association with micro vascular density (P=0.51) or survival (P=0.68). There was no significant association between MVD and VEGF-A. The measurable, clinical MVD parameters could be used as a reliable prognostic factor for the survival of patients with advanced NSCLC.

  6. Study of Microvessel Density and the Expression of Vascular Endothelial Growth Factors in Adrenal Gland Pheochromocytomas

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    Magdalena Białas

    2014-01-01

    Full Text Available Angiogenesis (neoangiogenesis, a process of neovascularization, is an essential step for local tumor growth and distant metastasis formation. We have analysed angiogenesis status: vascular architecture, microvessel density, and vascular endothelial growth factors expression in 62 adrenal pheochromocytomas: 57 benign and 5 malignant. Immunohistochemical evaluation revealed that vascular architecture and vessel density are different in the central and subcapsular areas of the tumor. Furthermore, we have observed a strong correlation between number of macrophages and microvessel density in the central and subcapsular areas of the tumor and between the expression of VEGF-A in tumor cells and microvessel density in central and subcapsular areas of the tumor. Secondary changes in these tumors influence the results and both vascular architecture and microvessel density are markedly disturbed by hemorrhagic and cystic changes in pheochromocytomas. These changes are partially caused by laparoscopic operation technique. However, no differences in vascular parameters were found between pheochromocytomas with benign and malignant clinical behavior. Our observation showed that analysis of angiogenesis, as a single feature, does not help in differentiating malignant and benign pheochromocytomas and has no independent prognostic significance. On the other hand, high microvessel density in pheochromocytoma is a promising factor for antiangiogenic therapy in malignant cases.

  7. Vascular Endothelial Growth Factor from Embryonic Status to Cardiovascular Pathology

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    Mohsen Azimi-Nezhad

    2014-05-01

    Full Text Available Vascular endothelial growth factor (VEGF is a multifunctional cytokine with distinct functions in angiogenesis, lymphangiogenesis, vascular permeability, and hematopoiesis. VEGF is a highly conserved, disulfide-bonded dimeric glycoprotein of 34 to 45 kDa produced by several cell types including fibroblasts, neutrophils, endothelial cells, and peripheral blood mononuclear cells, particularly T lymphocytes and macrophages. Six VEGF isoforms are generated as a result of alternative splicing from a single VEGF gene, consisting of 121, 145, 165, 183, 189, or 206 amino acids. VEGF121, VEGF145, and VEGF165 are secreted whereas VEGF183, VEGF189, and VEGF206 are cell membrane-bound. VEGF145 has a key role during the vascularization of the human ovarian follicle and corpus luteum, in the placentation and embryonic periods, and in bone and wound healing, while VEGF165 is the most abundant and biologically active isoform. VEGF has been linked with a number of vascular pathologies including cardiovascular diseases such ischemic heart disease, heart failure, stroke, and diabetes and its related complications. In this review we aimed to present some important roles of VEGF in a number of clinical issues and indicate its involvement in several phenomena from the initial steps of the embryonic period to cardiovascular diseases.

  8. Dobesilate is an angiogenesis inhibitor.

    Science.gov (United States)

    Cuevas, Pedro; Sanchez, I; Lozano, R M; Gimenez-Gallego, G

    2005-09-12

    Aberrant angiogenesis is essential for the progression of solid tumors and hematological malignancies. Antiangiogenic therapy is one of the most promising approaches to treat such diseases. Dobesilate is an oral agent for treatment of vascular complications of diabetic retinopathy. We have examined the possibility that this compound could interfere with the process of angiogenesis in a mouse gelatine sponge assay using acidic fibroblast growth factor (aFGF) as an inducer of neovascularization. According to the results reported here, dobesilate remarkably reduced vessel ingrowth in aFGF-containing subcutaneous sponges in mice. These findings suggest that dobesilate could be an effective agent in the treatment of angiogenesis-dependent diseases involving FGFs.

  9. Expression of Angiogenesis Regulatory Proteins and Epithelial-Mesenchymal Transition Factors in Platelets of the Breast Cancer Patients

    Directory of Open Access Journals (Sweden)

    Hui Han

    2014-01-01

    Full Text Available Platelets play a role in tumor angiogenesis and growth and are the main transporters of several angiogenesis regulators. Here, we aimed to determine the levels of angiogenesis regulators and epithelial-mesenchymal transition factors sequestered by circulating platelets in breast cancer patients and age-matched healthy controls. Platelet pellets (PP and platelet-poor plasma (PPP were collected by routine protocols. Vascular endothelial growth factor (VEGF, platelet-derived growth factor BB (PDGF-BB, thrombospondin-1 (TSP-1, platelet factor 4 (PF4, and transforming growth factor-β1 (TGF-β1 were measured by enzyme-linked immunosorbent assay. Angiogenesis-associated expression of VEGF (2.1 pg/106 platelets versus 0.9 pg/106 platelets, P < 0.001, PF4 (21.2 ng/106 platelets versus 10.2 ng/106 platelets, P < 0.001, PDGF-BB (42.9 pg/106 platelets versus 19.1 pg/106 platelets, P < 0.001, and TGF-β1 (15.3 ng/106 platelets versus 4.3 ng/106 platelets, P < 0.001 differed in the PP samples of cancer and control subjects. In addition, protein concentrations were associated with clinical characteristics (P<0.05. Circulating platelets in breast cancer sequester higher levels of PF4, VEGF, PDGF-BB, and TGF-β1, suggesting a possible target for early diagnosis. VEGF, PDGF, and TGF-β1 concentrations in platelets may be associated with prognosis.

  10. Soluble vascular endothelial growth factor in various blood transfusion components

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen; Werther, K; Mynster, T

    1999-01-01

    BACKGROUND: Blood transfusion may reduce survival after curative surgery for solid tumors. This may be related to extracellular content of cancer growth factors present in transfusion components. Vascular endothelial growth factor (VEGF) is a potent stimulator of angiogenesis in solid tumors....... The potential content of VEGF in various blood components for transfusion was evaluated. STUDY DESIGN AND METHODS: Soluble VEGF (sVEGF, isotype 165) was determined by an enzyme-linked immunosorbent assay (EIA) in serum and plasma samples and in lysed cells from healthy volunteers. Subsequently, total content......-reduced PRP. The sVEGF accumulated significantly in WB, SAGM blood, and BCP pools, depending on the storage time. CONCLUSION: The sVEGF (isotype 165) appears to be present in various blood transfusion components, depending on storage time....

  11. Aspirin decreases vascular endothelial growth factor release during myocardial ischemia.

    Science.gov (United States)

    Gerrah, Rabin; Fogel, Mina; Gilon, Dan

    2004-03-01

    Vascular Endothelial Growth Factor (VEGF) is an important angiogenesis factor involved in pathophysiology of cardiovascular diseases. Controlling this factor's level in the serum might have significant prognostic outcomes. Twenty-four patients undergoing coronary artery bypass grafting were prospectively categorized into two groups according to aspirin administration before surgery. Vascular Endothelial Growth Factor levels were compared and correlated and adjusted with platelets count between two groups in the serum, before and after the surgery. Serum creatine kinase (CK) levels were determined before and after the operation in parallel to other clinical data. Vascular Endothelial Growth Factor levels were significantly lower in patients of the aspirin group compared to those of the non-aspirin group; 94+/-61 vs. 241+/-118 pg/ml, p=0.0003, respectively, this-despite an absence of difference in the platelet count between the groups. These titers decreased postoperatively in both groups, 94+/-61 to 10+/-9 pg/ml, p=0.001 in aspirin group and from 241+/-118 to 84+/-54 pg/ml, p=0.001 in control group. Serum creatine kinase levels were higher in the non-aspirin group, 214+/-83 u/l compared to 70+/-32 u/l in the aspirin group. Creatine kinase levels increased significantly postoperatively in both groups; however, the aspirin group had a significantly lower creatine kinase levels compared to non-aspirin group, 107+/-51 vs. 401+/-127 u/l, respectively, p=<0.0001. A significant correlation was seen between VEGF levels and platelets count in both groups, r=0.5. Aspirin treated patients have lower Vascular Endothelial Growth Factor titer levels in the perioperative course. This difference between the aspirin and the non-aspirin group is not accounted for by the platelets count.

  12. Fibroblast Growth Factor-9 Activates c-Kit Progenitor Cells and Enhances Angiogenesis in the Infarcted Diabetic Heart

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    Dinender Singla

    2016-01-01

    Full Text Available We hypothesized that fibroblast growth factor-9 (FGF-9 would enhance angiogenesis via activating c-kit positive stem cells in the infarcted nondiabetic and diabetic heart. In brief, animals were divided into three groups: Sham, MI, and MI+FGF-9. Two weeks following MI or sham surgery, our data suggest that treatment with FGF-9 significantly diminished vascular apoptosis compared to the MI group in both C57BL/6 and db/db mice (p<0.05. Additionally, the number of c-kit+ve/SM α-actin+ve cells and c-kit+ve/CD31+ve cells were greatly enhanced in the MI+FGF-9 groups relative to the MI suggesting FGF-9 enhances c-Kit cell activation and their differentiation into vascular smooth muscle cells and endothelial cells, respectively (p<0.05. Histology shows that the total number of vessels were quantified for all groups and our data suggest that the FGF-9 treated groups had significantly more vessels than their MI counterparts (p<0.05. Finally, echocardiographic data suggests a significant improvement in left ventricular output, as indicated by fractional shortening and ejection fraction in both nondiabetic and diabetic animals treated with FGF-9 (p<0.05. Overall, our data suggests FGF-9 has the potential to attenuate vascular cell apoptosis, activate c-Kit progenitor cells, and enhance angiogenesis and neovascularization in C57BL/6 and db/db mice leading to improved cardiac function.

  13. Vascular endothelial growth factor coordinates islet innervation via vascular scaffolding

    Science.gov (United States)

    Reinert, Rachel B.; Cai, Qing; Hong, Ji-Young; Plank, Jennifer L.; Aamodt, Kristie; Prasad, Nripesh; Aramandla, Radhika; Dai, Chunhua; Levy, Shawn E.; Pozzi, Ambra; Labosky, Patricia A.; Wright, Christopher V. E.; Brissova, Marcela; Powers, Alvin C.

    2014-01-01

    Neurovascular alignment is a common anatomical feature of organs, but the mechanisms leading to this arrangement are incompletely understood. Here, we show that vascular endothelial growth factor (VEGF) signaling profoundly affects both vascularization and innervation of the pancreatic islet. In mature islets, nerves are closely associated with capillaries, but the islet vascularization process during embryonic organogenesis significantly precedes islet innervation. Although a simple neuronal meshwork interconnects the developing islet clusters as they begin to form at E14.5, the substantial ingrowth of nerve fibers into islets occurs postnatally, when islet vascularization is already complete. Using genetic mouse models, we demonstrate that VEGF regulates islet innervation indirectly through its effects on intra-islet endothelial cells. Our data indicate that formation of a VEGF-directed, intra-islet vascular plexus is required for development of islet innervation, and that VEGF-induced islet hypervascularization leads to increased nerve fiber ingrowth. Transcriptome analysis of hypervascularized islets revealed an increased expression of extracellular matrix components and axon guidance molecules, with these transcripts being enriched in the islet-derived endothelial cell population. We propose a mechanism for coordinated neurovascular development within pancreatic islets, in which endocrine cell-derived VEGF directs the patterning of intra-islet capillaries during embryogenesis, forming a scaffold for the postnatal ingrowth of essential autonomic nerve fibers. PMID:24574008

  14. Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung

    LENUS (Irish Health Repository)

    Sands, Michelle

    2011-01-25

    Abstract Background Chronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. In the non-diseased lung, angiogenesis occurs in chronic hypoxia and may act in a protective, adaptive manner. To date, little is known about the behaviour of individual vascular endothelial growth factor (VEGF) family ligands in hypoxia-induced pulmonary angiogenesis. The aim of this study was to examine the expression of placenta growth factor (PlGF) and VEGFB during the development of hypoxic pulmonary angiogenesis and their functional effects on the pulmonary endothelium. Methods Male Sprague Dawley rats were exposed to conditions of normoxia (21% O2) or hypoxia (10% O2) for 1-21 days. Stereological analysis of vascular structure, real-time PCR analysis of vascular endothelial growth factor A (VEGFA), VEGFB, placenta growth factor (PlGF), VEGF receptor 1 (VEGFR1) and VEGFR2, immunohistochemistry and western blots were completed. The effects of VEGF ligands on human pulmonary microvascular endothelial cells were determined using a wound-healing assay. Results Typical vascular remodelling and angiogenesis were observed in the hypoxic lung. PlGF and VEGFB mRNA expression were significantly increased in the hypoxic lung. Immunohistochemical analysis showed reduced expression of VEGFB protein in hypoxia although PlGF protein was unchanged. The expression of VEGFA mRNA and protein was unchanged. In vitro PlGF at high concentration mimicked the wound-healing actions of VEGFA on pulmonary microvascular endothelial monolayers. Low concentrations of PlGF potentiated the wound-healing actions of VEGFA while higher concentrations of PlGF were without this effect. VEGFB inhibited the wound-healing actions of VEGFA while VEGFB and PlGF together were mutually antagonistic. Conclusions VEGFB and PlGF can either inhibit or potentiate the

  15. Placenta growth factor and vascular endothelial growth factor B expression in the hypoxic lung

    Directory of Open Access Journals (Sweden)

    McLoughlin Paul

    2011-01-01

    Full Text Available Abstract Background Chronic alveolar hypoxia, due to residence at high altitude or chronic obstructive lung diseases, leads to pulmonary hypertension, which may be further complicated by right heart failure, increasing morbidity and mortality. In the non-diseased lung, angiogenesis occurs in chronic hypoxia and may act in a protective, adaptive manner. To date, little is known about the behaviour of individual vascular endothelial growth factor (VEGF family ligands in hypoxia-induced pulmonary angiogenesis. The aim of this study was to examine the expression of placenta growth factor (PlGF and VEGFB during the development of hypoxic pulmonary angiogenesis and their functional effects on the pulmonary endothelium. Methods Male Sprague Dawley rats were exposed to conditions of normoxia (21% O2 or hypoxia (10% O2 for 1-21 days. Stereological analysis of vascular structure, real-time PCR analysis of vascular endothelial growth factor A (VEGFA, VEGFB, placenta growth factor (PlGF, VEGF receptor 1 (VEGFR1 and VEGFR2, immunohistochemistry and western blots were completed. The effects of VEGF ligands on human pulmonary microvascular endothelial cells were determined using a wound-healing assay. Results Typical vascular remodelling and angiogenesis were observed in the hypoxic lung. PlGF and VEGFB mRNA expression were significantly increased in the hypoxic lung. Immunohistochemical analysis showed reduced expression of VEGFB protein in hypoxia although PlGF protein was unchanged. The expression of VEGFA mRNA and protein was unchanged. In vitro PlGF at high concentration mimicked the wound-healing actions of VEGFA on pulmonary microvascular endothelial monolayers. Low concentrations of PlGF potentiated the wound-healing actions of VEGFA while higher concentrations of PlGF were without this effect. VEGFB inhibited the wound-healing actions of VEGFA while VEGFB and PlGF together were mutually antagonistic. Conclusions VEGFB and PlGF can either inhibit or

  16. Preoperative serum levels of epidermal growth factor receptor, HER2, and vascular endothelial growth factor in malignant and benign ovarian tumors

    DEFF Research Database (Denmark)

    Dahl Steffensen, Karina; Waldstrøm, Marianne; Jeppesen, Ulla

    2008-01-01

    Background: Epidermal growth factor receptors ([EGFRs]; EGFR/HER1 and ErbB2/HER2) and vascular endothelial growth factor (VEGF) are essential to tumor growth and angiogenesis. The aim of the present study was to investigate the serum levels of these potential biomarkers in benign, borderline...

  17. Expression of vascular endothelial growth factor, stromal cell-derived factor-1, and CXCR4 in human limb muscle with acute and chronic ischemia

    NARCIS (Netherlands)

    Weel, V. van; Seghers, L.; Vries, M.R. de; Kuiper, E.J.; Schlingemann, R.O.; Bajema, I.M.; Lindeman, J.H.N.; Delis-Diemen, P.M. van; Hinsbergh, V.W.M. van; Bockel, J.H. van; Quax, P.H.A.

    2007-01-01

    OBJECTIVE - Vascular endothelial growth factor (VEGF)-induced stromal cell-derived factor-1 (SDF-1) has been implicated in angiogenesis in ischemic tissues by recruitment of CXCR4-positive bone marrow-derived circulating cells with paracrine functions in preclinical models. Here, evidence for this

  18. The Role of Vascular Endothelial Growth Factor Receptor-1 Signaling in the Recovery from Ischemia.

    Science.gov (United States)

    Amano, Hideki; Kato, Shintaro; Ito, Yoshiya; Eshima, Koji; Ogawa, Fumihiro; Takahashi, Ryo; Sekiguchi, Kazuki; Tamaki, Hideaki; Sakagami, Hiroyuki; Shibuya, Masabumi; Majima, Masataka

    2015-01-01

    Vascular endothelial growth factor (VEGF) is one of the most potent angiogenesis stimulators. VEGF binds to VEGF receptor 1 (VEGFR1), inducing angiogenesis through the receptor's tyrosine kinase domain (TK), but the mechanism is not well understood. We investigated the role of VEGFR1 tyrosine kinase signaling in angiogenesis using the ischemic hind limb model. Relative to control mice, blood flow recovery was significantly impaired in mice treated with VEGFA-neutralizing antibody. VEGFR1 tyrosine kinase knockout mice (TK-/-) had delayed blood flow recovery from ischemia and impaired angiogenesis, and this phenotype was unaffected by treatment with a VEGFR2 inhibitor. Compared to wild type mice (WT), TK-/- mice had no change in the plasma level of VEGF, but the plasma levels of stromal-derived cell factor 1 (SDF-1) and stem cell factor, as well as the bone marrow (BM) level of pro-matrix metalloproteinase-9 (pro-MMP-9), were significantly reduced. The recruitment of cells expressing VEGFR1 and C-X-C chemokine receptor type 4 (CXCR4) into peripheral blood and ischemic muscles was also suppressed. Furthermore, WT transplanted with TK-/- BM significantly impaired blood flow recovery more than WT transplanted with WT BM. These results suggest that VEGFR1-TK signaling facilitates angiogenesis by recruiting CXCR4+VEGFR1+ cells from BM.

  19. Ramucirumab (IMC-1121B): Monoclonal antibody inhibition of vascular endothelial growth factor receptor-2.

    Science.gov (United States)

    Spratlin, Jennifer

    2011-04-01

    Angiogenesis, a well-recognized characteristic of malignancy, has been exploited more than any other pathway targeted by biologic anti-neoplastic therapies. Vascular endothelial growth factor receptor-2 (VEGFR-2) is the critical receptor involved in malignant angiogenesis with its activation inducing a number of other cellular modifications resulting in tumor growth and metastases. Ramucirumab (IMC-1121B; ImClone Systems Corporation, Branchburg, NJ) is a fully human monoclonal antibody developed to specifically inhibit VEGFR-2. Ramucirumab is currently being investigated in multiple clinical trials across a variety of tumor types. Herein, angiogenesis inhibition in cancer is reviewed and up-to-date information on the clinical development of ramucirumab is presented.

  20. 45S5-Bioglass(®)-based 3D-scaffolds seeded with human adipose tissue-derived stem cells induce in vivo vascularization in the CAM angiogenesis assay.

    Science.gov (United States)

    Handel, Marina; Hammer, Timo R; Nooeaid, Patcharakamon; Boccaccini, Aldo R; Hoefer, Dirk

    2013-12-01

    Poor vascularization is the key limitation for long-term acceptance of large three-dimensional (3D) tissue engineering constructs in regenerative medicine. 45S5 Bioglass(®) was investigated given its potential for applications in bone engineering. Since native Bioglass(®) shows insufficient angiogenic properties, we used a collagen coating, to seed human adipose tissue-derived stem cells (hASC) confluently onto 3D 45S5 Bioglass(®)-based scaffolds. To investigate vascularization by semiquantitative analyses, these biofunctionalized scaffolds were then subjected to in vitro human umbilical vein endothelial cells formation assays, and were also investigated in the chorioallantoic membrane (CAM) angiogenesis model, an in vivo angiogenesis assay, which uses the CAM of the hen's egg. In their native, nonbiofunctionalized state, neither Bioglass(®)-based nor biologically inert fibrous polypropylene control scaffolds showed angiogenic properties. However, significant vascularization was induced by hASC-seeded scaffolds (Bioglass(®) and polypropylene) in the CAM angiogenesis assay. Biofunctionalized scaffolds also showed enhanced tube lengths, compared to unmodified scaffolds or constructs seeded with fibroblasts. In case of biologically inert hernia meshes, the quantification of vascular endothelial growth factor secretion as the key angiogenic stimulus strongly correlated to the tube lengths and vessel numbers in all models. This correlation proved the CAM angiogenesis assay to be a suitable semiquantitative tool to characterize angiogenic effects of larger 3D implants. In addition, our results suggest that combinations of suitable scaffold materials, such as 45S5 Bioglass(®), with hASC could be a promising approach for future tissue engineering applications.

  1. 45S5-Bioglass®-Based 3D-Scaffolds Seeded with Human Adipose Tissue-Derived Stem Cells Induce In Vivo Vascularization in the CAM Angiogenesis Assay

    Science.gov (United States)

    Handel, Marina; Hammer, Timo R.; Nooeaid, Patcharakamon; Boccaccini, Aldo R.

    2013-01-01

    Poor vascularization is the key limitation for long-term acceptance of large three-dimensional (3D) tissue engineering constructs in regenerative medicine. 45S5 Bioglass® was investigated given its potential for applications in bone engineering. Since native Bioglass® shows insufficient angiogenic properties, we used a collagen coating, to seed human adipose tissue-derived stem cells (hASC) confluently onto 3D 45S5 Bioglass®-based scaffolds. To investigate vascularization by semiquantitative analyses, these biofunctionalized scaffolds were then subjected to in vitro human umbilical vein endothelial cells formation assays, and were also investigated in the chorioallantoic membrane (CAM) angiogenesis model, an in vivo angiogenesis assay, which uses the CAM of the hen's egg. In their native, nonbiofunctionalized state, neither Bioglass®-based nor biologically inert fibrous polypropylene control scaffolds showed angiogenic properties. However, significant vascularization was induced by hASC-seeded scaffolds (Bioglass® and polypropylene) in the CAM angiogenesis assay. Biofunctionalized scaffolds also showed enhanced tube lengths, compared to unmodified scaffolds or constructs seeded with fibroblasts. In case of biologically inert hernia meshes, the quantification of vascular endothelial growth factor secretion as the key angiogenic stimulus strongly correlated to the tube lengths and vessel numbers in all models. This correlation proved the CAM angiogenesis assay to be a suitable semiquantitative tool to characterize angiogenic effects of larger 3D implants. In addition, our results suggest that combinations of suitable scaffold materials, such as 45S5 Bioglass®, with hASC could be a promising approach for future tissue engineering applications. PMID:23837884

  2. [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.

  3. A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development.

    Science.gov (United States)

    Villefranc, Jacques A; Nicoli, Stefania; Bentley, Katie; Jeltsch, Michael; Zarkada, Georgia; Moore, John C; Gerhardt, Holger; Alitalo, Kari; Lawson, Nathan D

    2013-04-01

    Vascular endothelial growth factor C (Vegfc) is a secreted protein that guides lymphatic development in vertebrate embryos. However, its role during developmental angiogenesis is not well characterized. Here, we identify a mutation in zebrafish vegfc that severely affects lymphatic development and leads to angiogenesis defects on sensitized genetic backgrounds. The um18 mutation prematurely truncated Vegfc, blocking its secretion and paracrine activity but not its ability to activate its receptor Flt4. When expressed in endothelial cells, vegfc(um18) could not rescue lymphatic defects in mutant embryos, but induced ectopic blood vessel branching. Furthermore, vegfc-deficient endothelial cells did not efficiently contribute to tip cell positions in developing sprouts. Computational modeling together with assessment of endothelial cell dynamics by time-lapse analysis suggested that an autocrine Vegfc/Flt4 loop plays an important role in migratory persistence and filopodia stability during sprouting. Our results suggest that Vegfc acts in two distinct modes during development: as a paracrine factor secreted from arteries to guide closely associated lymphatic vasculature and as an autocrine factor to drive migratory persistence during angiogenesis.

  4. Differential effects of vascular endothelial growth factor A isoforms in a mouse brain metastasis model of human melanoma.

    NARCIS (Netherlands)

    Kusters, B.; Waal, R.M.W. de; Wesseling, P.; Verrijp, K.; Maass, C.N.; Heerschap, A.; Barentsz, J.O.; Sweep, C.G.J.; Ruiter, D.J.; Leenders, W.P.J.

    2003-01-01

    We reported previously that vascular endothelial growth factor isoform A (VEGF-A) expression by Mel57 human melanoma cells led to tumor progression in a murine brain metastasis model in an angiogenesis-independent fashion by dilation of co-opted, pre-existing vessels and concomitant enhanced blood

  5. Vascular endothelial growth factor and not cyclooxygenase 2 promotes endothelial cell viability in the pancreatic tumor microenvironment.

    LENUS (Irish Health Repository)

    Toomey, Desmond P

    2010-07-01

    Cyclooxygenase 2 (COX-2) and vascular endothelial growth factor (VEGF), often coexpressed in cancer, are associated with poor prognosis. However, results from pancreatic cancer trials of their inhibitors were disappointing. This study delineated the role of COX-2 and nonsteroidal anti-inflammatory drugs in angiogenesis and VEGF regulation.

  6. Dual ETA/ETB blockade with macitentan improves both vascular remodeling and angiogenesis in pulmonary arterial hypertension

    Science.gov (United States)

    Nadeau, Valerie; Potus, Francois; Boucherat, Olivier; Paradis, Renee; Tremblay, Eve; Iglarz, Marc; Paulin, Roxane; Bonnet, Sebastien

    2017-01-01

    Dysregulated metabolism and rarefaction of the capillary network play a critical role in pulmonary arterial hypertension (PAH) etiology. They are associated with a decrease in perfusion of the lungs, skeletal muscles, and right ventricle (RV). Previous studies suggested that endothelin-1 (ET-1) modulates both metabolism and angiogenesis. We hypothesized that dual ETA/ETB receptors blockade improves PAH by improving cell metabolism and promoting angiogenesis. Five weeks after disease induction, Sugen/hypoxic rats presented severe PAH with pulmonary artery (PA) remodeling, RV hypertrophy and capillary rarefaction in the lungs, RV, and skeletal muscles (microCT angiogram, lectin perfusion, CD31 staining). Two-week treatment with dual ETA/ETB receptors antagonist macitentan (30 mg/kg/d) significantly improved pulmonary hemodynamics, PA vascular remodeling, and RV function and hypertrophy compared to vehicle-treated animals (all P = 0.05). Moreover, macitentan markedly increased lung, RV and quadriceps perfusion, and microvascular density (all P = 0.05). In vitro, these effects were associated with increases in oxidative phosphorylation (oxPhox) and markedly reduced cell proliferation of PAH-PA smooth muscle cells (PASMCs) treated with macitentan without affecting apoptosis. While macitentan did not affect oxPhox, proliferation, and apoptosis of PAH–PA endothelial cells (PAECs), it significantly improved their angiogenic capacity (tube formation assay). Exposure of control PASMC and PAEC to ET-1 fully mimicked the PAH cells phenotype, thus confirming that ET-1 is implicated in both metabolism and angiogenesis abnormalities in PAH. Dual ETA/ETB receptor blockade improved the metabolic changes involved in PAH-PASMCs’ proliferation and the angiogenic capacity of PAH-PAEC leading to an increased capillary density in lungs, RV, and skeletal muscles. PMID:29064353

  7. Melanoma Angiogenesis and Metastasis Modulated by Ribozyme Targeting of the Secreted Growth Factor Pleiotrophin

    Science.gov (United States)

    Czubayko, Frank; Schulte, Anke M.; Berchem, Guy J.; Wellstein, Anton

    1996-12-01

    Clinical and experimental evidence suggests that spreading of malignant cells from a localized tumor (metastasis) is directly related to the number of microvessels in the primary tumor. This tumor angiogenesis is thought to be mediated by tumor-cell-derived growth factors. However, most tumor cells express a multitude of candidate angiogenesis factors and it is difficult to decipher which of these are rate-limiting factors in vivo. Herein we use ribozyme targeting of pleiotrophin (PTN) in metastatic human melanoma cells to assess the significance of this secreted growth factor for angiogenesis and metastasis. As a model we used human melanoma cells (1205LU) that express high levels of PTN and metastasize from subcutaneous tumors to the lungs of experimental animals. In these melanoma cells, we reduced PTN mRNA and growth factor activity by transfection with PTN-targeted ribozymes and generated cell lines expressing different levels of PTN. We found that the reduction of PTN does not affect growth of the melanoma cells in vitro. In nude mice, however, tumor growth and angiogenesis were decreased in parallel with the reduced PTN levels and apoptosis in the tumors was increased. Concomitantly, the metastatic spread of the tumors from the subcutaneous site to the lungs was prevented. These studies support a direct link between tumor angiogenesis and metastasis through a secreted growth factor and identify PTN as a candidate factor that may be rate-limiting for human melanoma metastasis.

  8. 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.

  9. A sustained release formulation of novel quininib-hyaluronan microneedles inhibits angiogenesis and retinal vascular permeability in vivo.

    Science.gov (United States)

    Galvin, Orla; Srivastava, Akshay; Carroll, Oliver; Kulkarni, Rajiv; Dykes, Steve; Vickers, Steven; Dickinson, Keith; Reynolds, Alison L; Kilty, Claire; Redmond, Gareth; Jones, Rob; Cheetham, Sharon; Pandit, Abhay; Kennedy, Breandán N

    2016-07-10

    Pathologic neovascularisation and ocular permeability are hallmarks of proliferative diabetic retinopathy and age-related macular degeneration. Current pharmacologic interventions targeting VEGF are effective in only 30-60% of patients and require multiple intraocular injections associated with iatrogenic infection. Thus, our goal is to develop novel small molecule drugs that are VEGF-independent are amenable to sustained ocular-release, and which reduce retinal angiogenesis and retinal vascular permeability. Here, the anti-angiogenic drug quininib was formulated into hyaluronan (HA) microneedles whose safety and efficacy was evaluated in vivo. Quininib-HA microneedles were formulated via desolvation from quininib-HA solution and subsequent cross-linking with 4-arm-PEG-amine prior to freeze-drying. Scanning electron microscopy revealed hollow needle-shaped particle ultrastructure, with a zeta potential of -35.5mV determined by electrophoretic light scattering. The incorporation efficiency and pharmacokinetic profile of quininib released in vitro from the microneedles was quantified by HPLC. Quininib incorporation into these microneedles was 90%. In vitro, 20% quininib was released over 4months; or in the presence of increasing concentrations of hyaluronidase, 60% incorporated quininib was released over 4months. Zebrafish hyaloid vasculature assays demonstrated quininib released from these microneedles significantly (pmicroneedles allow for sustained release of quininib; are safe in vivo and quininib released from these microneedles effectively inhibits angiogenesis and RVP in vivo. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Epidermal growth factor-like domain 7 is a marker of the endothelial lineage and active angiogenesis.

    Science.gov (United States)

    Bambino, Kathryn; Lacko, Lauretta A; Hajjar, Katherine A; Stuhlmann, Heidi

    2014-07-01

    Epidermal growth factor-like domain 7 (Egfl7) expression in the developing embryo is largely restricted to sites of mesodermal progenitors of angioblasts/hemangioblasts and the vascular endothelium. We hypothesize that Egfl7 marks the endothelial lineage during embryonic development, and can be used to define the emergence of endothelial progenitor cells, as well as to visualize newly-forming vasculature in the embryo and during the processes of physiologic and pathologic angiogenesis in the adult. We have generated a transgenic mouse strain that expresses enhanced green fluorescent protein (eGFP) under the control of a minimal Egfl7 regulatory sequence (Egfl7:eGFP). Expression of the transgene recapitulated that of endogenous Egfl7 at sites of vasculogenesis and angiogenesis in the allantois, yolk sac, and in the embryo proper. The transgene was not expressed in the quiescent endothelium of most adult organs. However, the uterus and ovary, which undergo vascular growth and remodeling throughout the estrus cycle, expressed high levels of Egfl7:eGFP. Importantly, expression of the Egfl7:eGFP transgene was induced in adult neovasculature. We also found that increased Egfl7 expression contributed to pathologic revascularization in the mouse retina. To our knowledge, this is the first mouse model that enables monitoring of endothelial cells at sites of active vasculogenesis and angiogenesis. This model also facilitated the isolation and characterization of EGFL7(+) endothelial cell populations by fluorescence activated cell sorting (FACS). Together, our results demonstrate that the Egfl7:eGFP reporter mouse is a valuable tool that can be used to elucidate the mechanisms by which blood vessels form during development and under pathologic circumstances. © 2014 Wiley Periodicals, Inc.

  11. 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

  12. Imaging angiogenesis.

    Science.gov (United States)

    Charnley, Natalie; Donaldson, Stephanie; Price, Pat

    2009-01-01

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

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

    NARCIS (Netherlands)

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

    1999-01-01

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

  14. [Effect of cryotherapy over the expression of vascular endothelial growth factor and pigment epithelium-derived factor].

    Science.gov (United States)

    Toscano-Garibay, Julia Dolores; Quiroz-Mercado, Hugo; Espitia-Pinzón, Clara; Gil-Carrasco, Félix; Flores-Estrada, José Javier

    2014-01-01

    Cryotherapy is a no invasive technique that uses intense cold to freeze and destroy cancer tissues. There are no descriptions of its effects over the expression of vascular endothelial growth factor and pigment epithelium-derived factor. Experimental study in cryogenic spot were applied in the right sclera of twelve pigs for ten minutes. Other 3 pigs were used as normal controls. Animals were sacrificed at 7, 14 and 21 and the tissues of choriodes and retina were dissected in areas of approximately 1 cm2 surrounding cryogenic spots. Expression levels of vascular endothelial growth factor and pigment epithelium-derived factor were determined analyzed using polymerase chain reaction coupled to reverse-transcription. Vascular endothelial growth factor was significantly downregulated (24%, p< 0.05) seven days post-treatment meanwhile pigment epithelium-derived factor levels increased 44.8% (p< 0.05) as compared to normal controls (untreated). Both vascular endothelial growth factor and pigment epithelium-derived factor levels remain the same until day 14 but returned to basal expression at day 21. This work expose the relation of cryotherapy with the expression of two factors related to angiogenesis. RESULTS showed significant changes on the expression of vascular endothelial growth factor and pigment epithelium-derived factor illustrating that both proteins are regulated in response to cryogenic treatment in relatively short periods (21 days).

  15. Vascular factors in dementia and apathy

    NARCIS (Netherlands)

    Eurelings, L.S.M.

    2016-01-01

    The number of individuals suffering from dementia is expected to rise significantly in the future. Because so far no curative treatment exists, prevention remains paramount. A large body of evidence points to the direction of an important role of vascular risk factors in the aetiology of dementia

  16. Self-management of vascular risk factors

    NARCIS (Netherlands)

    Sol-de Rijk, B.G.M.

    2009-01-01

    Summary The aim of this thesis was to provide insight into the potential of a self-management approach in treatment of vascular risk factors and to develop a self-management intervention. Furthermore to examine if this intervention, based on self-efficacy promoting theory, is effective in reducing

  17. Acidic Fibroblast Growth Factor Promotes Vascular Repair

    Science.gov (United States)

    Bjornsson, Thorir D.; Dryjski, Maciej; Tluczek, John; Mennie, Robert; Ronan, John; Mellin, Theodore N.; Thomas, Kenneth A.

    1991-10-01

    Intravascular injury to arteries can result in thickening of the intimal smooth muscle layer adjacent to the lumen by migration and proliferation of cells from the underlying medial smooth muscle layer accompanied by deposition of extracellular matrix. This pathological response, which decreases lumen diameter, might, in part, be the result of the access of smooth muscle cells to plasma and platelet-derived growth factors as a consequence of denudation of the overlying confluent monolayer of vascular endothelial cells. Injured rat carotid arteries were treated by i.v. administration of acidic fibroblast growth factor, a heparin-binding protein that is chemotactic and mitogenic for vascular endothelial cells. The growth factor treatment resulted in dose-dependent inhibition of intimal thickening with parallel promotion of endothelial regeneration over the injured area. Therefore, acidic fibroblast growth factor might be efficacious in the prevention of restenosis caused by intimal thickening following angioplasty in humans.

  18. Ionizing radiation activates vascular endothelial growth factor-A transcription in human umbilical vein endothelial cells

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hyounji; Kim, Kwang Seok; Jeong, Jae Hoon; Lim, Young Bin [Radiation Cancer Biology Team, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2016-12-15

    Vascular endothelial growth factor (VEGF) is an essential paracrine factor for developmental and pathological angiogenesis. VEGF also exerts its effects in an autocrine manner in VEGF-producing cells. For instance, autocrine VEGF signaling occurs in tumor cells and contributes to key aspects of tumorigenesis, such as in the function of cancer stem cells and tumor initiation, which are independent of angiogenesis. In addition to tumors cells, non-transformed cells also express VEGF. For example, a VEGF dependent intracellular autocrine mechanism is crucial for the survival of hematopoietic stem cells and hematopoiesis. Stereotactic body radiation therapy (SBRT) is a novel treatment modality for early primary cancer and oligometastatic disease. SBRT delivers high-dose hypofractionated radiation, such as 20-60 Gy, to tumors in a single fraction or 2-5 fractions. As VEGF is a critical regulator of functional integrity and viability of vascular endothelial cells, we examined whether high-dose irradiation alters VEGF signaling by measuring the expression levels of VEGFA transcript. It is generally believed that endothelial cells do not produce VEGF in response to radiation. In present study, however, we provide the first demonstration of transcriptional regulation of VEGFA in human vascular endothelial cells by IR treatment. Irradiation with doses higher than 10 Gy in a single exposure triggers up-regulation of VEGFA transcription within 2 hours in HUVECs, whereas irradiation with 10 Gy does not alter VEGFA levels. Our data have shown that high-dose irradiation triggers immediate transactivation of VEGFA in human vascular endothelial cells.

  19. Role of angiogenesis in endodontics: contributions of stem cells and proangiogenic and antiangiogenic factors to dental pulp regeneration.

    Science.gov (United States)

    Saghiri, Mohammad Ali; Asatourian, Armen; Sorenson, Christine M; Sheibani, Nader

    2015-06-01

    Dental pulp regeneration is a part of regenerative endodontics, which includes isolation, propagation, and re-transplantation of stem cells inside the prepared root canal space. The formation of new blood vessels through angiogenesis is mandatory to increase the survival rate of re-transplanted tissues. Angiogenesis is defined as the formation of new blood vessels from preexisting capillaries, which has great importance in pulp regeneration and homeostasis. Here the contribution of human dental pulp stem cells and proangiogenic and antiangiogenic factors to angiogenesis process and regeneration of dental pulp is reviewed. A search was performed on the role of angiogenesis in dental pulp regeneration from January 2005 through April 2014. The recent aspects of the relationship between angiogenesis, human dental pulp stem cells, and proangiogenic and antiangiogenic factors in regeneration of dental pulp were assessed. Many studies have indicated an intimate relationship between angiogenesis and dental pulp regeneration. The contribution of stem cells and mechanical and chemical factors to dental pulp regeneration has been previously discussed. Angiogenesis is an indispensable process during dental pulp regeneration. The survival of inflamed vital pulp and engineered transplanted pulp tissue are closely linked to the process of angiogenesis at sites of application. However, the detailed regulatory mechanisms involved in initiation and progression of angiogenesis in pulp tissue require investigation. Published by Elsevier Inc.

  20. Vascular risk factors, cognitve decline, and dementia

    Directory of Open Access Journals (Sweden)

    E Duron

    2008-04-01

    Full Text Available E Duron, Olivier HanonBroca Hospital, Paris, FranceAbstract: Dementia is one of the most important neurological disorders in the elderly. Aging is associated with a large increase in the prevalence and incidence of degenerative (Alzheimer’s disease and vascular dementia, leading to a devastating loss of autonomy. In view of the increasing longevity of populations worldwide, prevention of dementia has turned into a major public health challenge. In the past decade, several vascular risk factors have been found to be associated with vascular dementia but also Alzheimer’s disease. Some longitudinal studies, have found significant associations between hypertension, diabetus mellitus, and metabolic syndrome, assessed at middle age, and dementia. Studies assessing the link between hypercholesterolemia, atrial fibrillation, smoking, and dementia have given more conflicting results. Furthermore, some studies have highlighted the possible protective effect of antihypertensive therapy on cognition and some trials are evaluating the effects of statins and treatments for insulin resistance. Vascular risk factors and their treatments are a promising avenue of research for prevention of dementia, and further long-term, placebo-controlled, randomized studies, need to be performed.Keywords: dementia, hypertension, diabetus mellitus, hypercholesterolemia, metabolic syndrome

  1. Adenovirus-mediated anti-sense extracellular signal-regulated kinase 2 gene therapy inhibits activation of vascular smooth muscle cells and angiogenesis, and ameliorates transplant arteriosclerosis.

    Science.gov (United States)

    Zhao, B; Li, X; Dai, X; Gong, N

    2013-03-01

    The aim of this study was to explore underlying mechanisms of transplant arteriosclerosis (TA) based on intimal thickening that involve activation of vascular smooth muscle cells (VSMCs) and angiogenesis. We also examined the effects of adenovirus-mediated anti-sense extracellular signal-regulated kinase 2 (ERK2) (Adanti-ERK2) gene therapy on TA. We employed a rat aorta transplantation model (Brown-Norway → Lewis). The animals were divided into: (1) an isograft group (n = 6), (2) an empty control group (n = 6), (3) the Ad-LacZ group (n = 6), and (4) the adanti-ERK2 group (n = 6). At 60 days after transplantation, we documented the ratio of intima/(intima + media) the isografts pathologically. Staining for α-actin and platelet-derived growth factor (PDGF)-BB was performed to analyze the migration and secretion of VSMCs. We evaluated angiogenesis and COX-2 staining. Isografts showed normal histology; allografts from the empty control group and the Ad-LacZ group displayed typical TA lesions, while the pathology was significantly improved among the adanti-ERK2 group. The ratios of intima/(intima + media) were 7.6 ± 2.1%, 81.4% ± 6.7%, 85.9% ± 9.4%, and 15.9% ± 4.1% among the isograft group, the empty control, the Ad-LacZ, and the adanti-ERK2 groups respectively. The α-actin+ cells in the intima per field (×400) were 2.1 ± 1.1, 71.3 ± 9.2, 76.4 ± 11.3, and 34.8 ± 5.3, PDGF-BB+ cells, 0.9 ± 0.5, 28.4 ± 3.4, 29.1 ± 3.2, and 8.6 ± 1.7; COX-2+ cells in new capillaries were none, 36.3 ± 8.3, 40.9 ± 9.2, and 10.4 ± 3.9 respectively (P < .05). Intimal thickening a key feature of TA, involves activation of VSMC (proliferation, migration and secretion), and the accompanying angiogenesis. Adanti-ERK2 gene therapy modulates the mechanisms, protecting allografts against TA. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Growth differentiation factor 11 improves neurobehavioral recovery and stimulates angiogenesis in rats subjected to cerebral ischemia/reperfusion.

    Science.gov (United States)

    Ma, Jingxi; Zhang, Lina; Niu, Tengfei; Ai, Chibo; Jia, Gongwei; Jin, Xinhao; Wen, Lan; Zhang, Keming; Zhang, Qinbin; Li, Changqing

    2018-02-09

    The recent suggestion that growth differentiation factor 11 (GDF11) acts as a rejuvenation factor has remained controversial. However, in addition to its role in aging, the relationship between GDF11 and cerebral ischemia is still an important area that needs more investigation. Here we examined effects of GDF11 on angiogenesis and recovery of neurological function in a rat model of stroke. Exogenous recombinant GDF11 (rGDF11) at different doses were directly injected into the tail vein in rats subjected to cerebral ischemia/reperfusion (I/R). Neurobehavioral tests were performed, the proliferation of endothelial cells (ECs) and GDF11 downstream signal activin-like kinase 5 (ALK5) were assessed, and functional microvessels were measured. Results showed that rGDF11 at a dosage of 0.1 mg/kg/day could effectively activate cerebral angiogenesis in vivo. In addition, rGDF11 improved the modified neurological severity scores and the adhesive removal somatosensory test, promoted proliferation of ECs, induced ALK5 and increased vascular surface area and the number of vascular branch points in the peri-infarct cerebral cortex after cerebral I/R. These effects were suppressed by blocking ALK5. Our novel findings shed new light on the role of GDF11. Our results strongly suggest that GDF11 improves neurofunctional recovery from cerebral I/R injury and that this effect is mediated partly through its proangiogenic effect in the peri-infarct cerebral cortex, which is associated with ALK5. Thus, GDF11/ALK5 may represent new therapeutic targets for aiding recovery from stroke. Copyright © 2018 Elsevier Inc. All rights reserved.

  3. Olive oil compounds inhibit vascular endothelial growth factor receptor-2 phosphorylation

    Energy Technology Data Exchange (ETDEWEB)

    Lamy, Sylvie, E-mail: lamy.sylvie@uqam.ca; Ouanouki, Amira; Béliveau, Richard; Desrosiers, Richard R.

    2014-03-10

    Vascular endothelial growth factor (VEGF) triggers crucial signaling processes that regulate tumor angiogenesis and, therefore, represents an attractive target for the development of novel anticancer therapeutics. Several epidemiological studies have confirmed that abundant consumption of foods from plant origin is associated with reduced risk of developing cancers. In the Mediterranean basin, the consumption of extra virgin olive oil is an important constituent of the diet. Compared to other vegetable oils, the presence of several phenolic antioxidants in olive oil is believed to prevent the occurrence of a variety of pathological processes, such as cancer. While the strong antioxidant potential of these molecules is well characterized, their antiangiogenic activities remain unknown. The aim of this study is to investigate whether tyrosol (Tyr), hydroxytyrosol (HT), taxifolin (Tax), oleuropein (OL) and oleic acid (OA), five compounds contained in extra virgin olive oil, can affect in vitro angiogenesis. We found that HT, Tax and OA were the most potent angiogenesis inhibitors through their inhibitory effect on specific autophosphorylation sites of VEGFR-2 (Tyr951, Tyr1059, Tyr1175 and Tyr1214) leading to the inhibition of endothelial cell (EC) signaling. Inhibition of VEGFR-2 by these olive oil compounds significantly reduced VEGF-induced EC proliferation and migration as well as their morphogenic differentiation into capillary-like tubular structures in Matrigel. Our study demonstrates that HT, Tax and OA are novel and potent inhibitors of the VEGFR-2 signaling pathway. These findings emphasize the chemopreventive properties of olive oil and highlight the importance of nutrition in cancer prevention. - Highlights: • We investigated five compounds contained in extra virgin olive oil on angiogenesis. • Hydroxytyrosol, taxifolin and oleic acid are the best angiogenesis inhibitors. • Olive oil compounds affect endothelial cell functions essential for

  4. Placental Growth Factor Contributes to Liver Inflammation, Angiogenesis, Fibrosis in Mice by Promoting Hepatic Macrophage Recruitment and Activation

    Directory of Open Access Journals (Sweden)

    Xi Li

    2017-07-01

    Full Text Available Placental growth factor (PlGF, a member of the vascular endothelial growth factor (VEGF family, mediates wound healing and inflammatory responses, exerting an effect on liver fibrosis and angiogenesis; however, the precise mechanism remains unclear. The aims of this study are to identify the role of PlGF in liver inflammation and fibrosis induced by bile duct ligation (BDL in mice and to reveal the underlying molecular mechanism. PlGF small interfering RNA (siRNA or non-targeting control siRNA was injected by tail vein starting 2 days after BDL. Liver inflammation, fibrosis, angiogenesis, macrophage infiltration, and hepatic stellate cells (HSCs activation were examined. Our results showed that PlGF was highly expressed in fibrotic livers and mainly distributed in activated HSCs and macrophages. Furthermore, PlGF silencing strongly reduced the severity of liver inflammation and fibrosis, and inhibited the activation of HSCs. Remarkably, PlGF silencing also attenuated BDL-induced hepatic angiogenesis, as evidenced by attenuated liver endothelial cell markers CD31 and von Willebrand factor immunostaining and genes or protein expression. Interestingly, these pathological ameliorations by PlGF silencing were due to a marked reduction in the numbers of intrahepatic F4/80+, CD68+, and Ly6C+ cell populations, which were reflected by a lower expression of these macrophage marker molecules in fibrotic livers. In addition, knockdown of PlGF by siRNA inhibited macrophages activation and substantially suppressed the expression of pro-inflammatory cytokines and chemokines in fibrotic livers. Mechanistically, evaluation of cultured RAW 264.7 cells revealed that VEGF receptor 1 (VEGFR1 mainly involved in mediating the role of PlGF in macrophages recruitment and activation, since using VEGFR1 neutralizing antibody blocking PlGF/VEGFR1 signaling axis significantly inhibited macrophages migration and inflammatory responses. Together, these findings indicate

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

    NARCIS (Netherlands)

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

    2008-01-01

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

  6. An in vitro cord formation assay identifies unique vascular phenotypes associated with angiogenic growth factors.

    Directory of Open Access Journals (Sweden)

    Beverly L Falcon

    Full Text Available Vascular endothelial growth factor (VEGF plays a dominant role in angiogenesis. While inhibitors of the VEGF pathway are approved for the treatment of a number of tumor types, the effectiveness is limited and evasive resistance is common. One mechanism of evasive resistance to inhibition of the VEGF pathway is upregulation of other pro-angiogenic factors such as fibroblast growth factor (FGF and epidermal growth factor (EGF. Numerous in vitro assays examine angiogenesis, but many of these assays are performed in media or matrix with multiple growth factors or are driven by VEGF. In order to study angiogenesis driven by other growth factors, we developed a basal medium to use on a co-culture cord formation system of adipose derived stem cells (ADSCs and endothelial colony forming cells (ECFCs. We found that cord formation driven by different angiogenic factors led to unique phenotypes that could be differentiated and combination studies indicate dominant phenotypes elicited by some growth factors. VEGF-driven cords were highly covered by smooth muscle actin, and bFGF-driven cords had thicker nodes, while EGF-driven cords were highly branched. Multiparametric analysis indicated that when combined EGF has a dominant phenotype. In addition, because this assay system is run in minimal medium, potential proangiogenic molecules can be screened. Using this assay we identified an inhibitor that promoted cord formation, which was translated into in vivo tumor models. Together this study illustrates the unique roles of multiple anti-angiogenic agents, which may lead to improvements in therapeutic angiogenesis efforts and better rational for anti-angiogenic therapy.

  7. Implicació de factors antiangiogènics endògens en la hipertensió portal i la cirrosi hepàtica

    OpenAIRE

    Coch Torres, Laura

    2014-01-01

    1) Disruption of negative feedback loop between vasohibin-1 and vascular endothelial growth factor decreases portal pressure, angiogenesis, and fibrosis in cirrhotic rats. Pathological angiogenesis represents a critical hallmark for chronic liver diseases. Understanding the mechanisms regulating angiogenesis is essential to develop new therapeutic strategies that specifically target pathological angiogenesis without affecting physiological angiogenesis. Here we investigated the con...

  8. Morpholino-Mediated Isoform Modulation of Vascular Endothelial Growth Factor Receptor-2 (VEGFR2) Reduces Colon Cancer Xenograft Growth

    Energy Technology Data Exchange (ETDEWEB)

    Stagg, Brian C., E-mail: briancstagg@gmail.com; Uehara, Hironori; Lambert, Nathan; Rai, Ruju; Gupta, Isha; Radmall, Bryce; Bates, Taylor; Ambati, Balamurali K. [John A Moran Eye Center, University of Utah, Salt Lake City, UT, 65 Mario Capecchi Drive, Salt Lake City, UT 84132 (United States)

    2014-11-26

    Angiogenesis plays a key role in tumor growth. Vascular endothelial growth factor (VEGF) is a pro-angiogenic that is involved in tumor angiogenesis. When VEGF binds to membrane-bound vascular endothelial growth factor receptor 2 (mVEGFR2), it promotes angiogenesis. Through alternative polyadenylation, VEGFR2 is also expressed in a soluble form (sVEGFR2). sVEGFR2 sequesters VEGF and is therefore anti-angiogenic. The aim of this study was to show that treatment with a previously developed and reported antisense morpholino oligomer that shifts expression from mVEGFR2 to sVEGFR2 would lead to reduced tumor vascularization and growth in a murine colon cancer xenograft model. Xenografts were generated by implanting human HCT-116 colon cancer cells into the flanks of NMRI nu/nu mice. Treatment with the therapeutic morpholino reduced both tumor growth and tumor vascularization. Because the HCT-116 cells used for the experiments did not express VEGFR2 and because the treatment morpholino targeted mouse rather than human VEGFR2, it is likely that treatment morpholino was acting on the mouse endothelial cells rather than directly on the tumor cells.

  9. Vascular endothelial growth factor inhibitors in the treatment of ovarian cancer

    Directory of Open Access Journals (Sweden)

    S. V. Khokhlova

    2010-01-01

    Full Text Available Angiogenesis plays a large role in the development and spread of a number of tumors particularly in the presence of female reproductive system neoplasms. The high expression of vascular endothelial growth factor (VEGF was found in both the primary tumor and metasta- ses and ascitic fluid in ovarian cancer (OC. Thus, the use of VEGF blockers may be effective in the treatment of OC. The most studied drug used to treat this nosological entity is bevacizumab, the high efficacy of which has been confirmed even when used as monotherapy in the patients who have received treatment many times.

  10. Regulation and localization of vascular endothelial growth factor within the mammary glands during the transition from late gestation to lactation.

    Science.gov (United States)

    VanKlompenberg, M K; Manjarín, R; Donovan, C E; Trott, J F; Hovey, R C

    2016-01-01

    The vascular network within the developing mammary gland (MG) grows in concert with the epithelium to prepare for lactation, although the mechanisms coordinating this vascular development are unresolved. Vascular endothelial growth factor A (VEGF-A) mediates angiogenesis and vascular permeability in the MG during pregnancy and lactation, where its expression is upregulated by prolactin. Given our previous finding that late-gestational hyperprolactinemia induced by domperidone (DOM) increased subsequent milk yield from gilts, we sought to establish changes in vascular development during late gestation and lactation in the MGs of these pigs and determine whether DOM altered MG angiogenesis and the factors regulating it. Gilts received either no treatment (n = 6) or DOM (n = 6) during late gestation, then had their MG biopsied from late gestation through lactation to assess microvessel density, VEGF-A distribution and messenger RNA expression, and aquaporin (AQP) gene expression. Microvessel density in the MG was unchanged during gestation then increased between days 2 and 21 of lactation (P lactation (P lactation in first-parity gilts and that VEGF-A is a part of the mammary secretome. Although late-gestational hyperprolactinemia increases milk yield, there was no evidence that it altered vascular development. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Cellular distribution of vascular endothelial growth factor A (VEGFA) and B (VEGFB) and VEGF receptors 1 and 2 in focal cortical dysplasia type IIB

    NARCIS (Netherlands)

    Boer, Karin; Troost, Dirk; Spliet, Wim G. M.; van Rijen, Peter C.; Gorter, Jan A.; Aronica, Eleonora

    2008-01-01

    Members of the vascular endothelial growth factor (VEGF) family are key signaling proteins in the induction and regulation of angiogenesis, both during development and in pathological conditions. However, signaling mediated through VEGF family proteins and their receptors has recently been shown to

  12. Local administration of platelet-derived growth factor B (PDGFB) improves follicular development and ovarian angiogenesis in a rat model of Polycystic Ovary Syndrome.

    Science.gov (United States)

    Di Pietro, Mariana; Scotti, Leopoldina; Irusta, Griselda; Tesone, Marta; Parborell, Fernanda; Abramovich, Dalhia

    2016-09-15

    Alterations in ovarian angiogenesis are common features in Polycystic Ovary Syndrome (PCOS) patients; the most studied of these alterations is the increase in vascular endothelial growth factor (VEGF) production by ovarian cells. Platelet-derived growth factor B (PDGFB) and D (PDGFD) are decreased in follicular fluid of PCOS patients and in the ovaries of a rat model of PCOS. In the present study, we aimed to analyze the effects of local administration of PDGFB on ovarian angiogenesis, follicular development and ovulation in a DHEA-induced PCOS rat model. Ovarian PDGFB administration to PCOS rats partially restored follicular development, decreased the percentage of cysts, increased the percentage of corpora lutea, and decreased the production of anti-Müllerian hormone. In addition, PDGFB administration improved ovarian angiogenesis by reversing the increase in periendothelial cell area and restoring VEGF levels. Our results shed light into the mechanisms that lead to altered ovarian function in PCOS and provide new data for potential therapeutic strategies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  13. Suppression of vascular endothelial growth factor expression by cannabinoids in a canine osteosarcoma cell line

    Directory of Open Access Journals (Sweden)

    Figueiredo AS

    2013-07-01

    Full Text Available Andreza S Figueiredo,1 Hiram J García-Crescioni,1 Sandra C Bulla,1 Matthew K Ross,2 Chelsea McIntosh,1 Kari Lunsford,3 Camilo Bulla11Department of Pathobiology and Population Medicine, 2Department of Basic Sciences, 3Department of Clinical Sciences and Animal Health Center, College of Veterinary Medicine, Mississippi State University, Mississippi State, MS, USAAbstract: Vascular endothelial growth factor (VEGF is a key regulator in both physiologic and pathologic angiogenesis, and cannabinoids decrease VEGF release in human and murine cancer cells. The aim of this study was to assess the in vitro effects of a synthetic cannabinoid, WIN-55,212-2, on the expression of the proangiogenic factor VEGF-A in the canine osteosarcoma cell line 8. After analysis of gene expression by quantitative real-time polymerase chain reaction, the compound decreased VEGF-A expression by 35% ± 10% (P < 0.0001 as compared with the control. This synthetic cannabinoid shows promise as a potential inhibitor of angiogenesis, and further studies are warranted to investigate its in vivo effects and to explore the potential of this and related compounds as adjuvant cancer therapy in the dog.Keywords: dog, cancer, angiogenesis, cannabinoids

  14. Identification of key contributory factors responsible for vascular dysfunction in idiopathic recurrent spontaneous miscarriage.

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    Priyanka Banerjee

    Full Text Available Poor endometrial perfusion during implantation window is reported to be one of the possible causes of idiopathic recurrent spontaneous miscarriage (IRSM. We have tested the hypothesis that certain angiogenic and vasoactive factors are associated with vascular dysfunction during implantation window in IRSM and, therefore, could play a contributory role in making the endometrium unreceptive in these women. This is a prospective case-controlled study carried out on 66 women with IRSM and age and BMI matched 50 fertile women serving as controls. Endometrial expression of pro-inflammatory (IL-1β, TNF-α, IFN-γ, TGF-β1, anti-inflammatory (IL-4, -10, angiogenesis-associated cytokines (IL-2, -6, -8, angiogenic and vasoactive factors including prostaglandin E2 (PGE2, vascular endothelial growth factor (VEGF, endothelial nitric oxide synthase (eNOS, nitric oxide (NO and adrenomedullin (ADM were measured during implantation window by ELISA. Subendometrial blood flow (SEBF was assessed by color Doppler ultrasonography. Multivariate analysis was used to identify the significant factor(s responsible for vascular dysfunction in IRSM women during window of implantation and further correlated with vascular dysfunction. Endometrial expression of pro-inflammatory cytokines and PGE2 were up-regulated and anti-inflammatory and angiogenesis-associated cytokines down-regulated in IRSM women as compared with controls. Further, the angiogenic and vasoactive factors including VEGF, eNOS, NO and ADM were found to be down-regulated and SEBF grossly affected in these women. Multivariate analysis identified IL-10, followed by VEGF and eNOS as the major factors contributing towards vascular dysfunction in IRSM women. Moreover, these factors strongly correlated with blood flow impairment. This study provides an understanding that IL-10, VEGF and eNOS are the principal key components having a contributory role in endometrial vascular dysfunction in women with IRSM. Down

  15. Clinical implications of angiogenesis in cancers

    Directory of Open Access Journals (Sweden)

    Roberta WC Pang

    2006-06-01

    Full Text Available Roberta WC Pang1, Ronnie TP Poon2 Departments of 1Medicine and 2Surgery, The University of Hong Kong, Pokfulam, Hong Kong, ChinaAbstract: Angiogenesis plays an important role in the growth and progression of cancer. The regulation of tumor angiogenesis depends on a net balance of angiogenic factors and antiangiogenic factors, which are secreted by both tumor cells and host-infiltrating cells. Numerous studies have indicated that assessment of angiogenic activity by either microvessel density or expression of angiogenic factors in cancer can provide prognostic information independent of conventional clinicopathological factors such as tumor staging. Some studies also suggested that assessment of tumor angiogenesis may predict cancer response to chemotherapy or radiotherapy. However, the most important clinical implication of tumor angiogenesis is the development of a novel strategy of anticancer therapy targeting tumor vessels instead of cancer cells. Antiangiogenic therapy aims to inhibit the growth of tumor, and current evidence suggests that it works best in combination with conventional cytotoxic chemotherapy. Recently, a monoclonal antibody against vascular endothelial growth factor, which is one of the most potent angiogenic factors, has been approved for clinical use in colorectal cancer patients after a clinical trial confirmed that combining the antibody with standard chemotherapy regimen could prolong patient survival. The clinical implications of angiogenesis in cancer are reviewed in this article.Keywords: angiogenesis, antiangiogenic therapy, cancer, prognosis

  16. Antiangiogenic activity of vitexicarpine in experimentally induced hepatocellular carcinoma: Impact on vascular endothelial growth factor pathway.

    Science.gov (United States)

    Hassoun, Shimaa M; Abdel-Rahman, Noha; Eladl, Entsar I; El-Shishtawy, Mamdouh M

    2017-06-01

    Angiogenesis plays important roles in progression of hepatocellular carcinoma. The antiangiogenic mechanisms of vitexicarpine are not fully defined. Therefore, we conducted the following study to evaluate the antiangiogenic mechanism and antitumor activity of vitexicarpine in vivo model of hepatocellular carcinoma through modulation of vascular endothelial growth factor signaling pathway. Hepatocellular carcinoma was induced in Sprague Dawley rats by thioacetamide. Hepatocellular carcinoma was assessed by measuring serum alpha-fetoprotein and investigating liver sections stained with hematoxylin/eosin. Hepatocellular carcinoma rats were injected with vitexicarpine (150 mg/kg) for 2 weeks. Hepatic vascular endothelial growth factor was measured by enzyme-linked immunosorbent assay. Protein and expression of hepatic phospho-Ser473-AKT (p-AKT) and phospho-Tyr419-Src (p-Src) were determined. The apoptotic pathway was evaluated by assessment of protein expression of caspase-3. Vitexicarpine increased rats' survival time and decreased serum alpha-fetoprotein as well as it ameliorated fibrosis and massive hepatic tissue breakdown. It attenuated hepatocellular carcinoma-induced protein and gene expression of vascular endothelial growth factor, p-AKT, p-Src, and caspase-3. In conclusion, this study suggests that vitexicarpine possesses both antiangiogenic and antitumor activities through inhibition of vascular endothelial growth factor, p-AKT/AKT, and p-Src with subsequent inhibition of apoptotic pathway.

  17. Anti-vascular endothelial growth factor treatment induces blood flow recovery through vascular remodeling in high-fat diet induced diabetic mice.

    Science.gov (United States)

    Xiao, Lamei; Yan, Kai; Yang, Yan; Chen, Ni; Li, Yongjie; Deng, Xin; Wang, Liqun; Liu, Yan; Mu, Lin; Li, Rong; Luo, Mao; Ren, Meiping; Wu, Jianbo

    2016-05-01

    Diabetes mellitus (DM) leads to the development of microvascular diseases and is associated with impaired angiogenesis. The presence of vascular endothelial growth factor (VEGF) can block PDGF-BB dependent regulation of neovascularization and vessel normalization. We tested the hypothesis that the inhibition of VEGF improves blood flow in a mouse hindlimb ischemia model produced by femoral artery ligation. In this study, we examined the effect of bevacizumab, a humanized monoclonal antibody against VEGF-A, on blood perfusion and angiogenesis after hindlimb ischemia. We showed that bevacizumab induces functional blood flow in high fat chow (HFC)-fed diabetic mice. Treatment with bevacizumab increased the expression of platelet derived growth factor-BB (PDGF-BB) in ischemic muscle, and led to vascular normalization. It also blocked vascular leakage by improving the recruitment of pericytes associated with nascent blood vessels, but it did not affect capillary formation. Furthermore, treatment with an anti-PDGF drug significantly inhibited blood flow perfusion in diabetic mice treated with bevacizumab. These results indicate that bevacizumab improves blood flow recovery through the induction of PDGF-BB in a diabetic mouse hindlimb ischemia model, and that vessel normalization may represent a useful strategy for the prevention and treatment of diabetic peripheral arterial disease. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Pregnancy stimulates tumor angiogenesis in breast carcinoma.

    Science.gov (United States)

    Genin, Anne-Sophie; Antoine, Martine; Aractingi, Selim; Rouzier, Roman

    2014-01-01

    The mechanisms responsible for the poor prognosis of pregnancy-associated breast cancer (PABC) remain not well-understood. We studied angiogenesis and lymphangiogenesis as they are known prognostic factors in breast cancer. We conducted a case control study of breast cancer comparing women with and without PABC matched for age and histological parameters. Surgical specimen sections were immunostained with anti-CD31 for angiogenesis and anti-D2-40 for lymphangiogenesis, then analyzed using vessel density, ratio of the vascular area and the Chalkley count. Seventeen patients with PABC and 22 controls were included. Angiogenesis was significantly increased in tumor tissues, and tended to be higher in healthy breast tissues from the PABC group compared to controls. In contrast, no difference between the two groups was found concerning lymphangiogenesis both in tumor and healthy breast tissues. Pregnancy enhances angiogenesis in breast cancer. This phenomenon appears to explain the poor prognosis of PABC.

  19. Angiogenesis in cancer

    Directory of Open Access Journals (Sweden)

    Naoyo Nishida

    2006-09-01

    Full Text Available Naoyo Nishida1,2, Hirohisa Yano1, Takashi Nishida3, Toshiharu Kamura2, Masamichi Kojiro1Departments of 1Pathology and 2Obstetrics and Gynecology and Research Center of Innovative Cancer Therapy of the 21 Century COE Program for Medical Science, Kurume University School of Medicine, Fukuoka, Japan; 3Hita Saiseikai Hospital, Oita, JapanAbstract: New growth in the vascular network is important since the proliferation, as well as metastatic spread, of cancer cells depends on an adequate supply of oxygen and nutrients and the removal of waste products. New blood and lymphatic vessels form through processes called angiogenesis and lymphangiogenesis, respectively. Angiogenesis is regulated by both activator and inhibitor molecules. More than a dozen different proteins have been identified as angiogenic activators and inhibitors. Levels of expression of angiogenic factors reflect the aggressiveness of tumor cells. The discovery of angiogenic inhibitors should help to reduce both morbidity and mortality from carcinomas. Thousands of patients have received antiangiogenic therapy to date. Despite their theoretical efficacy, antiangiogeic treatments have not proved beneficial in terms of long-term survival. There is an urgent need for a new comprehensive treatment strategy combining antiangiogenic agents with onventional cytoreductive treatments in the control of cancer.Keywords: angiogenesis, immunohistochemistry, prognosis

  20. Vascular remodelling in asthma.

    Science.gov (United States)

    Walters, Eugene Haydn; Soltani, Amir; Reid, David William; Ward, Chris

    2008-02-01

    We review the recent literature, focusing on 2006 and 2007, to produce an update on the patho-biology of angiogenesis and vascular endothelial growth factor in the asthmatic airway. In terms of conceptual development in asthma research, airway inflammation and remodelling have been regarded as separate processes or perhaps as sequential, with early inflammation leading later to remodelling. Recent insights identify a central role for vascular endothelial growth factor in stimulating both inflammation and vascular remodelling coincidentally, with the full panoply of vascular endothelial growth factor mediated events being complex and wide. Both nitric oxide and matrix metalloproteinase-9 induction may be important downstream pathogenic mechanisms. Virus-mediated exacerbations are a prime manifestation of the oscillating trajectory of clinical asthma. The early stimulation of vascular endothelial growth factor production is probably a central aetiological mechanism, with secondary inflammation and angiogenesis. The time scale of the latter, especially, fits with the time scale of clinico-physiological changes after exacerbation. These vascular endothelial growth factor induced changes are potentially modifiable with therapy. Insights into the importance of vascular endothelial growth factor and angiogenesis in asthma pathogenesis now lead to potential new therapeutic possibilities and elucidate why recent advances in asthma therapeutics have been so successful.

  1. 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

  2. Establishment of canine hemangiosarcoma xenograft models expressing endothelial growth factors, their receptors, and angiogenesis-associated homeobox genes

    Science.gov (United States)

    2009-01-01

    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 other tumors. Conclusion We

  3. Evaluation of an injectable polymeric delivery system for controlled and localized release of biological factors to promote therapeutic angiogenesis

    Science.gov (United States)

    Rocker, Adam John

    Cardiovascular disease remains as the leading cause of death worldwide and is frequently associated with partial or full occlusion of coronary arteries. Currently, angioplasty and bypass surgery are the standard approaches for treating patients with these ischemic heart conditions. However, a large number of patients cannot undergo these procedures. Therapeutic angiogenesis provides a minimally invasive tool for treating cardiovascular diseases by inducing new blood vessel growth from the existing vasculature. Angiogenic growth factors can be delivered locally through gene, cell, and protein therapy. Natural and synthetic polymer growth factor delivery systems are under extensive investigation due their widespread applications and promising therapeutic potential. Although biocompatible, natural polymers often suffer from batch-to-batch variability which can cause unpredictable growth factor release rates. Synthetic polymers offer advantages for growth factor delivery as they can be easily modified to control release kinetics. During the angiogenesis process, vascular endothelial growth factor (VEGF) is necessary to initiate neovessel formation while platelet-derived growth factor (PDGF) is needed later to help stabilize and mature new vessels. In the setting of myocardial infarction, additional anti-inflammatory cytokines like IL-10 are needed to help optimize cardiac repair and limit the damaging effects of inflammation following infarction. To meet these angiogenic and anti-inflammatory needs, an injectable polymer delivery system created from a sulfonated reverse thermal gel encapsulating micelle nanoparticles was designed and evaluated. The sulfonate groups on the thermal gel electrostatically bind to VEGF which controls its release rate, while the micelles are loaded with PDGF and are slowly released as the gel degrades. IL-10 was loaded into the system as well and diffused from the gel over time. An in vitro release study was performed which demonstrated the

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

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    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

  5. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

    DEFF Research Database (Denmark)

    Maae, Else; Olsen, Dorte Aalund; Steffensen, Karina Dahl

    2012-01-01

    Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic conditions...... such as ischemic heart disease, arthritis and tumor growth. Angiogenesis is a complex process with several growth factors involved. Because PlGF modulates VEGF-A responses, we investigated their mutual relationship and impact on breast cancer prognosis. Quantitative PlGF and VEGF-A levels were measured in 229...... tumor tissue specimen from primarily operated patients with unilateral breast cancer. Non-malignant breast tissue was also dissected near the tumor and quantitative measurements were available for 211 patients. PlGF and VEGF-A protein levels in homogenized tissue lysates were analyzed using the Luminex...

  6. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

    DEFF Research Database (Denmark)

    Maae, Else; Olsen, Dorte Aalund; Dahl Steffensen, Karina

    2012-01-01

    Background: Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic...... conditions such as ischemic heart disease, arthritis and tumor growth. Angiogenesis is a complex process with several growth factors involved. Because PlGF modulates VEGF-A responses we investigated their mutual relationship and impact on prognosis. Materials and methods: Quantitative PlGF and VEGF-A levels...... were measured in 229 tumor tissue specimen from primarily operated patients with unilateral breast cancer. Non-malignant breast tissue was also dissected near the tumor and quantitative measurements were available for 211 patients. PlGF and VEGF-A protein levels in homogenized tissue lysates were...

  7. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

    DEFF Research Database (Denmark)

    Maae, Else; Olsen, Dorte Aalund; Dahl Steffensen, Karina

    Background: Placenta growth factor (PlGF) and vascular endothelial growth factor A (VEGF-A) are angiogenic growth factors interacting competitively with the same receptors. VEGF-A is essential in both normal and pathologic conditions, but the functions of PlGF seem to be restricted to pathologic...... conditions such as ischemic heart disease, arthritis and tumor growth. Angiogenesis is a complex process with several growth factors involved. Because PlGF modulates VEGF-A responses we investigated their mutual relationship and impact on prognosis. Materials and methods: Quantitative PlGF and VEGF-A levels...... were measured in 229 tumor tissue specimen from primarily operated patients with unilateral breast cancer. Non-malignant breast tissue was also dissected near the tumor and quantitative measurements were available for 211 patients. PlGF and VEGF-A protein levels in homogenized tissue lysates were...

  8. Angiogenic factor AGGF1 promotes therapeutic angiogenesis in a mouse limb ischemia model.

    Directory of Open Access Journals (Sweden)

    Qiulun Lu

    Full Text Available BACKGROUND: Peripheral arterial disease (PAD is a common disease accounting for about 12% of the adult population, and causes significant morbidity and mortality. Therapeutic angiogenesis using angiogenic factors has been considered to be a potential treatment option for PAD patients. In this study, we assessed the potential of a new angiogenic factor AGGF1 for therapeutic angiogenesis in a critical limb ischemia model in mice for PAD. METHODS AND RESULTS: We generated a unilateral hindlimb ischemia model in mice by ligation of the right common iliac artery and femoral artery. Ischemic mice with intrasmuscular administration of DNA for an expression plasmid for human AGGF1 (AGGF1 group resulted in increased expression of both AGGF1 mRNA and protein after the administration compared with control mice with injection of the empty vector (control group. Color PW Doppler echocardiography showed that the blood flow in ischemic hindlimbs was significantly increased in the AGGF1 group compared to control mice at time points of 7, 14, and 28 days after DNA administration (n = 9/group, P = 0.049, 0.001, and 0.001, respectively. Increased blood flow in the AGGF1 group was correlated to increased density of CD31-positive vessels and decreased necrosis in muscle tissues injected with AGGF1 DNA compared with the control tissue injected with the empty vector. Ambulatory impairment was significantly reduced in the AGGF1 group compared to the control group (P = 0.004. The effect of AGGF1 was dose-dependent. At day 28 after gene transfer, AGGF1 was significantly better in increasing blood flow than FGF-2 (P = 0.034, although no difference was found for tissue necrosis and ambulatory impairment. CONCLUSIONS: These data establish AGGF1 as a candidate therapeutic agent for therapeutic angiogenesis to treat PAD.

  9. The effects ofan 8-month sports training on the levels ofvascular endothelial growth factor inyoung athletes – the role ofadaptive angiogenesis in the development of the aerobic capacity

    Directory of Open Access Journals (Sweden)

    Zbigniew Krenc

    2015-12-01

    Full Text Available A long-term sports training induces morphological and functional changes in the cardiovascular system, with the activation of angiogenesis being one of the most significant ones. Aim: The aim of the study was to assess the impact of an 8-month sports training on the serum levels of vascular endothelial growth factor and the physical performance in young athletes. Material and methods: A total of 28 sports middle school students (athletics faculty aged 13 years, including 14 boys and 14 girls, were included in the study. All participants underwent clinical assessment at  each stage of  the study. Electrocardiographic and echocardiographic examinations were performed. Furthermore, the levels of vascular endothelial growth factor were measured and a cardiac stress test was performed, the outcome of which was used to calculate the physical working capacity (PWC170. Results: There was a statistically significant decrease (274.3 ± 195.7 vs. 193.8 ± 153.8 ng/ml, p  0.05. Conclusions: Long-term sports training results in a decrease in the levels of vascular endothelial growth factor. At the same time, physical efficiency improvement is observed, which may suggest the involvement of adaptive, exerciseinduced angiogenesis in the skeletal muscles. However, the observed changes show distinct differences depending on the sex.

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

    Directory of Open Access Journals (Sweden)

    Fleshner Neil E

    2010-06-01

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

  11. Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1.

    Science.gov (United States)

    Gohongi, T; Fukumura, D; Boucher, Y; Yun, C O; Soff, G A; Compton, C; Todoroki, T; Jain, R K

    1999-10-01

    Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-beta1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-beta1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte-endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-beta1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor-host interactions.

  12. 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.)

  13. Nelumbo nucifera Gaertn leaves extract inhibits the angiogenesis and metastasis of breast cancer cells by downregulation connective tissue growth factor (CTGF) mediated PI3K/AKT/ERK signaling.

    Science.gov (United States)

    Chang, Chun-Hua; Ou, Ting-Tsz; Yang, Mon-Yuan; Huang, Chi-Chou; Wang, Chau-Jong

    2016-07-21

    Nelumbo nucifera Gaertn (Nymphaeaceae) has been recognized as a medicinal plant, which was distributed throughout the Asia. The aqueous extract of Nelumbo nucifera leaves extract (NLE) has various biologically active components such as polyphenols, flavonoids, oligomeric procyanidines. However, the role of NLE in breast cancer therapy is poorly understood. The purpose of this study was to identify the hypothesis that NLE can suppress tumor angiogenesis and metastasis through CTGF (connective tissue growth factor), which has been implicated in tumor angiogenesis and progression in breast cancer MDA-MB-231 cells. We examined the effects of NLE on angiogenesis in the chicken chorioallantoic membrane (CAM) model. The data showed that NLE could reduce the chorionic plexus at day 17 in CAM and the duration of this inhibition was dose-dependent. In Xenograft model, NLE treatment significantly reduced tumor weight and CD31 (capillary density) over control, respectively. We examined the role of angiogenesis involved restructuring of endothelium using human umbilical vein endothelial cell (HUVEC) in Matrigel angiogenesis model. The results indicated that vascular-like structure formation was further blocked by NLE treatment. Moreover, knockdown of CTGF expression markedly reduced the expression of MMP2 as well as VEGF, and attenuated PI3K-AKT-ERK activation, indication that these signaling pathways are crucial in mediating CTGF function. The present results suggest that NLE might be useful for treatment in therapy-resistance triple negative breast cancer. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  14. Adeno-associated virus vector-mediated delivery of pigment epithelium-derived factor restricts neuroblastoma angiogenesis and growth.

    Science.gov (United States)

    Streck, Christian J; Zhang, Youbin; Zhou, Junfang; Ng, Catherine; Nathwani, Amit C; Davidoff, Andrew M

    2005-01-01

    The purpose of this study was to evaluate the ability of adeno-associated virus (AAV) vector-mediated delivery of pigment epithelium-derived factor (PEDF) to inhibit neuroblastoma (NB) xenograft growth. Pigment epithelium-derived factor was chosen for this study because, in addition to being a potent inhibitor of angiogenesis, it is capable of inducing neuronal differentiation. Cohorts of mice received either recombinant AAV encoding human PEDF (rAAV-hPEDF) at a range of doses or control vector via tail vein. Subsequent hPEDF expression was measured by enzyme-linked immunoassay. After 6 weeks, the mice were given human NB cells by retroperitoneal injection and then killed 5 weeks later. Tumor weight, microvessel density, tumor differentiation, apoptosis, and levels of intratumoral vascular endothelial growth factor (VEGF) expression were determined at that time. In subsequent cohorts of mice, AAV-mediated murine PEDF expression was tested against both human NB xenografts and murine tumors. In a series of in vitro studies, PEDF was shown to inhibit endothelial cell activation and to stimulate differentiation of NB cell lines. After tail vein injection of rAAV-hPEDF, stable transgene expression was generated and correlated with levels of vector administration. Human NB xenograft growth was restricted by hPEDF in a dose-dependent fashion. Intratumoral VEGF expression and microvessel density were decreased, and tumor cell apoptosis was increased in PEDF-treated mice. Treatment with PEDF had a significant impact on NB growth in mice when delivered continuously using a gene therapy-mediated approach. The activity of PEDF appears to be mediated in part by inhibition of tumor-induced angiogenesis through down-regulation of tumor-elaborated VEGF, with subsequent intratumoral apoptosis. Furthermore, hPEDF was able to induce NB differentiation in vitro and in vivo. In addition, antitumor efficacy was seen when mouse PEDF was used to treat syngeneic murine tumors. In our

  15. Headache as Risk Factor for Vascular Disease

    OpenAIRE

    J Gordon Millichap

    2010-01-01

    The association of severe or recurrent headache or migraine with vascular disease in childhood or adolescence was examined by a National Health and Nutrition Survey at the National Institute of Neurological Disease and Stroke and of Mental Health, Bethesda, MD.

  16. Evidence for a vascular factor in migraine

    DEFF Research Database (Denmark)

    Asghar, Mohammad S; Hansen, Adam E; Amin, Faisal Mohammad

    2011-01-01

    It has been suggested that migraine is caused by neural dysfunction without involvement of vasodilatation. Because dismissal of vascular mechanisms seemed premature, we examined diameter of extra- and intracranial vessels in migraine without aura patients....

  17. Astrocyte-derived vascular endothelial growth factor stabilizes vessels in the developing retinal vasculature.

    Directory of Open Access Journals (Sweden)

    Andrew Scott

    2010-07-01

    Full Text Available Vascular endothelial growth factor (VEGF plays a critical role in normal development as well as retinal vasculature disease. During retinal vascularization, VEGF is most strongly expressed by not yet vascularized retinal astrocytes, but also by retinal astrocytes within the developing vascular plexus, suggesting a role for retinal astrocyte-derived VEGF in angiogenesis and vessel network maturation. To test the role of astrocyte-derived VEGF, we used Cre-lox technology in mice to delete VEGF in retinal astrocytes during development. Surprisingly, this only had a minor impact on retinal vasculature development, with only small decreases in plexus spreading, endothelial cell proliferation and survival observed. In contrast, astrocyte VEGF deletion had more pronounced effects on hyperoxia-induced vaso-obliteration and led to the regression of smooth muscle cell-coated radial arteries and veins, which are usually resistant to the vessel-collapsing effects of hyperoxia. These results suggest that VEGF production from retinal astrocytes is relatively dispensable during development, but performs vessel stabilizing functions in the retinal vasculature and might be relevant for retinopathy of prematurity in humans.

  18. Nerve growth factor injected into the gastric ulcer base incorporates into endothelial, neuronal, glial and epithelial cells: implications for angiogenesis, mucosal regeneration and ulcer healing.

    Science.gov (United States)

    Tanigawa, T; Ahluwalia, A; Watanabe, T; Arakawa, T; Tarnawski, A S

    2015-08-01

    A previous study has demonstrated that locally administered growth factors such as epidermal growth factor, basic fibroblast growth factor and hepatocyte growth factor can accelerate healing of experimental gastric ulcers in rats. That study indicates that locally administered growth factors can exert potent biological effects resulting in enhanced gastric ulcers healing. However, the fate of injected growth factors, their retention and localization to specific cellular compartments have not been examined. In our preliminary study, we demonstrated that local injection of nerve growth factor to the base of experimental gastric ulcers dramatically accelerates ulcer healing, increases angiogenesis - new blood vessel formation, and improves the quality of vascular and epithelial regeneration. Before embarking on larger, definitive and time sequence studies, we wished to determine whether locally injected nerve growth factor is retained in gastric ulcer's tissues and taken up by specific cells during gastric ulcer healing. Gastric ulcers were induced in anesthetized rats by local application of acetic acid using standard methods; and, 60 min later fluorescein isothiocyanate-labeled nerve growth factor was injected locally to the ulcer base. Rats were euthanized 2, 5 and 10 days later. Gastric specimens were obtained and processed for histology. Unstained paraffin sections were examined under a fluorescence microscope, and the incorporation of fluorescein isothiocyanate-labeled nerve growth factor into various gastric tissue cells was determined and quantified. In addition, we performed immunostaining for S100β protein that is expressed in neural components. Five and ten days after ulcer induction labeled nerve growth factor (injected to the gastric ulcer base) was incorporated into endothelial cells of blood vessels, neuronal, glial and epithelial cells, myofibroblasts and muscle cells. This study demonstrates for the first time that during gastric ulcer healing

  19. Paracrine Factors from Irradiated Peripheral Blood Mononuclear Cells Improve Skin Regeneration and Angiogenesis in a Porcine Burn Model.

    Science.gov (United States)

    Hacker, Stefan; Mittermayr, Rainer; Nickl, Stefanie; Haider, Thomas; Lebherz-Eichinger, Diana; Beer, Lucian; Mitterbauer, Andreas; Leiss, Harald; Zimmermann, Matthias; Schweiger, Thomas; Keibl, Claudia; Hofbauer, Helmut; Gabriel, Christian; Pavone-Gyöngyösi, Mariann; Redl, Heinz; Tschachler, Erwin; Mildner, Michael; Ankersmit, Hendrik Jan

    2016-04-29

    Burn wounds pose a serious threat to patients and often require surgical treatment. Skin grafting aims to achieve wound closure but requires a well-vascularized wound bed. The secretome of peripheral blood mononuclear cells (PBMCs) has been shown to improve wound healing and angiogenesis. We hypothesized that topical application of the PBMC secretome would improve the quality of regenerating skin, increase angiogenesis, and reduce scar formation after burn injury and skin grafting in a porcine model. Full-thickness burn injuries were created on the back of female pigs. Necrotic areas were excised and the wounds were covered with split-thickness mesh skin grafts. Wounds were treated repeatedly with either the secretome of cultured PBMCs (Sec(PBMC)), apoptotic PBMCs (Apo-Sec(PBMC)), or controls. The wounds treated with Apo-Sec(PBMC) had an increased epidermal thickness, higher number of rete ridges, and more advanced epidermal differentiation than controls. The samples treated with Apo-Sec(PBMC) had a two-fold increase in CD31+ cells, indicating more angiogenesis. These data suggest that the repeated application of Apo-Sec(PBMC) significantly improves epidermal thickness, angiogenesis, and skin quality in a porcine model of burn injury and skin grafting.

  20. Paracrine Factors from Irradiated Peripheral Blood Mononuclear Cells Improve Skin Regeneration and Angiogenesis in a Porcine Burn Model

    Science.gov (United States)

    Hacker, Stefan; Mittermayr, Rainer; Nickl, Stefanie; Haider, Thomas; Lebherz-Eichinger, Diana; Beer, Lucian; Mitterbauer, Andreas; Leiss, Harald; Zimmermann, Matthias; Schweiger, Thomas; Keibl, Claudia; Hofbauer, Helmut; Gabriel, Christian; Pavone-Gyöngyösi, Mariann; Redl, Heinz; Tschachler, Erwin; Mildner, Michael; Ankersmit, Hendrik Jan

    2016-01-01

    Burn wounds pose a serious threat to patients and often require surgical treatment. Skin grafting aims to achieve wound closure but requires a well-vascularized wound bed. The secretome of peripheral blood mononuclear cells (PBMCs) has been shown to improve wound healing and angiogenesis. We hypothesized that topical application of the PBMC secretome would improve the quality of regenerating skin, increase angiogenesis, and reduce scar formation after burn injury and skin grafting in a porcine model. Full-thickness burn injuries were created on the back of female pigs. Necrotic areas were excised and the wounds were covered with split-thickness mesh skin grafts. Wounds were treated repeatedly with either the secretome of cultured PBMCs (SecPBMC), apoptotic PBMCs (Apo-SecPBMC), or controls. The wounds treated with Apo-SecPBMC had an increased epidermal thickness, higher number of rete ridges, and more advanced epidermal differentiation than controls. The samples treated with Apo-SecPBMC had a two-fold increase in CD31+ cells, indicating more angiogenesis. These data suggest that the repeated application of Apo-SecPBMC significantly improves epidermal thickness, angiogenesis, and skin quality in a porcine model of burn injury and skin grafting. PMID:27125302

  1. Angiogenesis in the degeneration of the lumbar intervertebral disc

    Science.gov (United States)

    David, Gh; Iencean, SM; Mohan, A

    2010-01-01

    The goal of the study is to show the histological and biochemical changes that indicate the angiogenesis of the intervertebral disc in lumbar intervertebral disc hernia and the existence of epidemiological correlations between these changes and the risk factors of lumbar intervertebral disc hernia, as well as the patient's quality of life (QOL). We have studied 50 patients aged between 18 and 73 years old, who have undergone lumbar intervertebral disc hernia surgery, making fibroblast growth factor and vascular endothelial growth factor level measurements, as elements in the process of appreciating the disc angiogenesis. Also, pre–surgery and post–surgery QOL has been measured, as well as the intensity of the pain syndrome. We have identified factors capable of stimulating vascular endothelial growth (VEGF, FGF–2) for the examined disc material, but histological examination did not show angiogenesis. The process of angiogenesis at the degenerated intervertebral disc level affects the patient's quality of life both pre and postoperatively, and may be a predictive factor for the post–operative results. Patients can prevent the appearance of angiogenesis type degenerative processes of the intervertebral disc by avoiding angiogenesis correlated factors (weight control, physical effort, and smoking). PMID:20968201

  2. Factors of angiogenesis in the development of physiological and pathological processes of the female gonads

    Directory of Open Access Journals (Sweden)

    V. G. Zenkina

    2016-01-01

    Full Text Available The literature review focuses on the role of various growth factors in the developing vasculature of the ovary. Vascularization plays an important role in physiological processes such as development and atresia of a follicle, the formation of the yellow body and the pathological: ovarian hyperstimulation syndrome, the formation of follicular cysts, the development of cystic ovaries, endometriosis, dysfunctional uterine bleeding. The main angiogenic factor identified vascular endothelial growth factor, participates independently and through the mediating factors in baryogenesis, which plays an important role in endothelial cell differentiation and development of vascular pattern, stimulating endothelial proliferation, migration and survival of extravascular cells of the ovary. Angiogenic activity in the ovary is also under the control of other growth factors: fibroblast growth factor, epidermal growth factor, platelet growth factor, insulin-like growth factor-1 and cytokines such as tumor necrotic factor, interleukins, components of the extracellular matrix (laminin, fibronectin and their receptors (integrins, matrix metalloproteinases and their tissue inhibitors and regulators, proteases (plasminogen, activators urokinase and urokinase tissue type, as well as hypoxia, hypoglycemia and stress. Presents different points of view on the problem of vasculogenesis in the female gonad, as well as directions for future fundamental and practical research.

  3. 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....

  4. In situ formation of poly(vinyl alcohol–heparin hydrogels for mild encapsulation and prolonged release of basic fibroblast growth factor and vascular endothelial growth factor

    Directory of Open Access Journals (Sweden)

    Justine J Roberts

    2016-11-01

    Full Text Available Heparin-based hydrogels are attractive for controlled growth factor delivery, due to the native ability of heparin to bind and stabilize growth factors. Basic fibroblast growth factor and vascular endothelial growth factor are heparin-binding growth factors that synergistically enhance angiogenesis. Mild, in situ encapsulation of both basic fibroblast growth factor and vascular endothelial growth factor and subsequent bioactive dual release has not been demonstrated from heparin-crosslinked hydrogels, and the combined long-term delivery of both growth factors from biomaterials is still a major challenge. Both basic fibroblast growth factor and vascular endothelial growth factor were encapsulated in poly(vinyl alcohol-heparin hydrogels and demonstrated controlled release. A model cell line, BaF32, was used to show bioactivity of heparin and basic fibroblast growth factor released from the gels over multiple days. Released basic fibroblast growth factor promoted higher human umbilical vein endothelial cell outgrowth over 24 h and proliferation for 3 days than the poly(vinyl alcohol-heparin hydrogels alone. The release of vascular endothelial growth factor from poly(vinyl alcohol-heparin hydrogels promoted human umbilical vein endothelial cell outgrowth but not significant proliferation. Dual-growth factor release of basic fibroblast growth factor and vascular endothelial growth factor from poly(vinyl alcohol-heparin hydrogels resulted in a synergistic effect with significantly higher human umbilical vein endothelial cell outgrowth compared to basic fibroblast growth factor or vascular endothelial growth factor alone. Poly(vinyl alcohol-heparin hydrogels allowed bioactive growth factor encapsulation and provided controlled release of multiple growth factors which is beneficial toward tissue regeneration applications.

  5. Vascular endothelial growth factor A protein level and gene expression in intracranial meningiomas with brain edema

    DEFF Research Database (Denmark)

    Nassehi, Damoun; Dyrbye, Henrik; Andresen, Morten

    2011-01-01

    (VEGF) is an endothelial cell-specific mitogen and angiogen. VEGF-A protein, which is identical to vascular permeability factor, is a regulator of angiogenesis. In this study, 101 patients with meningiomas, and possible co-factors to PTBE, such as meningioma subtypes and tumor location, were examined....... Forty-three patients had primary, solitary, supratentorial meningiomas with PTBE. In these, correlations in PTBE, edema index, VEGF-A protein, VEGF gene expression, capillary length, and tumor water content were investigated. DNA-branched hybridization was used for measuring VEGF gene expression...... in tissue homogenates prepared from frozen tissue samples. The method for VEGF-A analysis resembled an ELISA assay, but was based on chemiluminescence. The edema index was positively correlated to VEGF-A protein (p = 0.014) and VEGF gene expression (p

  6. Prevalence, pattern and risk factors for retinal vascular occlusions in ...

    African Journals Online (AJOL)

    Introduction: Retinal vascular occlusions are the second most common retinal vascular diseases following diabetic retinopathy. They are associated with several systemic and ocular pathologies and are significant causes of visual loss. Objective: This study aims to determine the prevalence, pattern and risk factors for retinal ...

  7. Preparation and features of polycaprolactone vascular grafts with the incorporated vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Sevostyanova, V. V., E-mail: sevostyanova.victoria@gmail.com; Khodyrevskaya, Y. I.; Glushkova, T. V.; Antonova, L. V.; Kudryavtseva, Y. A.; Barbarash, O. L.; Barbarash, L. S. [Research Institute for Complex Issues of Cardiovascular Diseases, Kemerovo (Russian Federation)

    2015-10-27

    The development of tissue-engineered small-diameter vascular grafts is an urgent issue in cardiovascular surgery. In this study, we assessed how the incorporation of the vascular endothelial growth factor (VEGF) affects morphological and mechanical properties of polycaprolactone (PCL) vascular grafts along with its release kinetics. Vascular grafts were prepared using two-phase electrospinning. In pursuing our aims, we performed scanning electron microscopy, mechanical testing, and enzyme-linked immunosorbent assay. Our results demonstrated the preservation of a highly porous structure and improvement of PCL/VEGF scaffold mechanical properties as compared to PCL grafts. A prolonged VEGF release testifies the use of this construct as a scaffold for tissue-engineered vascular grafts.

  8. Vascular Endothelial Growth Factor Levels in Patients with Hypothyroidism

    Directory of Open Access Journals (Sweden)

    O.M. Didushko

    2016-01-01

    Full Text Available The objective of the investigation was to determine the levels of vascular endothelial growth factor in patients with primary hypothyroidism. Having examined 133 patients with manifested hypothyroidism, we discovered that levels of vascular endothelial growth factor significantly increased in blood plasma of both obese and non-obese patients, but the highest indices have been found in patients with hypothyroidism resulting from autoimmune thyroiditis and with obesity. The obtained correlations indicate mutually aggravating effect of thyroid hypofunction, obesity and hypercholesterolemia on the development of endothelial dysfunction in patients with primary hypothyroidism, in particular on the increase of vascular endothelial growth factor levels.

  9. Possible role of vascular risk factors in Alzheimer's disease and vascular dementia.

    Science.gov (United States)

    Hasnain, Mehrul; Vieweg, W Victor R

    2014-01-01

    The contribution of vascular risk factors to Alzheimer-vascular spectrum dementias is increasingly being recognized. We provide an overview of recent literature on this subject. Overweight and obesity as well as underweight during midlife predict cognitive decline and dementia later in life. Hypertension during midlife is also associated with dementia later in life and the association is stronger for untreated hypertension. Calcium channel blockers, angiotensin converting enzyme inhibitors, and angiotensin-1 receptor-blockers may be particularly beneficial in diminishing the risk of dementia associated with hypertension. Studies have fairly consistently shown that type 2 diabetes is a risk factor for dementia. Episodes of hypoglycemia add to this risk. Regular physical exercise during any point in the lifespan protects against cognitive decline and dementia. Most benefit is realized with physical exercise during early and midlife. Dyslipidemia also increases the risk of dementia but the findings are less consistent. Findings on the possible benefit of lipid-lowering agents (statins) are conflicting. Earlier studies identified smoking as protective of dementia but recent better designed studies have consistently shown that smoking increases the risk of dementia. The association of vascular risk factors with dementia is more robust for vascular dementia than Alzheimer's disease. Heterogeneity of studies and lack of trials specifically designed to assess cognition as an endpoint make firm conclusions difficult. But considering the expected global burden of dementia and projected attributable risk of vascular risk factors to it, there is sufficient evidence to promote vascular risk factor reduction strategies as dementia prevention interventions.

  10. Angiogenesis is inhibitory for mammalian digit regeneration

    Science.gov (United States)

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

    2014-01-01

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

  11. Expression of vascular endothelial growth factor (VEGF) in vulvar squamous cancer and VIN.

    Science.gov (United States)

    Lewy-Trenda, Iwona; Wierzchniewska-ławska, Agnieszka; Papierz, Wielisław

    2005-01-01

    Angiogenesis plays an important role both in progression of solid tumors and in metastasizing. An invasive growth of a neoplasm is mainly connected with appearing of blood vessels within a tumor. Inhibition of angiogenesis in solid neoplasms may deter both tumor growth and metastases. New treatment strategies based on suppressing of angiogenesis and selective damaging of neoplastic blood vessels may prove to be as efficient as those based on direct destruction of neoplastic cells. One of important angiogenic factors is vascular endothelial growth factor (VEGF), which is produced by neoplastic cells and shows high promitotic activity almost entirely for endothelial cells (paracrine activity). We decided to investigate VEGF expression in precancerous lesions as well as in squamous cancers of vulva. Our material included 31 cases of vulvar squamous cancer, 28 cases of VIN (vulvar intraepithelial neoplasia) III, 10 VIN II cases and 12 VIN I cases. A diagnosis was established according to WHO criteria on the ground of post-operative histopathological examination complemented with proliferation index estimated by the use of MIB-1 antibody. Immunohistochemical examinations were performed on paraffin-embedded material, using MIB-1 antibody (Immunotech), VEGF antibody (Santa Cruz), Goat serum Normal (DAKO), DAKO StreptAB-Complex/HRP Duet, Mouse/Rabbit DAKO DAB Chromogen Tablets, TBS (Sigma). Positive cytoplasmic expression of anti-VEGF polyclonal antibody (diffuse and/or focal and of various intensity) was observed in almost all samples from precancerous and cancerous lesions. The expression was especially strong and diffuse in all cancer cases; in cases of VIN it was mainly focal and weak.

  12. Pulp tissue inflammation and angiogenesis after pulp capping with transforming growth factor β1

    Directory of Open Access Journals (Sweden)

    Sri Kunarti

    2008-06-01

    Full Text Available In Restorative dentistry the opportunity to develop biomemitic approaches has been signalled by the possible use of various biological macromolecules in direct pulp capping reparation. The presence of growth factors in dentin matrix and the putative role indicating odontoblast differentiation during embryogenesis has led to the examination on the effect of endogenous TGF-β1. TGF-β1 is one of the Growth Factors that plays an important role in pulp healing. The application of exogenous TGF-β1 in direct pulp capping treatment should be experimented in fibroblast tissue in-vivo to see the responses of inflammatory cells and development of new blood vessels. The increase in food supplies always occurs in the process of inflammation therefore the development of angiogenesis is required to fulfil the requirement. This in-vivo study done on orthodontic patients indicated for premolar extraction between 10–15 years of age. A class V cavity preparation was created in the buccal aspect 1 mm above gingival margin to pulp exposure. The cavity was slowly irrigated with saline solution and dried using a sterile small cotton pellet. The sterile absorbable collagen membrane was applied and soaked in 5 ml TGF-β1. It was covered by a Teflon pledge to separate from Glass Ionomer Cement restoration. Evaluation was performed on day 7; 14; and 21. All samples were histopathologycally examined and data was statistically analysed using one way ANOVA and Dunnet T3.There were no inflammatory symptoms in clinical examination on both Ca(OH2 and TGF-β1, but they increased the infiltration of inflammatory cells on histopathological examination. There were no significant differences (p > 0.05 between Ca(OH2 and TGF-β1 in inflammation cell and significant differences (p < 0.05 in angiogenesis on day 7 and 14. There were no significant differences (p > 0.05 in inflammation cell with in TGF-β1 groups and significant differences (p < 0.05 with in Ca(OH2 groups on day 7

  13. [Tumoral angiogenesis: physiopathology, prognostic value and therapeutic perspectives].

    Science.gov (United States)

    André, T; Chastre, E; Kotelevets, L; Vaillant, J C; Louvet, C; Balosso, J; Le Gall, E; Prévot, S; Gespach, C

    1998-12-01

    Angiogenesis activation plays a crucial role in tumoral growth and metastases dissemination. This review summarizes and analyzes current knowledge on molecular mechanisms related to angiogenesis and the prognostic value of its effectors. It also focuses on the therapeutical relevance of various drugs that might inhibit angiogenesic processes. Tumor angiogenesis involves complex interactions between tumoral, stromal, endothelial cells, fibroblasts and the extracellular matrix. Normal and malignant angiogenesis depends on the balance of proangiogenic and antiangiogenic factors. Endothelial cells are activated by growth factors, such as Vascular Endothelial Growth Factor (VEGF), and proliferate; they release proteases able to induce degradation of the basement membrane and extracellular matrix, and undergo migration and tubulogenesis. Angiostatin and endostatin are two powerful inhibitors of angiogenesis in experimental models. Assessment of intratumoral microvessel density and quantification of angiogenic factors, including VEGF, are of prognostic value in most cancers, particularly in breast cancer. However, the use of these prognosis markers in clinical practice is still controversial due to the lack of prospective studies and to technical limits inherent to the scoring and standardization of immunohistochemical methods. Better understanding of the molecular basis of angiogenesis allows the development of new therapeutical strategies. Biochemical targets of antiangiogenic therapy are: the interaction between angiogenic factors and their receptors; the interaction of endothelial cells with the extracellular matrix; and intracellular signaling pathways. Angiogenesis inhibitors may not cause tumor regression, but inhibit cellular growth and produce "disease dormancy". Extensive phase I to III clinical trials involving antiangiogenesis therapy are in progress.

  14. SLIT3-ROBO4 activation promotes vascular network formation in human engineered tissue and angiogenesis in vivo.

    Science.gov (United States)

    Paul, Jonathan D; Coulombe, Kareen L K; Toth, Peter T; Zhang, Yanmin; Marsboom, Glenn; Bindokas, Vytas P; Smith, David W; Murry, Charles E; Rehman, Jalees

    2013-11-01

    Successful implantation and long-term survival of engineered tissue grafts hinges on adequate vascularization of the implant. Endothelial cells are essential for patterning vascular structures, but they require supportive mural cells such as pericytes/mesenchymal stem cells (MSCs) to generate stable, functional blood vessels. While there is evidence that the angiogenic effect of MSCs is mediated via the secretion of paracrine signals, the identity of these signals is unknown. By utilizing two functionally distinct human MSC clones, we found that so-called "pericytic" MSCs secrete the pro-angiogenic vascular guidance molecule SLIT3, which guides vascular development by directing ROBO4-positive endothelial cells to form networks in engineered tissue. In contrast, "non-pericytic" MSCs exhibit reduced activation of the SLIT3/ROBO4 pathway and do not support vascular networks. Using live cell imaging of organizing 3D vascular networks, we show that siRNA knockdown of SLIT3 in MSCs leads to disorganized clustering of ECs. Knockdown of its receptor ROBO4 in ECs abolishes the generation of functional human blood vessels in an in vivo xenogenic implant. These data suggest that the SLIT3/ROBO4 pathway is required for MSC-guided vascularization in engineered tissues. Heterogeneity of SLIT3 expression may underlie the variable clinical success of MSCs for tissue repair applications. © 2013. Published by Elsevier Ltd. All rights reserved.

  15. Vascular risk factors and adipocyte dysfunction in metabolic syndrome

    NARCIS (Netherlands)

    Hajer, G.R.

    2008-01-01

    The cluster of vascular risk factors closely associated with obesity, consists of fasting and postprandial dyslipidemia, hypertension, and insulin resistance, also known as metabolic syndrome, is associated with an increased cardiovascular morbidity and mortality. In addition, adipose tissue in

  16. Serum vascular endothelial growth factors a, C and d in human breast tumors.

    Science.gov (United States)

    Gisterek, Iwona; Matkowski, Rafal; Lacko, Aleksandra; Sedlaczek, Pawel; Szewczyk, Krzysztof; Biecek, Przemyslaw; Halon, Agnieszka; Staszek, Urszula; Szelachowska, Jolanta; Pudelko, Marek; Bebenek, Marek; Harlozinska-Szmyrka, Antonina; Kornafel, Jan

    2010-09-01

    Available evidence suggests that vascular endothelial growth factor (VEGF) a potent regulator of vasculogenesis and tumor angiogenesis may be a predictor of recurrence in breast cancer patients. We sought to determine whether VEGF serum levels (VEGF-A, VEGF-C and VEGF-D) in 377 patients with malignant and benign breast tumors differ and whether there is association between vascular growth factors, clinicopathologic features and prognosis. There was no significant difference in investigated circulating angiogenic markers between patients with malignant and non malignant lesions. We found strong correlation between VEGF-A and VEGF-D and between VEGF- C and VEGF-D. Besides serum VEGF-D levels and estrogen receptor (ER) expressions no other correlations between VEGF and clinicopathologic variables were observed. However, elevated VEGF-A and VEGF-C concentrations were associated with increased number of erythrocytes, leukocytes and platelets. In Cox model values of angiogenic serum markers and recognized prognostic markers in breast cancer, VEGF-C turned out as independent prognostic factor. Our study is the first analysis showing correlation between serum concentrations of three angiogenic factors: VEGF-A, VEGF-C, VEGF-D. Associations between angiogenic cytokines and number of blood cells may be due to release of VEGF from platelets and leucocytes. Prognostic role of VEGF is still uncertain, though VEGF-C has a potential to serve as a prognostic marker.

  17. Angiogenesis in Dermatology - Insights of Molecular Mechanisms and Latest Developments.

    Science.gov (United States)

    Richarz, N A; Boada, A; Carrascosa, J M

    Angiogenesis is the growth of new blood vessels from pre-existing vessels. It is a biological process essential in physiological wound healing or pathological inflammation and tumor growth, which underlies a complex interplay of stimulating and inhibiting signals. Extracellular matrix, cells of innate and adaptive immunity and endothelial cells itself are a major source of angiogenic factors that activate or inhibit specific receptors and consequently influence intracellular signaling pathways. Most inflammatory and neoplastic diseases in dermatology are characterized by excessive angiogenesis, such as psoriasis, atopic dermatitis, as well as melanoma, non-melanoma skin cancer, but also benign vascular neoplasia. In this article we describe current knowledge of angiogenesis and its most relevant mechanisms in different dermatological disorders with particular emphasis on the angiogenic factors (vascular endothelial growth factor) and angiopoietins as a target of current and future directions of anti-angiogenic therapy. Copyright © 2017 AEDV. Publicado por Elsevier España, S.L.U. All rights reserved.

  18. Cytokines and Angiogenesis in the Corpus Luteum

    Directory of Open Access Journals (Sweden)

    António M. Galvão

    2013-01-01

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

  19. Phylogenetic analysis and positive-selection site detecting of vascular endothelial growth factor family in vertebrates.

    Science.gov (United States)

    He, Wenwu; Tang, Yanyan; Qi, Bin; Lu, Chuansen; Qin, Chao; Wei, Yunfei; Yi, Jiachao; Chen, Mingwu

    2014-02-10

    Vascular endothelial growth factor (VEGF), known to play an important role in vascular homeostasis, vascular integrity and angiogenesis, is little known about the evolutionary relationship of its five members especially the role of gene duplication and natural selection in the evolution of the VEGF family. In this study, seventy-five full-length cDNA sequences from 33 vertebrate species were extracted from the NCBI's GenBank, UniProt protein database and the Ensembl database. By phylogenetic analyses, we investigated the origin, conservation, and evolution of the VEGFs. Five VEGF family members in vertebrates might be formed by gene duplication. The inferred evolutionary transitions that separate members which belong to different gene clusters correlated with changes in functional properties. Selection analysis and protein structure analysis were combined to explain the relationship of the site-specific evolution in the vertebrate VEGF family. Eleven positive selection sites, one transmembrane region and the active sites were detected in this process. © 2013.

  20. Epidermal growth factor receptor inhibition reduces angiogenesis via hypoxia-inducible factor-1α and Notch1 in head neck squamous cell carcinoma.

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    Wei-Ming Wang

    Full Text Available Angiogenesis, a marker of cancer development, affects response to radiotherapy sensibility. This preclinical study aims to understand the receptor tyrosine kinase-mediated angiogenesis in head neck squamous cell carcinoma (HNSCC. The receptor tyrosine kinase activity in a transgenic mouse model of HNSCC was assessed. The anti-tumorigenetic and anti-angiogenetic effects of cetuximab-induced epidermal growth factor receptor (EGFR inhibition were investigated in xenograft and transgenic mouse models of HNSCC. The signaling transduction of Notch1 and hypoxia-inducible factor-1α (HIF-1α was also analyzed. EGFR was overexpressed and activated in the Tgfbr1/Pten deletion (2cKO mouse model of HNSCC. Cetuximab significantly delayed tumor onset by reducing tumor angiogenesis. This drug exerted similar effects on heterotopic xenograft tumors. In the human HNSCC tissue array, increased EGFR expression correlated with increased HIF-1α and micro vessel density. Cetuximab inhibited tumor-induced angiogenesis in vitro and in vivo by significantly downregulating HIF-1α and Notch1. EGFR is involved in the tumor angiogenesis of HNSCC via the HIF-1α and Notch1 pathways. Therefore, targeting EGFR by suppressing hypoxia- and Notch-induced angiogenesis may benefit HNSCC therapy.

  1. Olive oil compounds inhibit vascular endothelial growth factor receptor-2 phosphorylation.

    Science.gov (United States)

    Lamy, Sylvie; Ouanouki, Amira; Béliveau, Richard; Desrosiers, Richard R

    2014-03-10

    Vascular endothelial growth factor (VEGF) triggers crucial signaling processes that regulate tumor angiogenesis and, therefore, represents an attractive target for the development of novel anticancer therapeutics. Several epidemiological studies have confirmed that abundant consumption of foods from plant origin is associated with reduced risk of developing cancers. In the Mediterranean basin, the consumption of extra virgin olive oil is an important constituent of the diet. Compared to other vegetable oils, the presence of several phenolic antioxidants in olive oil is believed to prevent the occurrence of a variety of pathological processes, such as cancer. While the strong antioxidant potential of these molecules is well characterized, their antiangiogenic activities remain unknown. The aim of this study is to investigate whether tyrosol (Tyr), hydroxytyrosol (HT), taxifolin (Tax), oleuropein (OL) and oleic acid (OA), five compounds contained in extra virgin olive oil, can affect in vitro angiogenesis. We found that HT, Tax and OA were the most potent angiogenesis inhibitors through their inhibitory effect on specific autophosphorylation sites of VEGFR-2 (Tyr951, Tyr1059, Tyr1175 and Tyr1214) leading to the inhibition of endothelial cell (EC) signaling. Inhibition of VEGFR-2 by these olive oil compounds significantly reduced VEGF-induced EC proliferation and migration as well as their morphogenic differentiation into capillary-like tubular structures in Matrigel. Our study demonstrates that HT, Tax and OA are novel and potent inhibitors of the VEGFR-2 signaling pathway. These findings emphasize the chemopreventive properties of olive oil and highlight the importance of nutrition in cancer prevention. © 2013 The Authors. Published by Elsevier Inc. All rights reserved.

  2. Infiltration of plasma rich in growth factors enhances in vivo angiogenesis and improves reperfusion and tissue remodeling after severe hind limb ischemia.

    Science.gov (United States)

    Anitua, Eduardo; Pelacho, Beatriz; Prado, Roberto; Aguirre, José Javier; Sánchez, Mikel; Padilla, Sabino; Aranguren, Xabier L; Abizanda, Gloria; Collantes, María; Hernandez, Milagros; Perez-Ruiz, Ana; Peñuelas, Ivan; Orive, Gorka; Prosper, Felipe

    2015-03-28

    PRGF is a platelet concentrate within a plasma suspension that forms an in situ-generated fibrin-matrix delivery system, releasing multiple growth factors and other bioactive molecules that play key roles in tissue regeneration. This study was aimed at exploring the angiogenic and myogenic effects of PRGF on in vitro endothelial cells (HUVEC) and skeletal myoblasts (hSkMb) as well as on in vivo mouse subcutaneously implanted matrigel and on limb muscles after a severe ischemia. Human PRGF was prepared and characterized. Both proliferative and anti-apoptotic responses to PRGF were assessed in vitro in HUVEC and hSkMb. In vivo murine matrigel plug assay was conducted to determine the angiogenic capacity of PRGF, whereas in vivo ischemic hind limb model was carried out to demonstrate PRGF-driven vascular and myogenic regeneration. Primary HUVEC and hSkMb incubated with PRGF showed a dose dependent proliferative and anti-apoptotic effect and the PRGF matrigel plugs triggered an early and significant sustained angiogenesis compared with the control group. Moreover, mice treated with PRGF intramuscular infiltrations displayed a substantial reperfusion enhancement at day 28 associated with a fibrotic tissue reduction. These findings suggest that PRGF-induced angiogenesis is functionally effective at expanding the perfusion capacity of the new vasculature and attenuating the endogenous tissue fibrosis after a severe-induced skeletal muscle ischemia. Copyright © 2015 Elsevier B.V. All rights reserved.

  3. Vascular Endothelial Growth Factor as an Angiogenic Marker in Malignant Astrocytoma and Oligodendroglioma: An Indian Scenario

    Science.gov (United States)

    Vokuda, Ramya S; Srinivas, Bheemanathi Hanuman; Madhugiri, Venkatesh S

    2017-01-01

    Introduction The role of Vascular Endothelial Growth Factor (VEGF) in angiogenesis has been extensively studied in gliomas, such as astrocytoma and oligodendrogliomas, worldwide. However, there is limited information available with regard to the Indian population. Aim To study, whether VEGF is expressed in the Indian population in a pattern similar to that in other population. Materials and Methods In this prospective study approved by the Institute Ethics Committee for Human Studies at Jawaharlal Institute of Post Graduate Medical Education and Research (JIPMER) the patients operated for glioma in 2014 and 2015 (n = 60) were included. Tumours were graded as per the World Health Organization (WHO) grading system. VEGF expression in various grades was analysed using immunohistochemistry. Results Of the 60 patients included in this study, 15 were Grade II- (diffuse astrocytomas – 12; oligodendrogliomas- 3), 15 were Grade III-(anaplastic astrocytomas- 2; anaplastic oligodendrogliomas – 13) and 30 were Grade IV-glioblastomas. For VEGF antibody staining, two patients (3.33%) showed negative results and 58 patients (96%) showed positive results. VEGF positivity was 100% in Grade II and III, while it was 93.3% (28/30) in Grade IV tumours (p=0.012). Conclusion The expression of VEGF was associated with the grade of tumour, which gradually increased from Grade II to Grade IV. We conclude that VEGF-regulated angiogenesis plays an important role in tumour progression of astrocytomas and oligodendrogliomas in the Indian population as observed worldwide. PMID:28384867

  4. Magnetic fluid hyperthermia inhibits the growth of breast carcinoma and downregulates vascular endothelial growth factor expression

    Science.gov (United States)

    WANG, GUIHUA; XU, DERONG; CHAI, QIN; TAN, XIAOLANG; ZHANG, YU; GU, NING; TANG, JINTIAN

    2014-01-01

    The application of magnetic fluid hyperthermia (MFH) with nanoparticles has been shown to inhibit tumor growth in several animal models. However, the feasibility of using MFH in vivo to treat breast cancer is uncertain, and the mechanism is unclear. In the present study, it was observed that the intratumoral administration of MFH induced hyperthermia significantly in rats with Walker-265 breast carcinomas. The hyperthermia treatment with magnetic nanoparticles inhibited tumor growth in vivo and promoted the survival of the tumor-bearing rats. Furthermore, it was found that MFH treatment downregulated the protein expression of vascular endothelial growth factor (VEGF) in the tumor tissue, as observed by immunohistochemistry. MFH treatment also decreased the gene expression of VEGF and its receptors, VEGF receptor 1 and 2, and inhibited angiogenesis in the tumor tissues. Taken together, these results indicate that the application of MFH with nanoparticles is feasible for the treatment of breast carcinoma. The MFH-induced downregulation of angiogenesis may also contribute to the induction of an anti-tumor effect. PMID:24765139

  5. Magnetic fluid hyperthermia inhibits the growth of breast carcinoma and downregulates vascular endothelial growth factor expression.

    Science.gov (United States)

    Wang, Guihua; Xu, Derong; Chai, Qin; Tan, Xiaolang; Zhang, Yu; Gu, Ning; Tang, Jintian

    2014-05-01

    The application of magnetic fluid hyperthermia (MFH) with nanoparticles has been shown to inhibit tumor growth in several animal models. However, the feasibility of using MFH in vivo to treat breast cancer is uncertain, and the mechanism is unclear. In the present study, it was observed that the intratumoral administration of MFH induced hyperthermia significantly in rats with Walker-265 breast carcinomas. The hyperthermia treatment with magnetic nanoparticles inhibited tumor growth in vivo and promoted the survival of the tumor-bearing rats. Furthermore, it was found that MFH treatment downregulated the protein expression of vascular endothelial growth factor (VEGF) in the tumor tissue, as observed by immunohistochemistry. MFH treatment also decreased the gene expression of VEGF and its receptors, VEGF receptor 1 and 2, and inhibited angiogenesis in the tumor tissues. Taken together, these results indicate that the application of MFH with nanoparticles is feasible for the treatment of breast carcinoma. The MFH-induced downregulation of angiogenesis may also contribute to the induction of an anti-tumor effect.

  6. Antitumor activity of cytotoxic T lymphocytes engineered to target vascular endothelial growth factor receptors

    Science.gov (United States)

    Niederman, Thomas M. J.; Ghogawala, Zoher; Carter, Bob S.; Tompkins, Hillary S.; Russell, Margaret M.; Mulligan, Richard C.

    2002-05-01

    The demonstration that angiogenesis is required for the growth of solid tumors has fueled an intense interest in the development of new therapeutic strategies that target the tumor vasculature. Here we report the development of an immune-based antiangiogenic strategy that is based on the generation of T lymphocytes that possess a killing specificity for cells expressing vascular endothelial growth factor receptors (VEGFRs). To target VEGFR-expressing cells, recombinant retroviral vectors were generated that encoded a chimeric T cell receptor comprised of VEGF sequences linked to intracellular signaling sequences derived from the chain of the T cell receptor. After transduction of primary murine CD8 lymphocytes by such vectors, the transduced cells were shown to possess an efficient killing specificity for cells expressing the VEGF receptor, Flk-1, as measured by in vitro cytotoxicity assays. After adoptive transfer into tumor-bearing mice, the genetically modified cytotoxic T lymphocytes strongly inhibited the growth of a variety of syngeneic murine tumors and human tumor xenografts. An increased effect on in vivo tumor growth inhibition was seen when this therapy was combined with the systemic administration of TNP-470, a conventional angiogenesis inhibitor. The utilization of the immune system to target angiogenic markers expressed on tumor vasculature may prove to be a powerful means for controlling tumor growth.

  7. Imbalance of angiogenesis in diabetic complications: The mechanisms

    Directory of Open Access Journals (Sweden)

    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.

  8. Macrophage migration inhibitory factor induces vascular leakage via autophagy

    Directory of Open Access Journals (Sweden)

    Hong-Ru Chen

    2015-01-01

    Full Text Available Vascular leakage is an important feature of acute inflammatory shock, which currently has no effective treatment. Macrophage migration inhibitory factor (MIF is a pro-inflammatory cytokine that can induce vascular leakage and plays an important role in the pathogenesis of shock. However, the mechanism of MIF-induced vascular leakage is still unclear. In this study, using recombinant MIF (rMIF, we demonstrated that MIF induced disorganization and degradation of junction proteins and increased the permeability of human endothelial cells in vitro. Western blotting analysis showed that rMIF treatment induced LC3 conversion and p62 degradation. Inhibition of autophagy with a PI3K inhibitor (3-MA, a ROS scavenger (NAC or autophagosomal-lysosomal fusion inhibitors (bafilomycin A1 and chloroquine rescued rMIF-induced vascular leakage, suggesting that autophagy mediates MIF-induced vascular leakage. The potential involvement of other signaling pathways was also studied using different inhibitors, and the results suggested that MIF-induced vascular leakage may occur through the ERK pathway. In conclusion, we showed that MIF triggered autophagic degradation of endothelial cells, resulting in vascular leakage. Inhibition of MIF-induced autophagy may provide therapeutic targets against vascular leakage in inflammatory shock.

  9. Psoriasis and Cardiovascular Comorbidities: Focusing on Severe Vascular Events, Cardiovascular Risk Factors and Implications for Treatment

    Directory of Open Access Journals (Sweden)

    Stephen Chu-Sung Hu

    2017-10-01

    Full Text Available Psoriasis is a common and chronic inflammatory disease of the skin. It may impair the physical and psychosocial function of patients and lead to decreased quality of life. Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints. More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities. In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke. In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population. Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders. In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment.

  10. Psoriasis and Cardiovascular Comorbidities: Focusing on Severe Vascular Events, Cardiovascular Risk Factors and Implications for Treatment.

    Science.gov (United States)

    Hu, Stephen Chu-Sung; Lan, Cheng-Che E

    2017-10-21

    Psoriasis is a common and chronic inflammatory disease of the skin. It may impair the physical and psychosocial function of patients and lead to decreased quality of life. Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints. More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities. In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke. In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population. Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders. In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment.

  11. Psoriasis and Cardiovascular Comorbidities: Focusing on Severe Vascular Events, Cardiovascular Risk Factors and Implications for Treatment

    Science.gov (United States)

    Hu, Stephen Chu-Sung; Lan, Cheng-Che E.

    2017-01-01

    Psoriasis is a common and chronic inflammatory disease of the skin. It may impair the physical and psychosocial function of patients and lead to decreased quality of life. Traditionally, psoriasis has been regarded as a disease affecting only the skin and joints. More recently, studies have shown that psoriasis is a systemic inflammatory disorder which can be associated with various comorbidities. In particular, psoriasis is associated with an increased risk of developing severe vascular events such as myocardial infarction and stroke. In addition, the prevalence rates of cardiovascular risk factors are increased, including hypertension, diabetes mellitus, dyslipidemia, obesity, and metabolic syndrome. Consequently, mortality rates have been found to be increased and life expectancy decreased in patients with psoriasis, as compared to the general population. Various studies have also shown that systemic treatments for psoriasis, including methotrexate and tumor necrosis factor-α inhibitors, may significantly decrease cardiovascular risk. Mechanistically, the presence of common inflammatory pathways, secretion of adipokines, insulin resistance, angiogenesis, oxidative stress, microparticles, and hypercoagulability may explain the association between psoriasis and cardiometabolic disorders. In this article, we review the evidence regarding the association between psoriasis and cardiovascular comorbidities, focusing on severe vascular events, cardiovascular risk factors and implications for treatment. PMID:29065479

  12. Vascular Risk Factors and Clinical Progression in Spinocerebellar Ataxias

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    Raymond Y. Lo

    2015-02-01

    Full Text Available Background: The contributions of vascular risk factors to spinocerebellar ataxia (SCA are not known.Methods: We studied 319 participants with SCA 1, 2, 3, and 6 and repeatedly measured clinical severity using the Scale for Assessment and Rating of Ataxia (SARA for 2 years. Vascular risk factors were summarized by CHA2DS2-VASc scores as the vascular risk factor index. We employed regression models to study the effects of vascular risk factors on ataxia onset and progression after adjusting for age, sex, and pathological CAG repeats. Our secondary analyses took hyperlipidemia into account.Results: Nearly 60% of SCA participants were at low vascular risks with CHA2DS2-VASc = 0, and 31% scored 2 or greater. Higher CHA2DS2-VASc scores were not associated with either earlier onset or faster progression of ataxia. These findings were not altered after accounting for hyperlipidemia. Discussion: Vascular risks are not common in SCAs and are not associated with earlier onset or faster ataxia progression.

  13. Mast Cell Proteases 6 and 7 Stimulate Angiogenesis by Inducing Endothelial Cells to Release Angiogenic Factors.

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    Devandir Antonio de Souza Junior

    Full Text Available Mast cell proteases are thought to be involved with tumor progression and neo-vascularization. However, their exact role is still unclear. The present study was undertaken to further elucidate the function of specific subtypes of recombinant mouse mast cell proteases (rmMCP-6 and 7 in neo-vascularization. SVEC4-10 cells were cultured on Geltrex® with either rmMCP-6 or 7 and tube formation was analyzed by fluorescence microscopy and scanning electron microscopy. Additionally, the capacity of these proteases to induce the release of angiogenic factors and pro and anti-angiogenic proteins was analyzed. Both rmMCP-6 and 7 were able to stimulate tube formation. Scanning electron microscopy showed that incubation with the proteases induced SVEC4-10 cells to invade the gel matrix. However, the expression and activity of metalloproteases were not altered by incubation with the mast cell proteases. Furthermore, rmMCP-6 and rmMCP-7 were able to induce the differential release of angiogenic factors from the SVEC4-10 cells. rmMCP-7 was more efficient in stimulating tube formation and release of angiogenic factors than rmMCP-6. These results suggest that the subtypes of proteases released by mast cells may influence endothelial cells during in vivo neo-vascularization.

  14. Mechanisms of Angiogenesis and Lymphangiogenesis in TSC Skin Tumors

    Science.gov (United States)

    2011-09-16

    factor (HIF-1α) 24 xiv     • Role of hypoxia in angiogenesis 26 LYMPHANGIOGENESIS 27 Lymphatic vascular system 27 Embryology of the lymphatic...functions leads to 29 a number of disease processes such as cancer metastasis, lymphedema and various inflammatory disorders131. Embryology of the

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

    Directory of Open Access Journals (Sweden)

    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.

  16. Vascular endothelial growth factor blockade alters magnetic resonance imaging biomarkers of vascular function and decreases barrier permeability in a rat model of lung cancer brain metastasis.

    Science.gov (United States)

    Pishko, Gregory L; Muldoon, Leslie L; Pagel, Michael A; Schwartz, Daniel L; Neuwelt, Edward A

    2015-02-17

    Blockade of vascular endothelial growth factor (VEGF) to promote vascular normalization and inhibit angiogenesis has been proposed for the treatment of brain metastases; however, vascular normalization has not been well-characterized in this disease. We investigated the effect of treatment with bevacizumab anti-VEGF antibody on magnetic resonance imaging (MRI) biomarkers of brain tumor vascular characteristics in comparison to small molecule delivery in a rat model of human lung cancer brain metastasis. Athymic rats with A549 human lung adenocarcinoma intracerebral xenografts underwent MRI at 11.75 T before and one day after treatment with bevacizumab (n = 8) or saline control (n = 8) to evaluate tumor volume, free water content (edema), blood volume and vascular permeability (Ktrans). One day later, permeability to 14C-aminoisobutyric acid (AIB) was measured in tumor and brain to assess the penetration of a small drug-like molecule. In saline control animals, tumor volume, edema and permeability increased over the two day assessment period. Compared to controls, bevacizumab treatment slowed the rate of tumor growth (P = 0.003) and blocked the increase in edema (P = 0.033), but did not alter tumor blood volume. Bevacizumab also significantly reduced Ktrans (P = 0.033) and AIB passive permeability in tumor (P = 0.04), but not to peritumoral tissue or normal brain. Post-treatment Ktrans correlated with AIB levels in the bevacizumab-treated rats but not in the saline controls. The correlation of an MRI biomarker for decreased vascular permeability with decreased AIB concentration in tumor after antiangiogenic treatment suggests that bevacizumab partially restored the normal low permeability characteristics of the blood-brain barrier in a model of human lung cancer brain metastasis.

  17. Growth factor release from a chemically modified elastomeric poly(1,8-octanediol-co-citrate) thin film promotes angiogenesis in vivo.

    Science.gov (United States)

    Sharma, Arun K; Bury, Matthew I; Fuller, Natalie J; Rozkiewicz, Dorota I; Hota, Partha V; Kollhoff, David M; Webber, Matthew J; Tapaskar, Natalie; Meisner, Jay W; Lariviere, Patrick J; Destefano, Samantha; Wang, Deli; Ameer, Guillermo A; Cheng, Earl Y

    2012-03-01

    The ultimate success of in vivo organ formation utilizing ex vivo expanded "starter" tissues relies heavily upon the level of vascularization provided by either endogenous or artificial induction of angiogenic or vasculogenic events. To facilitate proangiogenic outcomes and promote tissue growth, an elastomeric scaffold previously shown to be instrumental in the urinary bladder regenerative process was modified to release proangiogenic growth factors. Carboxylic acid groups on poly(1,8-octanediol-co-citrate) films (POCfs) were modified with heparan sulfate creating a heparan binding POCf (HBPOCf). Release of proangiogenic growth factors vascular endothelial growth factor (VEGF), fibroblast growth factor 2 (FGF2), and insulin-like growth factor 1 (IGF-1) from HBPOCfs demonstrated an approximate threefold increase over controls during a 30-day time course in vitro. Atomic force microscopy demonstrated significant topological differences between films. Subcutaneous implantation of POCf alone, HBPOCf, POCf-VEGF, and HBPOCf-VEGF within the dorsa of nude rats yielded increased vascular growth in HBPOCf-VEGF constructs. Vessel quantification studies revealed that POCfs alone contained 41.1 ± 4.1 vessels/mm², while HBPOCf, POCf-VEGF, and HBPOCF-VEGF contained 41.7 ± 2.6, 76.3 ± 9.4, and 167.72 ± 15.3 vessels/mm², respectively. Presence of increased vessel growth was demonstrated by CD31 and vWF immunostaining in HBPOCf-VEGF implanted areas. Data demonstrate that elastomeric POCfs can be chemically modified and possess the ability to promote angiogenesis in vivo. Copyright © 2011 Wiley Periodicals, Inc.

  18. Association between Risk Factors for Vascular Dementia and Adiponectin

    Science.gov (United States)

    Lee, Won Taek; Park, Kyung Ah

    2014-01-01

    Vascular dementia is caused by various factors, including increased age, diabetes, hypertension, atherosclerosis, and stroke. Adiponectin is an adipokine secreted by adipose tissue. Adiponectin is widely known as a regulating factor related to cardiovascular disease and diabetes. Adiponectin plasma levels decrease with age. Decreased adiponectin increases the risk of cardiovascular disease and diabetes. Adiponectin improves hypertension and atherosclerosis by acting as a vasodilator and antiatherogenic factor. Moreover, adiponectin is involved in cognitive dysfunction via modulation of insulin signal transduction in the brain. Case-control studies demonstrate the association between low adiponectin and increased risk of stroke, hypertension, and diabetes. This review summarizes the recent findings on the association between risk factors for vascular dementia and adiponectin. To emphasize this relationship, we will discuss the importance of research regarding the role of adiponectin in vascular dementia. PMID:24860814

  19. Is Pseudoexfoliation Syndrome a Risk Factor for Cerebro Vascular Disease?

    Science.gov (United States)

    Kan, Emrah; Yılmaz, Ahmet; Demirağ, Mehmet Derya; Çalık, Murat

    2017-01-01

    To determine the relationship between cerebro vascular disease and pseudoexfoliation syndrome. This cross-sectional case control study consisted of 50 patients with ischemic-type cerebro vascular disease and 50 control subjects. All subjects were investigated for diabetes mellitus and hypertension status and underwent a detailed ophthalmic examination. A diagnosis of pseudoexfoliation syndrome was made if characteristic greyish particulate matter was found on the anterior lens capsule after pupillary dilatation by slit-lamp examination. All subjects were compared in terms of pseudoexfoliation syndrome, diabetes mellitus, and hypertension. Pearson Chi Square and Student's t test were used for statistical analysis. Logistic regression analyses of the risk factors between groups were also made. The presence of pseudoexfoliation syndrome was significantly higher in patients with cerebro vascular disease when compared to the control subjects (p = 0.02). The frequency of diabetes mellitus was similar between the two groups. Arterial hypertension was significantly more frequent in the patient group when compared to the control subjects (p cerebro vascular disease. In the present study, we found that pseudoexfoliation syndrome frequency was found to be higher in patients with cerebro vascular disease than in control subjects. A slit-lamp examination of the eye could be an important marker that indicates the risk of cerebro vascular disease. We recommend an evaluation of all subjects with pseudoexfoliation syndrome for the presence of cerebro vascular disease. Longitudinal studies with larger populations are needed to confirm this relationship.

  20. Expression of the vascular endothelial growth factor receptor neuropilin-1 at the human embryo-maternal interface.

    Science.gov (United States)

    Baston-Buest, Dunja M; Porn, Anne C; Schanz, Andrea; Kruessel, Jan-S; Janni, Wolfgang; Hess, Alexandra P

    2011-02-01

    Angiogenesis is required for successful implantation of the invading blastocyst. Vascular endothelial growth factor (VEGF) is an important key player in angiogenesis and vascular remodeling during the implantation process. Besides its well-characterized receptors VEGFR1 and VEGFR2, neuropilin-1 (NRP-1) has been shown to play an additional role in the signaling process of angiogenesis in human endometrium during the menstrual cycle, as a co-receptor of VEGF. These findings led to the hypothesis that NRP-1 might play a role in the vascular remodeling process during embryo implantation and the establishment of a pregnancy. NRP-1 mRNA transcript and protein expression were investigated in human choriocarcinoma cell lines (JEG-3, Jar and BeWo) aiming to evaluate the expression of NRP-1 in vitro, as well as in human decidua of all three trimesters of pregnancy, by western blot analysis (three samples of each trimester of pregnancy). The localization of NRP-1 in human decidua of all three trimesters of pregnancy was analyzed by immunohistochemistry (five samples of each trimester of pregnancy). NRP-1 transcript and protein were expressed in all cell lines examined. Corresponding to the analysis of human tissue by western blot and the localization by immunohistochemistry, NRP-1 protein higher expressed in samples of early pregnancy in comparison to the end of pregnancy. NRP-1 was expressed in the decidua, villi and invading cytotrophoblast of all samples investigated. This is the first study clearly showing the expression of NRP-1 in human decidua and trophoblast, suggesting an important role for the VEGF co-receptor NRP-1 besides the established receptor VEGFR2 at the embryo-maternal interface during embryonic implantation and placentation. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  1. Calcium-Alginate Hydrogel-Encapsulated Fibroblasts Provide Sustained Release of Vascular Endothelial Growth Factor

    Science.gov (United States)

    Hunt, Nicola C.; Shelton, Richard M.; Henderson, Deborah J.

    2013-01-01

    Vascularization of engineered or damaged tissues is essential to maintain cell viability and proper tissue function. Revascularization of the left ventricle (LV) of the heart after myocardial infarction is particularly important, since hypoxia can give rise to chronic heart failure due to inappropriate remodeling of the LV after death of cardiomyocytes (CMs). Fibroblasts can express vascular endothelial growth factor (VEGF), which plays a major role in angiogenesis and also acts as a chemoattractant and survival factor for CMs and cardiac progenitors. In this in vitro model study, mouse NIH 3T3 fibroblasts encapsulated in 2% w/v Ca-alginate were shown to remain viable for 150 days. Semiquantitative reverse transcription–polymerase chain reaction and immunohistochemistry demonstrated that over 21 days of encapsulation, fibroblasts continued to express VEGF, while enzyme-linked immunosorbent assay showed that there was sustained release of VEGF from the Ca-alginate during this period. The scaffold degraded gradually over the 21 days, without reduction in volume. Cells released from the Ca-alginate at 7 and 21 days as a result of scaffold degradation were shown to retain viability, to adhere to fibronectin in a normal manner, and continue to express VEGF, demonstrating their potential to further contribute to maintenance of cardiac function after scaffold degradation. This model in vitro study therefore demonstrates that fibroblasts encapsulated in Ca-alginate provide sustained release of VEGF. PMID:23082964

  2. Radionuclide imaging of tumor angiogenesis

    NARCIS (Netherlands)

    Dijkgraaf, I.; Boerman, O.C.

    2009-01-01

    Angiogenesis is a multistep process regulated by pro- and antiangiogenic factors. In order to grow and metastasize, tumors need a constant supply of oxygen and nutrients. For growth beyond 1-2 mm in size, tumors are dependent on angiogenesis. Inhibition of angiogenesis is a new cancer treatment

  3. 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

  4. Increased vascular endothelial growth factor (VEGF) expression in ...

    African Journals Online (AJOL)

    Vascular endothelial growth factor (VEGF), a well known angiogenic factor, has been shown to have direct and/or indirect influence on spinal cord injury (SCI). The purpose of this study is to observe VEGF expression changes in rats with SCI by bone marrow stromal cells (BMSCs) treatment. The mRNA expression of VEGF ...

  5. A mutein of human basic fibroblast growth factor TGP-580 accelerates colonic ulcer healing by stimulating angiogenesis in the ulcer bed in rats.

    Science.gov (United States)

    Satoh, H; Szabo, S

    2015-10-01

    Previously, we reported that TGP-580, a mutein of human basic fibroblast growth factor (bFGF), accelerated the healing of gastric and duodenal ulcers in rats. In the present study, we examined the effect of TGP-580 on the healing of colonic ulcers. In male Sprague Dawley rats, ulcers were induced in the colon 6 cm from the anus by enema of 50 μl of 3% N-ethylmaleimide, a sulfhydryl alkylator. The lesions were examined under a dissecting microscope (x10). The concentration of bFGF in the ulcerated colon was measured by enzyme immunoassay, and both the distribution of bFGF and the density of microvessels in the ulcer bed were examined by immunohistochemical staining. The content of bFGF in the ulcerated colon was markedly increased associated with ulcer healing, and ulcer healing was significantly delayed by intravenous administration of a monoclonal antibody for bFGF (MAb 3H3) once daily for 10 days. In the ulcer bed, many cells such as fibroblasts, vascular endothelial cells and macrophages were positively stained with bFGF antiserum. TGP-580, human bFGF or dexamethasone was given intracolonally twice daily for 10 days, starting the day after ulcer induction. TGP-580 (0.2 - 20 μg/ml, 200 μl/rat) dose-dependently accelerated ulcer healing, and its effect was more than 10 times stronger than that of human bFGF. Density (μm/0.01 mm(2)) of microvessels in the ulcer bed was significantly increased by treatment with TGP-580, and there was a good correlation between the density of microvessels and the decrease of ulcerated area (R(2) = 0.633). On the other hand dexamethasone (20 μg/ml) inhibited angiogenesis in the ulcer bed and delayed ulcer healing. These results suggest that angiogenesis in the ulcer bed plays an important role in ulcer healing, and that bFGF mutein TGP-580 accelerated colonic ulcer healing, at least in part, by stimulating angiogenesis, whereas glucocorticoids may delay the healing by inhibiting angiogenesis.

  6. Mussel-inspired immobilization of vascular endothelial growth factor (VEGF) for enhanced endothelialization of vascular grafts.

    Science.gov (United States)

    Shin, Young Min; Lee, Yu Bin; Kim, Seok Joo; Kang, Jae Kyeong; Park, Jong-Chul; Jang, Wonhee; Shin, Heungsoo

    2012-07-09

    Most polymeric vascular prosthetic materials have low patency rate for replacement of small diameter vessels (polydopamine-mediated immobilization of growth factors on the surface of polymeric materials as a versatile tool to modify surface characteristics of vascular grafts potentially for accelerated endothelialization. Polydopamine was deposited on the surface of biocompatible poly(L-lactide-co-ε-caprolactone) (PLCL) elastomer, on which vascular endothelial growth factor (VEGF) was subsequently immobilized by simple dipping. Surface characteristics and composition were investigated by using scanning electron microscopy, atomic force microscopy, and X-ray photoelectron spectroscopy. Immobilization of VEGF on the polydopamine-deposited PLCL films was effective (19.8 ± 0.4 and 197.4 ± 19.7 ng/cm(2) for DPv20 and DPv200 films, respectively), and biotin-mediated labeling of immobilized VEGF revealed that the fluorescence intensity increased as a function of the concentration of VEGF solution. The effect of VEGF on adhesion of HUVECs was marginal, which may have been masked by polydopamine layer that also enhanced cell adhesion. However, VEGF-immobilized substrate significantly enhanced proliferation of HUVECs for over 7 days of in vitro culture and also improved their migration. In addition, immobilized VEGF supported robust cell to cell interactions with strong expression of CD 31 marker. The same process was effective for immobilization of basic fibroblast growth factor, demonstrating the robustness of polydopamine layer for secondary ligation of growth factors as a simple and novel surface modification strategy for vascular graft materials.

  7. Hambatan Ekspresi Vascular Endothelial Growth Factor oleh Ekstrak Daun Sambung Nyawa pada Endotel Membran Korioalantois (EFFECTIVITY OF SAMBUNG NYAWA LEAF EXTRACT TO INHIBIT VASCULAR ENDOTHELIAL GROWTH FACTOR EXPRESSION ON ENDOTHELIALS OF CHORIOALLANTOIC

    Directory of Open Access Journals (Sweden)

    Iwan Sahrial Hamid

    2013-08-01

    Full Text Available Angiogenesis is the new blood vessels formation normality and important on growth and developmentof individu. Angiogenesis also have contribution to carcinogenesis or uncontrolled and malignant cancercell development, become pathologic condition like inflammatory and infection. The purpose of this researchfor knew the effectivities of Gynura procumbens extract on various dose for inhibition Vascular EndothelialGrowth Factor (VEGF expression. This research was done to effort cancer progress inhibition. However,angiogenesis is part of carcinogenesis causes. The Chorio Allantoic Membrane (CAM methods was usedfor this aim. Eggs at the age of nine days were divided into 6 groups. Group I were negative control ofvehicle, group II were zero treatment: 60 ng bFGF which aplicated into paper dish. The next four groupswere extract of Gynura procumbens that divided in four dose: 60, 75, 90 and 110 µg + bFGF 60 ng whichapplicated into  paper dish.  At the twelve days old, VEGF expression analysis was done whichimunohystochemical method with anti VEGF’s antibody. The result of this research showed that therewas significant different (p<0.05 on give of Gynura procumbens extract to VEGF expression. The mostsignificant VEGF inhibition by Gynura procumbens extract with dose 110 µg. The conclusion on this studywas Gynura procumbens extract effective to inhibit the VEGF expression on CAM embrio chick.

  8. Proinflammatory Role of Vascular Endothelial Growth Factor in the Pathogenesis of Rheumatoid Arthritis: Prospects for Therapeutic Intervention

    Directory of Open Access Journals (Sweden)

    Seung-Ah Yoo

    2008-01-01

    Full Text Available Recent experimental and clinical studies have placed new emphasis on the role of angiogenesis in chronic inflammatory disease. Vascular endothelial growth factor (VEGF and its receptors are the best characterized system in the regulation of rheumatoid arthritis (RA by angiogenesis. Furthermore, in addition to its angiogenic role, VEGF can act as a direct proinflammatory mediator during the pathogenesis of RA, and protect rheumatoid synoviocytes from apoptosis, which contributes to synovial hyperplasia. Therefore, the developments of synovial inflammation, hyperplasia, and angiogenesis in the joints of RA patients seem to be regulated by a common cue, namely, VEGF. Agents that target VEGF, such as anti-VEGF antibody and aptamer, have yielded promising clinical data in patients with cancer or macular degeneration, and in RA patients, pharmacologic modulations targeting VEGF or its receptor may offer new therapeutic approaches. In this review, the authors integrate current knowledge of VEGF signaling and information on VEGF antagonists gleaned experimentally and place emphasis on the use of synthetic anti-VEGF hexapeptide to prevent VEGF interacting with its receptor.

  9. The angiogenic makeup of human hepatocellular carcinoma does not favor vascular endothelial growth factor/angiopoietin-driven sprouting neovascularization.

    Science.gov (United States)

    Zeng, Wenjiao; Gouw, Annette S H; van den Heuvel, Marius C; Zwiers, Peter J; Zondervan, Pieter E; Poppema, Sibrand; Zhang, Nong; Platteel, Inge; de Jong, Koert P; Molema, Grietje

    2008-11-01

    Quantitative data on the expression of multiple factors that control angiogenesis in hepatocellular carcinoma (HCC) are limited. A better understanding of the mechanisms underlying angiogenesis in HCC will improve the rational choice of anti-angiogenic treatment. We quantified gene and protein expression of members of the vascular endothelial growth factor (VEGF) and angiopoietin systems and studied localization of VEGF, its receptors VEGFR-1 and VEGFR-2, Angiopoietin (Ang)-1 and Ang-2, and their receptor, in HCC in noncirrhotic and cirrhotic livers. We employed real-time reverse transcription polymerase chain reaction (RT-PCR), western blot, and immunohistology, and compared the outcome with highly angiogenic human renal cell carcinoma (RCC). HCC in noncirrhotic and cirrhotic livers expressed VEGF and its receptors to a similar extent as normal liver, although in cirrhotic background, VEGFR-2 levels in both tumor and adjacent tissue were decreased. Ang-1 expression was slightly increased compared with normal liver, whereas Tie-2 was strongly down-regulated in the tumor vasculature. Ang-2 messenger RNA (mRNA) levels were also low in HCCs of both noncirrhotic and cirrhotic livers, implying that VEGF-driven angiogenic sprouting accompanied by angiopoietin-driven vascular destabilization is not pronounced. In RCC, VEGF-A levels were one order of magnitude higher. At the same time, endothelially expressed Ang-2 was over 30-fold increased compared with expression in normal kidney, whereas Ang-1 expression was decreased. In hepatocellular carcinoma, tumor vascularization is not per se VEGF/angiopoietin driven. However, increased CD31 expression and morphological changes representative of sinusoidal capillarization in tumor vasculature indicate that vascular remodeling is taking place. This portends that therapeutic intervention of HCC at the level of the vasculature is optional, and that further studies into the molecular control thereof are warranted.

  10. Vascular endothelial growth factor and the potential therapeutic use of pegaptanib (macugen) in diabetic retinopathy.

    Science.gov (United States)

    Starita, Carla; Patel, Manju; Katz, Barrett; Adamis, Anthony P

    2007-01-01

    Both clinical and preclinical findings have implicated vascular endothelial growth factor (VEGF) in the pathophysiology of diabetic macular edema (DME). VEGF is both a potent enhancer of vascular permeability and a key inducer of angiogenesis. VEGF levels are elevated in the eyes of patients with DME, and in animal models of diabetes this elevation coincides with the breakdown of the blood-retinal barrier. Moreover, injection of VEGF (the VEGF165 isoform in particular) into healthy eyes of animals can induce diabetes-associated ocular pathologies.Pegaptanib, a novel RNA aptamer currently used in the treatment of agerelated macular degeneration, binds and inactivates VEGF165 and has been shown in animal models to reverse the blood-retinal barrier breakdown associated with diabetes. These findings formed the basis of a phase II trial involving 172 patients with DME, in which intravitreous pegaptanib (0.3 mg, 1 mg, 3 mg) or sham injections were administered every 6 weeks for 12 weeks, with the option of continuing for 18 more weeks or undergoing laser treatment. Compared to sham, patients receiving 0.3 mg displayed superior visual acuity (p = 0.04) as well as a reduction in retinal thickness of 68 micrometers compared to a slight increase under sham treatment (p = 0.021). These data support the use of pegaptanib in the treatment of DME.

  11. On vascular factors, apathy and dementia

    NARCIS (Netherlands)

    van Dalen, J.-W.

    2018-01-01

    Part one of this dissertation describes the results of a randomized controlled trial in 3500 older people evaluating the effect cardiovascular risk factor treatment on incident dementia. The effects on white matter brain anomalies are evaluated in a subset of 200 participants. The main conclusion is

  12. The effect of vascular endothelial growth factor-1 expression on ...

    African Journals Online (AJOL)

    Riyad Bendardaf

    2017-02-28

    Feb 28, 2017 ... Colorectal cancer is third leading cause of cancer mortality. About 60% of patients had already developed metastasis at the time of diagnosis. Vascular endothelial growth factor. (VEGF) is crucial for the development of neovascularization and hence metastasis. This study aimed at investigating the relation ...

  13. Renal expression of vascular endothelial growth factor in lupus ...

    African Journals Online (AJOL)

    Background: Vascular endothelial growth factor (VEGF) plays a crucial role in preservation of renal functions and may also serve as a useful biomarker in monitoring the progression of lupus nephritis (LN). Objective: We thought to correlate VEGF expression in the kidney with renal histopathology in lupus nephritis to unveil ...

  14. Circulating vascular endothelial growth factor during the normal menstrual cycle

    NARCIS (Netherlands)

    Kusumanto, YH; Hospers, GAP; Sluiter, WJ; Dam, WA; Meijer, C; Mulder, NH

    2004-01-01

    Background: The purpose of the study was to investigate whether cycle-related variations in circulating Vascular Endothelial Growth Factor (VEGF) levels would increase the metastatic potential at specific times during the menstrual cycle. Materials and Methods: VEGF levels in serum and whole blood

  15. Vascular endothelial growth factor a in eyes with uveal melanoma.

    NARCIS (Netherlands)

    Missotten, G.S.; Notting, I.C.; Schlingemann, R.O.; Zijlmans, H.J.; Lau, C.; Eilers, P.H.; Keunen, J.E.E.; Jager, M.J.

    2006-01-01

    OBJECTIVES: To determine the presence of vascular endothelial growth factor A (VEGF-A) in the aqueous humor of eyes with uveal melanoma and to identify its source. METHODS: The VEGF-A concentrations were determined in aqueous humor samples obtained after enucleation from 74 eyes with untreated uveal

  16. Novel Selective Detection Method of Tumor Angiogenesis Factors Using Living Nano-Robots.

    Science.gov (United States)

    Al-Fandi, Mohamed; Alshraiedeh, Nida; Owies, Rami; Alshdaifat, Hala; Al-Mahaseneh, Omamah; Al-Tall, Khadijah; Alawneh, Rawan

    2017-07-14

    This paper reports a novel self-detection method for tumor cells using living nano-robots. These living robots are a nonpathogenic strain of E. coli bacteria equipped with naturally synthesized bio-nano-sensory systems that have an affinity to VEGF, an angiogenic factor overly-expressed by cancer cells. The VEGF-affinity/chemotaxis was assessed using several assays including the capillary chemotaxis assay, chemotaxis assay on soft agar, and chemotaxis assay on solid agar. In addition, a microfluidic device was developed to possibly discover tumor cells through the overexpressed vascular endothelial growth factor (VEGF). Various experiments to study the sensing characteristic of the nano-robots presented a strong response toward the VEGF. Thus, a new paradigm of selective targeting therapies for cancer can be advanced using swimming E. coli as self-navigator miniaturized robots as well as drug-delivery vehicles.

  17. Differential regulation of blood flow-induced neovascularization and mural cell recruitment by vascular endothelial growth factor and angiopoietin signalling.

    Science.gov (United States)

    Stone, Oliver A; Carter, James G; Lin, P Charles; Paleolog, Ewa; Machado, Maria J C; Bates, David O

    2017-03-01

    Combining nitric oxide (NO)-mediated increased blood flow with angiopoietin-1-Tie2 receptor signalling induces arteriolargenesis - the formation of arterioles from capillaries - in a model of physiological angiogenesis. This NO-Tie-mediated arteriolargenesis requires endogenous vascular endothelial growth factor (VEGF) signalling. Inhibition of VEGF signalling increases pericyte coverage in microvessels. Together these findings indicate that generation of functional neovasculature requires close titration of NO-Tie2 signalling and localized VEGF induction, suggesting that the use of exogenous VEGF expression as a therapeutic for neovascularization may not be successful. Signalling through vascular endothelial growth factor (VEGF) receptors and the tyrosine kinase with IgG and EGF domains-2 (Tie2) receptor by angiopoietins is required in combination with blood flow for the formation of a functional vascular network. We tested the hypothesis that VEGF and angiopoietin-1 (Ang1) contribute differentially to neovascularization induced by nitric oxide (NO)-mediated vasodilatation, by comparing the phenotype of new microvessels in the mesentery during induction of vascular remodelling by over-expression of endothelial nitric oxide synthase in the fat pad of the adult rat mesentery during inhibition of angiopoietin signalling with soluble Tie2 (sTie2) and VEGF signalling with soluble Fms-like tyrosine kinase receptor-1 (sFlt1). We found that NO-mediated angiogenesis was blocked by inhibition of VEGF with sFlt1 (from 881 ± 98% increase in functional vessel area to 279 ± 72%) and by inhibition of angiopoietin with sTie2 (to 337 ± 67%). Exogenous angiopoietin-1 was required to induce arteriolargenesis (8.6 ± 1.3% of vessels with recruitment of vascular smooth muscle cells; VSMCs) in the presence of enhanced flow. sTie2 and sFlt1 both inhibited VSMC recruitment (both 0%), and VEGF inhibition increased pericyte recruitment to newly formed vessels (from 27 ± 2 to

  18. Sugar-sweetened beverages, vascular risk factors and events

    DEFF Research Database (Denmark)

    Keller, Amelie; Heitmann, Berit L; Olsen, Nanna

    2015-01-01

    OBJECTIVE: A high intake of sugar-sweetened beverages (SSB) has been linked to weight gain, obesity and type 2 diabetes; however, the influence on CVD risk remains unclear. Therefore, our objective was to summarize current evidence for an association between SSB consumption and cardiovascular risk...... or blood sugar, or CVD events such as stroke or myocardial infarction. Only intervention and longitudinal studies were included. SUBJECTS: Only studies in adults (aged 18+ years old) were considered. RESULTS: Two of four prospective studies found clear direct associations between SSB consumption and CHD...... pressure, blood lipid or blood sugar. CONCLUSIONS: The reviewed studies generally showed that SSB intake was related to vascular risk factors, whereas associations with vascular events were less consistent. Due to a limited number of published papers, especially regarding vascular events, the strength...

  19. Interaction between monocytes and vascular smooth muscle cells induces expression of hepatocyte growth factor.

    Science.gov (United States)

    Okada, M; Hojo, Y; Ikeda, U; Takahashi, M; Takizawa, T; Morishita, R; Shimada, K

    2000-12-01

    To investigate the expression of hepatocyte growth factor (HGF)--a multifunctional factor implicated in tissue regeneration, wound healing and angiogenesis--that is induced by cell-to-cell interactions between monocytes and vascular smooth muscle cells (VSMCs), using coculture of human VSMCs and cells of the human monocytoid cell line, THP-1. We collected supernatant from the coculture medium and measured HGF concentrations with an enzyme-linked immunosorbent assay. Northern blot analysis of HGF mRNA was performed using a specific cDNA. To explore which types of cells produce HGF, we performed immunohistochemistry. Coculture of VSMCs with THP-1 cells for 24 h caused a fivefold increase in HGF concentrations over that in control VSMC culture. Northern blot analysis showed an induction of HGF mRNA in the coculture with a peak at 3 h. Separated cocultures demonstrated that both direct contact and soluble factors contribute to the production of HGF. Immunohistochemistry demonstrated that both types of cells in the coculture produce HGF. Neutralizing antibodies against tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6 inhibited the HGF production in THP-1 cells and VSMCs that was induced by the coculture conditioned medium. The protein kinase C inhibitors H-7, calphostin C and K252b, and the tyrosine kinase inhibitor, genistein, significantly inhibited the production of HGF in the coculture. Cell-to-cell interactions between monocytes and VSMCs induced HGF synthesis in both types of cells, suggesting that local HGF production induced by this cell-to-cell interaction has an important role in the pathogenesis of hypertension, atherosclerosis or vascular remodelling.

  20. Cerebral ischemia-induced angiogenesis is dependent on tumor necrosis factor receptor 1-mediated upregulation of α5β1 and αVβ3 integrins.

    Science.gov (United States)

    Huang, Heng; Huang, Qijuan; Wang, Fuxin; Milner, Richard; Li, Longxuan

    2016-09-01

    The pro-inflammatory cytokine, tumor necrosis factor-α (TNF-α), is expressed in ischemic tissue and is known to modulate angiogenesis; however, the role of the two distinct TNF-α receptors, TNFR1 and TNFR2, in mediating angiogenic signaling after cerebral ischemic stroke is relatively unknown. C57BL6 mice were subject to 90 min of ischemia by temporary occlusion of the middle cerebral artery (MCAO) and given daily intra-cerebroventricular injections of antibodies against TNFR1, TNFR2 or control IgG (doses of 10, 50, and 100 ng/day) for 4 days following 90 min MCAO. Vascular remodeling and α5β1 and αVβ3 integrin expression were then examined in the brains of these mice after 4, 7, and 14 days post-ischemia. In parallel in vitro studies, flow cytometry was used to determine the influence of TNF-α on proliferation and integrin expression of human brain microvascular endothelial cells (HBMECs). The post-ischemic cerebral angiogenic response was inhibited by antibodies against TNFR1 but not TNFR2, and this correlated with reduced endothelial proliferation and decreased α5β1 and αVβ3 integrin expression after 4 and 7 days post-ischemia. Consistent with these findings, in vitro studies showed that TNF-α induced endothelial proliferation and upregulation of α5β1 and αVβ3 integrins was abrogated by anti-TNFR1 but not anti-TNFR2 antibodies in cultured HBMECs. In addition, blocking antibodies to α5β1 and αVβ3 integrins significantly inhibited TNF-α-induced HBMEC proliferation. Our results suggest that TNFR1-mediated signaling plays a critical role in triggering angiogenic integrins and subsequent angiogenic responses following cerebral ischemia. These novel findings could form a platform for future therapeutic strategies aimed at stimulating angiogenesis following cerebral ischemia.

  1. Vascular endothelial growth factor and nitric oxide synthase expression in human tooth germ development.

    Science.gov (United States)

    Mastrangelo, F; Sberna, M T; Tettamanti, L; Cantatore, G; Tagliabue, A; Gherlone, E

    2016-01-01

    Vascular Endothelia Growth Factor (VEGF) and Nitric Oxide Synthase (NOS) expression, were evaluated in human tooth germs at two different stages of embryogenesis, to clarify the role of angiogenesis during tooth tissue differentiation and growth. Seventy-two third molar germ specimens were selected during oral surgery. Thirty-six were in the early stage and 36 in the later stage of tooth development. The samples were evaluated with Semi-quantitative Reverse Transcription-Polymerase chain Reaction analyses (RT-PcR), Western blot analysis (WB) and immunohistochemical analysis. Western blot and immunohistochemical analysis showed a VEGF and NOS 1-2-3 positive reaction in all samples analysed. VEGF high positive decrease reaction was observed in stellate reticulum cells, ameloblast and odontoblast clusters in early stage compared to later stage of tooth germ development. Comparable VEGF expression was observed in endothelial cells of early and advanced stage growth. NOS1 and NOS3 expressions showed a high increased value in stellate reticulum cells, and ameloblast and odontoblast clusters in advanced stage compared to early stage of development. The absence or only moderate positive reaction of NOS2 was detected in all the different tissues. Positive NOS2 expression showed in advanced stage of tissue development compared to early stage. The action of VEGF and NOS molecules are important mediators of angiogenesis during dental tissue development. VEGF high positive expression in stellate reticulum cells in the early stage of tooth development compared to the later stage and the other cell types, suggests a critical role of the stellate reticulum during dental embryo-morphogenesis.

  2. Modelling Tumor-induced Angiogenesis: Combination of Stochastic Sprout Spacing and Sprout Progression

    Directory of Open Access Journals (Sweden)

    Hosseini F.

    2017-09-01

    Full Text Available Background: Angiogenesis initiated by cancerous cells is the process by which new blood vessels are formed to enhance oxygenation and growth of tumor. Objective: In this paper, we present a new multiscale mathematical model for the formation of a vascular network in tumor angiogenesis process. Methods: Our model couples an improved sprout spacing model as a stochastic mathematical model of sprouting along an existing parent blood vessel, with a mathematical model of sprout progression in the extracellular matrix (ECM in response to some tumor angiogenic factors (TAFs. We perform simulations of the siting of capillary sprouts on an existing blood vessel using finite difference approximation of the dynamic equations of some angiogenesis activators and inhibitors. Angiogenesis activators are chemicals secreted by hypoxic tumor cells for initiating angiogenesis, and inhibitors of the angiogenesis are chemicals that are produced around every new sprout during tumor angiogenesis to inhibit the formation of further sprouts as a feedback of sprouting in angiogenesis. Moreover, for modelling sprout progression in ECM, we use three equations for the motility of endothelial cells at the tip of the activated sprouts, the consumption of TAF and the production and uptake of Fibronectin by endothelial cells. Results: Coupling these two basic models not only does provide a better time estimation of angiogenesis process, but also it is more compatible with reality. Conclusion: This model can be used to provide basic information for angiogenesis in the related studies. Related simulations can estimate the position and number of sprouts along parent blood vessel during the initial steps of angiogenesis and models the process of sprout progression in ECM until they vascularize a tumor.

  3. Retinal vascular calibres are significantly associated with cardiovascular risk factors

    DEFF Research Database (Denmark)

    von Hanno, T.; Bertelsen, G.; Sjølie, Anne K.

    2014-01-01

    Purpose: To describe the association between retinal vascular calibres and cardiovascular risk factors. Methods: Population-based cross-sectional study including 6353 participants of the TromsO Eye Study in Norway aged 38-87years. Retinal arteriolar calibre (central retinal artery equivalent....... Association between retinal vessel calibre and the cardiovascular risk factors was assessed by multivariable linear and logistic regression analyses. Results: Retinal arteriolar calibre was independently associated with age, blood pressure, HbA1c and smoking in women and men, and with HDL cholesterol in men...... cardiovascular risk factors were independently associated with retinal vascular calibre, with stronger effect of HDL cholesterol and BMI in men than in women. Blood pressure and smoking contributed most to the explained variance....

  4. Primitive retroperitoneal tumors. Vascular involvement--a major prognostic factor.

    Science.gov (United States)

    Lazar, A M; Brătucu, E; Straja, N D; Daha, C; Marincaş, M; Cirimbei, C; Prunoiu, V

    2012-01-01

    Primitive retroperitoneal tumors, although very rare, arouse an increased interest, because of the poor prognosis, unsatisfactory surgical and complementary therapy results. Up to now, the very low number of cases has impeded the acquisition of a unitary view of these tumors, a unanimously accepted algorithm of diagnostic and treatment being absent. Randomized trials regarding the effects of different therapies have not been possible. The main factor that can fundamentally increase the survival of these patients is radical resection, some authors even recommending compartmental surgery. We found no significant statistical difference between the survival rates of the patients with different types of non-radical interventions, that shoud be therefore, as much as possible, avoided. Our study evidences that vascular involvement is the main limiting factor in achieving radicality. The involvement of large retroperitoneal vessels makes often impossible a radical intervention, usually because of the lack of an adequate material and human endowment for ample vascular resections followed by laborious reconstructions. That is why, in our study, vascular involvement was associated with a decreased survival rate for operated patients. Therefore, we underline the necessity both of a solid material base and of establishing multidisciplinary surgical teams for adequate vascular interventions in oncologic general surgery.

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

    Science.gov (United States)

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

    2017-11-15

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

  6. [Influence of the thymidine phosphorylase (platelet-derived endothelial cell growth factor) on tumor angiogenesis. Catalytic activity of enzyme inhibitors].

    Science.gov (United States)

    Miszczak-Zaborska, Elzbieta; Smolarek, Monika; Bartkowiak, Jacek

    2010-01-01

    Thymidine phosphorylase, also known as platelet-derived endothelial cell growth factor, is a potent angiogenic factor. Thymidine phosphorylase is overexpressed in various human tumors and plays an important role in angiogenesis. A novel inhibitor of thymidine phosphorylase (TP), 5-chloro-6-[1-(2-iminopyrrolidinyl) methyl] uracil hydrochloride (TPI) is about 1000-fold more active than 6-amino-5-chlorouracil, one of the most potent TP inhibitors to 1999 year. Thymidine phosphorylase is also inhibited by 5'-O-trityl-inosine (KIN59) and related compounds, 2-deoxy-L-ribose and glycosides isolated from the bark of Symplocos racemosa.

  7. KSHV-Mediated Angiogenesis in Tumor Progression

    Directory of Open Access Journals (Sweden)

    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.

  8. Three-dimensional contrast enhanced ultrasound score and dynamic contrast-enhanced magnetic resonance imaging score in evaluating breast tumor angiogenesis: Correlation with biological factors

    Energy Technology Data Exchange (ETDEWEB)

    Jia, Wan-Ru, E-mail: jiawanru@126.com [Department of Diagnostic Ultrasound, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, No. 197 Rui Jin 2nd Road, Shanghai 200025 (China); Chai, Wei-Min, E-mail: chai_weimin@yahoo.com.cn [Department of Radiology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, No. 197 Rui Jin 2nd Road, Shanghai 200025 (China); Tang, Lei, E-mail: jessietang1003@163.com [Department of Diagnostic Ultrasound, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, No. 197 Rui Jin 2nd Road, Shanghai 200025 (China); Wang, Yi, E-mail: xiatian.0602@163.com [Department of Diagnostic Ultrasound, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, No. 197 Rui Jin 2nd Road, Shanghai 200025 (China); Fei, Xiao-Chun, E-mail: xcf0222@163.com [Department of Pathology, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, No. 197 Rui Jin 2nd Road, Shanghai 200025 (China); Han, Bao-San, E-mail: hanbaosan@126.com [Department of Comprehensive Breast Health Center, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, No. 197 Rui Jin 2nd Road, Shanghai 200025 (China); Chen, Man, E-mail: lucyjia1370@126.com [Department of Diagnostic Ultrasound, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, No. 197 Rui Jin 2nd Road, Shanghai 200025 (China)

    2014-07-15

    Objective: To explore the clinical value of three-dimensional contrast enhanced ultrasound (3D-CEUS) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) score systems in evaluating breast tumor angiogenesis by comparing their diagnostic efficacy and correlation with biological factors. Methods: 3D-CEUS was performed in 183 patients with breast tumors by Esaote Mylab90 with SonoVue (Bracco, Italy), DCE-MRI was performed on a dedicated breast magnetic resonance imaging (DBMRI) system (Aurora Dedicated Breast MRI Systems, USA) with a dedicated breast coil. 3D-CEUS and DCE-MRI score systems were created based on tumor perfusion and vascular characteristics. Microvessel density (MVD), vascular endothelial growth factor (VEGF) and matrix metalloproteinases (MMP-2, MMP-9) expression were measured by immunohistochemistry. Results: Pathological results showed 35 benign and 148 malignant breast tumors. MVD (P = 0.000, r = 0.76), VEGF (P = 0.000, r = 0.55), MMP-2 (P = 0.000, r = 0.39) and MMP-9 (P = 0.000, r = 0.41) expression were all significantly different between benignity and malignancy. Regarding 3D-CEUS 4 points as cutoff value, the sensitivity, specificity and accuracy were 85.1%, 94.3% and 86.9%, respectively, and correlated well with MVD (P = 0.000, r = 0.50), VEGF (P = 0.000, r = 0.50), MMP-2 (P = 0.000, r = 0.50) and MMP-9 (P = 0.000, r = 0.66). Taking DCE-MRI 5 points as cutoff value, the sensitivity, specificity and accuracy were 86.5%, 94.3% and 88.0%, respectively and also correlated well with MVD (P = 0.000, r = 0.52), VEGF (P = 0.000, r = 0.44), MMP-2 (P = 0.000, r = 0.42) and MMP-9 (P = 0.000, r = 0.35). Conclusions: 3D-CEUS score system displays inspiring diagnostic performance and good agreement with DCE-MRI scoring. Moreover, both score systems correlate well with MVD, VEGF, MMP-2 and MMP-9 expression, and thus have great potentials in tumor angiogenesis evaluation.

  9. Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis

    National Research Council Canada - National Science Library

    Pratheeshkumar, Poyil; Son, Young-Ok; Budhraja, Amit; Wang, Xin; Ding, Songze; Wang, Lei; Hitron, Andrew; Lee, Jeong-Chae; Kim, Donghern; Divya, Sasidharan Padmaja; Chen, Gang; Zhang, Zhuo; Luo, Jia; Shi, Xianglin

    2012-01-01

    .... In vitro studies using rat aortic ring assay showed that luteolin at non-toxic concentrations significantly inhibited microvessel sprouting and proliferation, migration, invasion and tube formation...

  10. Vascular risk factors as treatment target to prevent cognitive decline.

    Science.gov (United States)

    Richard, Edo; Moll van Charante, Eric P; van Gool, Willem A

    2012-01-01

    Epidemiological studies have consistently shown that vascular risk factors including hypertension, diabetes, obesity, hypercholesterolemia, smoking, and lack of physical exercise are associated with an increased risk of cognitive decline and dementia. Neuroradiological and neuropathological studies have confirmed the importance of cerebrovascular lesions in the etiology of late onset dementia. We have reviewed the literature and conclude that up until now randomized controlled clinical trials targeting individual risk factors and assessing cognitive decline or dementia as an outcome have not convincingly shown that treatment of vascular risk factors can actually prevent or postpone cognitive decline and dementia. New studies targeting several vascular risk factors at the same time and using cognitive decline or dementia as primary outcome might answer the question whether cognitive decline can really be postponed or even prevented. The design of such studies is not straightforward and long follow-up is required. In this review we discuss several pertinent methodological issues that need to be addressed to achieve an optimal design of new randomized controlled trials.

  11. Angiogenesis in the atherosclerotic plaque

    Directory of Open Access Journals (Sweden)

    Caroline Camaré

    2017-08-01

    Full Text Available Atherosclerosis is a multifocal alteration of the vascular wall of medium and large arteries characterized by a local accumulation of cholesterol and non-resolving inflammation. Atherothrombotic complications are the leading cause of disability and mortality in western countries. Neovascularization in atherosclerotic lesions plays a major role in plaque growth and instability. The angiogenic process is mediated by classical angiogenic factors and by additional factors specific to atherosclerotic angiogenesis. In addition to its role in plaque progression, neovascularization may take part in plaque destabilization and thromboembolic events. Anti-angiogenic agents are effective to reduce atherosclerosis progression in various animal models. However, clinical trials with anti-angiogenic drugs, mainly anti-VEGF/VEGFR, used in anti-cancer therapy show cardiovascular adverse effects, and require additional investigations.

  12. The Role of Vascular Endothelial Growth Factor in Metastatic Prostate Cancer to the Skeleton

    Directory of Open Access Journals (Sweden)

    Emma Roberts

    2013-01-01

    Full Text Available Despite the clinical implication and high incidence of bone and spinal metastases, the molecular mechanisms behind prostate cancer metastasis to bone and spine are not well understood. In this review the molecular mechanisms that may contribute to the highly metastatic phenotype of prostate cancer are discussed. Proangiogenic factors such as vascular endothelial growth factor (VEGF have been shown to not only aid in the metastatic capabilities of prostate cancer but also encourage the colonization and growth of prostate tumour cells in the skeleton. The importance of VEGF in the complex process of prostate cancer dissemination to the skeleton is discussed, including its role in the development of the bone premetastatic niche, metastatic tumour cell recognition of bone, and bone remodeling. The expression of VEGF has also been shown to be upregulated in prostate cancer and is associated with clinical stage, Gleason score, tumour stage, progression, metastasis, and survival. Due to the multifaceted effect VEGF has on tumour angiogenesis, tumour cell proliferation, and bone destruction, therapies targeting the VEGF pathways have shown promising clinical application and are being investigated in clinical trials.

  13. Anti-angiogenesis in neuroblastoma.

    Science.gov (United States)

    Ribatti, Domenico

    2013-06-01

    The nature of the angiogenic balance in neuroblastoma is complex, and a spectrum of angiogenesis stimulators and inhibitors have been detected in neuroblastoma tumours. The complex relationships between angiogenic cascade and anti-angiogenic agents in the tumour vascular phase have indicated that anti-angiogenesis can be considered as a strategy for the adjuvant therapy of neuroblastoma. The major goal is to establish if inhibition of angiogenesis is a realistic therapeutic strategy for inhibiting tumour cell dissemination and the formation of metastasis in neuroblastoma. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  14. Soluble vascular endothelial growth factor levels in patients with primary colorectal carcinoma. The Danish RANX05 Colorectal Cancer Study Group

    DEFF Research Database (Denmark)

    Werther, K; Christensen, Ib Jarle; Brünner, N

    2000-01-01

    INTRODUCTION: Angiogenesis is decisive in tumour progression and metastasis. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor, and increased VEGF levels in patients with carcinomas may facilitate growth of both primary and secondary tumours. METHODS: Soluble (s) VEGF levels...... were determined in serum from 91 volunteer healthy blood donors and from 614 patients scheduled to undergo resection for primary colorectal cancer. None of the patients received pre- and/or post-operative chemo- and/or radiotherapy. The results of sVEGF were analysed with respect to Dukes>> stage...... disease, who had comparable values. Patients with the primary tumour localized in the colon had significantly (Pprimary tumour localized in the rectum. By classifying the patients into two groups, based on the upper limit of the 95(th)percentile of s...

  15. The Dutch Vascular Factors in Dementia Study: rationale and design.

    Science.gov (United States)

    van Kooten, F; Bots, M L; Breteler, M M; Haverkate, F; van Swieten, J C; Grobbee, D E; Koudstaal, P J; Kluft, C

    1998-01-01

    Dementia is a rapidly increasing health problem in the industrialized countries. With the ageing of the population the number of demented persons increases both in relative and absolute terms. Obviously, there is a need for prevention and intervention strategies. We describe the methods and baseline findings of a large study aimed at identifying potentially modifiable vascular, thrombogenic, and metabolic determinants of dementia. The study population consists of subjects 55 years of age or older. Since the vascular wall of the cerebral vessels is different from that of the coronary or peripheral vessels, we formed three subgroups in which vascular risk factors for dementia are studied. Subjects with stroke were distinguished from subjects with coronary or peripheral artery disease, and from subjects without stroke or coronary or peripheral artery disease. To obtain a large enough number of subjects with stroke, cases and controls from a stroke registry were combined with cases and controls of a population-based study from the same region. For the diagnosis of dementia the DSM-III-R criteria were used. Extensive information on cardiovascular risk factors was collected, including indicators of atherosclerosis. Blood and urine were sampled to study platelet function and thrombogenic and metabolic factors. The study population consists of 7,466 subjects, of whom 300 were recruited from a hospital-based stroke registry. Coronary or peripheral artery disease was present in 956 subjects and stroke in 617. Dementia was present in 434 (5.8%) of all subjects. The prevalence of dementia was 3.0, 24.0, and 4.4% in subjects with a history of coronary or peripheral artery disease, a history of stroke, and subjects without a history of coronary or peripheral artery disease or stroke, respectively. The study will allow us to investigate the role of vascular factors in dementia, irrespective of its cause.

  16. Statin usage, vascular diagnosis and vascular risk factors in Parkinson's disease.

    Science.gov (United States)

    Cheng, Kelvin Kw; Swallow, Diane Ma; Grosset, Katherine A; Grosset, Donald G

    2017-08-01

    Background and aims Vascular disease is a common comorbidity in Parkinson's disease patients. Statins are potentially neuroprotective for Parkinson's disease through non-vascular mechanisms. We investigated prevailing statin use in a Parkinson's disease cohort. Methods and results Data on diagnostic indication for statins, anti-Parkinson therapy, vascular risk factors, and statin prescription, were obtained from electronic medical record review for consecutive Parkinson's disease patients. The ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network system was used to calculate future cardiovascular risk and identify those warranting statin use. Of 441 patients included, 59.9% were male, with a mean age of 68.9 years (standard deviation 10.3). One hundred and seventy-four (39.5%) patients had at least one diagnostic indication for statin use, of whom 136 (78.2%) were prescribed a statin. In the 267 (60.5%) cases without a diagnostic indication, 54 (20.2%) were excluded owing to age limitations defined in ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network. Of the remaining 213, 62 (29.1%) had an ASsessing cardiac risk using Scottish Intercollegiate Guidelines Network score in the recommended range for statin therapy, of whom 15 (24.1%) were prescribed statins. Conclusion There is suboptimal implementation of statin therapy in Parkinson's disease patients. Given the possible neuroprotective effects of statins in Parkinson's disease in addition to reducing cardiovascular risk, reasons for suboptimal implementation warrant further investigation.

  17. Vascular endothelial cadherin and vascular endothelial growth factor in periodontitis and smoking.

    Science.gov (United States)

    Sakallioğlu, E E; Sakallioğlu, U; Lütfioğlu, M; Pamuk, F; Kantarci, A

    2015-03-01

    This study investigated the vascularization in periodontal disease process via revealing: (i) vascular endothelial cadherin (VE-cadherin) and vascular endothelial growth factor (VEGF) productions in periodontitis and (ii) the impact of smoking on this phenomenon. Fifteen smokers and 15 non-smokers with/without periodontitis were allocated by split-mouth randomization regarding their smoking and periodontal statuses. The teeth with periodontitis in smokers (group 1), without periodontitis in smokers (group 2), with periodontitis in non-smokers (group 3), and without periodontitis in non-smokers (group 4) constituted the study groups. Gingival crevicular fluid (GCF) levels of VE-cadherin and VEGF were determined by ELISA to evaluate their profiles in the groups. There were increased VE-cadherin levels in groups 1 and 3 compared with groups 2 and 4 (P  0.05). There were no correlations between the VE-cadherin and VEGF levels in all groups (P > 0.05). The results suggest that VE-cadherin and VEGF may increase in periodontitis, and smoking may uniquely cause VE-cadherin production in GCF. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  18. Vascular endothelial growth factor (VEGF) expression in the lung in toxic septic shock.

    Science.gov (United States)

    Manoilescu, Irina; Teleman, S; Cojocaru, Elena; Mihăilă, Doina; Plămădeală, P

    2011-01-01

    The need for reasoning with medical evidence the different types of shock, especially when there are medical and legal implications, has determined the search of biological markers of the shock. In the case of toxic septic shock, the most important markers to be used are: the cytokines, the tumor necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6), procalcitonin, lactoferin and the vascular endothelial growth factor (VEGF). VEGF has an essential role in angiogenesis and vascular permeability. In our study group, we included 30 cases of different types of shock in which we studied the VEGF expression in the lungs. We added also 10 fragments of lung as control group. According to the etiology, the 30 cases of shock were: 15 with a toxic septic shock and 15 with a hemorrhagic shock. In all these cases we used the classical Hematoxylin and Eosin staining method and the immunohistochemical reactions for VEGF-A. Statistical analysis was performed using SPSS 13.0. The VEGF expression was decreased in all the cases of toxic septic shock, in the endothelium and also in the alveolar epithelium, compared to a high level of expression in other cases of shock and in the control lung. These data allow us to appreciate that VEGF has a different expression in different types of shock and in the normal lung. We observed a statistically significant difference between VEGF expression in toxic septic shock and hemorrhagic shock (p=0.000001). There is a similarity of VEGF expression between hemorrhagic shock and the control lungs (p=0.00001). An obviously low VEGF expression in the toxic septic shock represents a useful biological marker in the forensic medical cases.

  19. Decreased expression of serum and microvascular vascular endothelial growth factor receptor-2 in meningococcal sepsis*.

    NARCIS (Netherlands)

    Flier, M. van der; Baerveldt, E.M.; Miedema, A.; Hartwig, N.G.; Hazelzet, J.A.; Emonts, M.; Groot, R. de; Prens, E.P.; Vught, A.J. van; Jansen, N.J.

    2013-01-01

    OBJECTIVES: To determine the skin microvessel expression of vascular endothelial growth factor receptor 2 and serum-soluble vascular endothelial growth factor receptor 2 levels in children with meningococcal sepsis. DESIGN: Observational study. SETTING: Two tertiary academic children hospital PICUs.

  20. Docosapentaenoic acid (22:5, n-3) suppressed tube-forming activity in endothelial cells induced by vascular endothelial growth factor.

    Science.gov (United States)

    Tsuji, Masako; Murota, Se-itsu; Morita, Ikuo

    2003-05-01

    It is generally accepted that n-3 polyunsaturated fatty acids have beneficial effects on vascular homeostasis. Among the several functions of endothelial cells, angiogenesis contributes to tumor growth, inflammation, and microangiopathy. We have already demonstrated that eicosapentaenoic acid (EPA, 20:5, n-3) suppressed angiogenesis. In this paper, we examined the effect of docosapentaenoic acid (DPA, 22:5, n-3), an elongated metabolite of EPA, on tube-forming activity in bovine aortic endothelial cells (BAE cells) incubated between type I collagen gels. The pretreatment of BAE cells with DPA suppressed tube-forming activity induced by vascular endothelial growth factor (VEGF). The effect of DPA was stronger than those of EPA and docosahexaenoic acid (22:6, n-3). The migrating activity of endothelial cells stimulated with VEGF was also suppressed by DPA pretreatment. The treatment of BAE cells with DPA caused the suppression of VEGF receptor-2 (VEGFR-2, the kinase insert domain-containing receptor, KDR) expression in both plastic dish and collagen gel cultures. These data indicate that DPA has a potent inhibitory effect on angiogenesis through the suppression of VEGFR-2 expression.

  1. WISP-1 positively regulates angiogenesis by controlling VEGF-A expression in human osteosarcoma.

    Science.gov (United States)

    Tsai, Hsiao-Chi; Tzeng, Huey-En; Huang, Chun-Yin; Huang, Yuan-Li; Tsai, Chun-Hao; Wang, Shih-Wei; Wang, Po-Chuan; Chang, An-Chen; Fong, Yi-Chin; Tang, Chih-Hsin

    2017-04-13

    In recent years, much research has focused on the role of angiogenesis in osteosarcoma, which occurs predominantly in adolescents and young adults. The vascular endothelial growth factor-A (VEGF-A) pathway is the key regulator of angiogenesis and in osteosarcoma. VEGF-A expression has been recognized as a prognostic marker in angiogenesis. Aberrant WNT1-inducible signaling pathway protein-1 (WISP-1) expression is associated with various cancers. However, the function of WISP-1 in osteosarcoma angiogenesis is poorly understood. We demonstrate a positive correlation between WISP-1 and VEGF-A expression in human osteosarcoma. Moreover, we show that WISP-1 promotes VEGF-A expression in human osteosarcoma cells, subsequently inducing human endothelial progenitor cell (EPC) migration and tube formation. The focal adhesion kinase (FAK), Jun amino-terminal kinase (JNK), and hypoxia-inducible factor (HIF)-1α signaling pathways were activated after WISP-1 stimulation, while FAK, JNK, and HIF-1α inhibitors or small interfering RNA (siRNA) abolished WISP-1-induced VEGF-A expression and angiogenesis. In vitro and in vivo studies revealed down-regulation of microRNA-381 (miR-381) in WISP-1-induced VEGF-A expression and angiogenesis. Our findings reveal that WISP-1 enhances VEGF-A expression and angiogenesis through the FAK/JNK/HIF-1α signaling pathways, as well as via down-regulation of miR-381 expression. WISP-1 may be a promising target in osteosarcoma angiogenesis.

  2. The multitasking neutrophils and their involvement in angiogenesis.

    Science.gov (United States)

    Seignez, Cédric; Phillipson, Mia

    2017-01-01

    This review describes the mechanisms by which neutrophils contribute to angiogenesis in hypoxic tissues during different conditions and diseases (e.g., menstrual cycle, wound healing, ischemic diseases, cancers), with particular focus on the recently described proangiogenic neutrophil subpopulation. The importance of neutrophils in initiation of angiogenesis has been described during the past decade, and is believed to occur through release of the well-known proangiogenic factors Bv8, vascular endothelial growth factor A, and matrix metalloproteinase 9. However, additional proangiogenic actions of neutrophils have been outlined this year, mediated through for example pyruvate kinase M2, 14,15-epoxyeicosatrienoic acid, and formation of neutrophil extracellular traps, although their distinct mechanisms of action remain partly unknown. Neutrophils can also limit angiogenesis by secreting for example neutrophil elastase and α-defensins, which generate angiostatic molecules and proteolytically inactivate proangiogenic factors, respectively. These opposing neutrophil actions can be the consequence of on-site education or recruitment of distinct subpopulations from circulation. Indeed, a circulating proangiogenic neutrophil subpopulation was recently described in mice and men, which was rapidly recruited to hypoxic tissues by vascular endothelial growth factor A. These recent findings have highlighted the diversity of actions performed by neutrophils in the angiogenic process and identified new opportunities to regulate angiogenesis.

  3. Disruption of vascular homeostasis in patients with Kawasaki disease: Involvement of vascular endothelial growth factor and angiopoietins

    NARCIS (Netherlands)

    Breunis, Willemijn B.; Davila, Sonia; Shimizu, Chisato; Oharaseki, Toshiaki; Takahashi, Kei; van Houdt, Michel; Khor, Chiea Chuen; Wright, Victoria J.; Levin, Michael; Burns, Jane C.; Burgner, David; Hibberd, Martin L.; Kuijpers, Taco W.; Odam, Miranda; Christiansen, Frank; Witt, Campbell; Goldwater, Paul; Curtis, Nigel; Palasanthiran, Pamela; Ziegler, John; Nissan, Michael; Nourse, Clare; Kuipers, Irene M.; Ottenkamp, Jaap J.; Geissler, Judy; Tacke, Carline C. E.; Ng, Sarah B.; Li, Yi; Bonnard, Carine; Ling, Ling; Brogan, Paul; Klein, Nigel; Shah, Vanita; Dillon, Michael; Booy, Robert; Shingadia, Delane; Bose, Anu; Mukasa, Thomas; Tulloh, Robert; Michie, Colin; Shike, Hiroko; Nievergelt, Caroline M.; Schork, Nicholas J.; Newburger, Jane W.; Baker, Annette L.; Sundel, Robert P.; Rowley, Anne H.; Shulman, Stanford T.

    2012-01-01

    Objective In Kawasaki disease (KD), a pediatric vasculitis of medium-sized arteries, the coronary arteries are most commonly affected. Angiopoietins and vascular endothelial growth factor (VEGF) play an important role in maintaining vascular homeostasis. Recently, we identified ANGPT1 and VEGFA as

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

    Directory of Open Access Journals (Sweden)

    Mien V Hoang

    2010-10-01

    Full Text Available 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.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.These findings implicate VEGF-induction of calpain activity and impairment of cytoskeletal dynamics in the failure of VEGF-induced neovessels to form and

  5. Vascular endothelial growth factor (VEGFA gene variation in polycystic ovary syndrome in a Tunisian women population

    Directory of Open Access Journals (Sweden)

    Assila Ben Salem

    2016-10-01

    Full Text Available Abstract Background Polycystic ovary syndrome (PCOS is characterized by the growth of a number of small cysts on the ovaries which leads to sex hormonal imbalance. Women who are affected by this syndrome suffer from irregular menstrual cycles, decline in their fertility, excessive hair growth, obesity, acne and most importantly cardiac function problems. The vascular endothelial growth factor (VEGF plays a pivotal role in tissue vascularization in general and in the pathogenesis of many diseases. The PCOS was found to be associated with high expression levels of VEGF. In women who undergo assisted reproductive procedures (ART, VEGF was found to be a key mediator of other factors to control ovary angiogenesis. Here, we set out to examine the association of VEGFA gene polymorphism with PCOS and its components in a population of Tunisia women to enhance our understanding of the genetic background leading angiogenesis and vascularization abnormalities in PCOS. Methods The association of VEGFA gene with PCOS and its components was examined in a cohort of 268 women from Tunisia involving 118 PCOS patients and 150 controls. VEGFA gene variations were assessed through the analysis of the following SNPs rs699947 (A/C, rs833061 (C/T, rs1570360 (G/A, rs833068 (G/A, rs3025020 (C/T, and rs3025039 (C/T. The linkage disequilibrium between SNPs was assessed using HAPLOVIEW software while combination of SNPs into haplotypes in the population and the reconstruction of the cladogram were carried-out by PHASE and ARLEQUIN programs, respectively. Genetic association and genotype-phenotype correlations were calculated by logistic regression and non-parametric tests (Kruskall-Wallis and Mann–Whitney tests, respectively, using StatView program. Results We observed 10 haplotypes in our studied cohort whereH1 (ACGG, H2 (ACAG, H7 (CTGG and H8 (CTGA were the most frequent. We observed the association of the genotype CT of the SNP rs30225039 with PCOS phenotype (P = 0

  6. Anatomical specificity of vascular endothelial growth factor expression in glioblastomas: a voxel-based mapping analysis

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Xing [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); Wang, Yinyan [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); Capital Medical University, Department of Neuropathology, Beijing Neurosurgical Institute, Beijing (China); Wang, Kai; Ma, Jun; Li, Shaowu [Capital Medical University, Department of Neuroradiology, Beijing Tiantan Hospital, Beijing (China); Liu, Shuai [Chinese Academy of Medical Sciences and Peking Union Medical College, Departments of Neurosurgery, Peking Union Medical College Hospital, Beijing (China); Liu, Yong [Chinese Academy of Sciences, Brainnetome Center, Institute of Automation, Beijing (China); Jiang, Tao [Capital Medical University, Department of Neurosurgery, Beijing Tiantan Hospital, Beijing (China); Beijing Academy of Critical Illness in Brain, Department of Clinical Oncology, Beijing (China)

    2016-01-15

    The expression of vascular endothelial growth factor (VEGF) is a common genetic alteration in malignant gliomas and contributes to the angiogenesis of tumors. This study aimed to investigate the anatomical specificity of VEGF expression levels in glioblastomas using voxel-based neuroimaging analysis. Clinical information, MR scans, and immunohistochemistry stains of 209 patients with glioblastomas were reviewed. All tumor lesions were segmented manually and subsequently registered to standard brain space. Voxel-based regression analysis was performed to correlate the brain regions of tumor involvement with the level of VEGF expression. Brain regions identified as significantly associated with high or low VEGF expression were preserved following permutation correction. High VEGF expression was detected in 123 (58.9 %) of the 209 patients. Voxel-based statistical analysis demonstrated that high VEGF expression was more likely in tumors located in the left frontal lobe and the right caudate and low VEGF expression was more likely in tumors that occurred in the posterior region of the right lateral ventricle. Voxel-based neuroimaging analysis revealed the anatomic specificity of VEGF expression in glioblastoma, which may further our understanding of genetic heterogeneity during tumor origination. This finding provides primary theoretical support for potential future application of customized antiangiogenic therapy. (orig.)

  7. [Expression of vascular endothelial growth factor in different breast tissues and clinical significance thereof].

    Science.gov (United States)

    Xu, Wei-Guo; Wang, Gang; Liu, Yang; Zou, Yu-Huan; Song, Ji-Ning; Yang, Xiao-Qing; Wang, Wen-Ya

    2008-03-25

    To investigate the differences in the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) count in breast benign affection, breast atypical hyperplasia, and breast carcinoma in situ and to clarify the association of VEGF expression and MVD with the clinicopathological features of these diseases. Immunohistochemistry (SP-method) was used to examine the expression of VEGF and MVD count in 100 samples of breast benign affection (including 35 cases of breast fibroid tumor, 35 cases of breast cystic hyperplasia, and 30 cases of intraductal papilloma), and 15 samples of breast atypical hyperplasia, and 25 samples of breast carcinoma in situ, obtained during operation. The positive rate of VEGF of the breast carcinoma in situ group was 56% , significantly higher than hose of the breast benign affection and breast atypical hyperplasia groups (22% and 33% respectively, P breast fibroid tumor, breast cystic hyperplasia, and intraductal papilloma (all P > 0.05). The MVD value of the breast carcinoma in situ group was 20.1 +/- 6.1, significantly higher than those of the breast benign affection group and breast atypical hyperplasia groups (14.3 +/- 3. 5 and 18.5 +/- 3.6 respectively, both P breast fibroid tumor, breast cystic hyperplasia, and intraductal papilloma (all P > 0.05). In breast tumors, angiogenesis is probably mediated mainly by VEGF. The occurrence and progression of breast cancer may be related with the expression of VEGF.

  8. Expression of Vascular Endothelial Growth Factor in Nasal Polyp and Chronic Rhinosinusitis.

    Science.gov (United States)

    Azizzadeh Delshad, Alireza; Jalali Nadoushan, Mohammadreza; Davati, Ali; Rostami, Aida

    2016-01-01

    Nasal inflammatory disorders such as chronic rhinosinusitis and nasal polyp are among the most prevalent complications with high socioeconomic costs. Vascular Endothelial Growth Factor (VEGF) plays a key role in angiogenesis and cell proliferation. In the present study the effect of VEGF on the development and prognosis of chronic rhinosinusitis and nasal polyp was investigated. This cross sectional study was performed on the nasal histological specimens of two groups of patients suffering from nasal polyp or chronic rhinosinusitis, and the expression of VEGF in the two groups was compared immunohistochemically. Based on the percentage of VEGF-positive cells the specimens were classified into four scores. Furthermore, the relations between the VEGF expression and some demographic characteristics were evaluated. The VEGF immunohistochemistry findings indicated a significantly higher expression of VEGF in nasal polyp group compared to chronic rhinosinusitis without nasal polyp group. In terms of VEGF-expression scoring, in both groups most of the specimens were classified as score-2, namely indicating 10-50% of VEGF-positive epithelial cells. In both groups no significant relation between VEGF expression and age or sex of the patients could be seen. Local modulation of VEGF expression might be taken as a putative therapeutic strategy in management of sinunasal inflammatory disorders, especially nasal polyps.

  9. Melasma treatment: A novel approach using a topical agent that contains an anti-estrogen and a vascular endothelial growth factor inhibitor.

    Science.gov (United States)

    Cohen, Philip R

    2017-04-01

    Melasma is an acquired disorder of pigmentation that presents with asymptomatic symmetric darkening of the face. The pathogenesis of this condition is multifactorial and influenced by several factors including female sex hormones, genetic predisposition and ultraviolet light exposure. The management of melasma is usually directed at more than one of the causative etiologic factors and often incorporates a combination of topical agents, with or without the addition of physical modalities. Estrogen and angiogenesis are significant factors in the etiology of melasma. A useful addition to the therapeutic armentarium for treating melasma would include a topical agent that could effect both of these causative factors. Specifically, a topical preparation consisting of an anti-estrogen and a vascular endothelial growth factor inhibitor would accomplish this goal. Suitable candidates that target estrogen receptors and vascular endothelial growth factor are currently used in medical oncology as systemic antineoplastic agents. The anti-estrogen could be either a selective estrogen receptor modulator (such as tamoxifen or raloxifene) or an aromatase inhibitor (such as anastrozole or letrozole or exemestane). The vascular endothelial growth factor inhibitor would be bevacizumab. In conclusion, a novel-topically administered-therapy for melasma would combine an anti-estrogen and a vascular endothelial growth factor inhibitor. Copyright © 2017 Elsevier Ltd. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Quantification of vascular endothelial growth factor and neuropilins mRNAs during rat brain maturation by real-time PCR.

    Science.gov (United States)

    Adris, Soraya; Ojeda, Elizabeth; Genero, Mario; Argibay, Pablo

    2005-09-01

    1. Vascular endothelial growth factor (VEGF) has been related with several brain functions such as angiogenesis, neuroprotection, and neurogenesis. 2. We studied the mRNA expression of the two most important isoforms of VEGF (VEGF120 and VEGF164) as well as one type of VEGF receptors, neuropilins (NRP), during maturation in the rat brain using real-time PCR. 3. Today, real-time PCR is the method of choice for rapid and reliable quantification of mRNA transcription. 4. VEGF120 has little changes in its expression between P5 and P30. 5. However, VEGF164 increased its expression 2-folds at P15 in comparison to P5, remaining at this level in the adult brain (P30). 6. Both types of NRP, NRP-1 and NRP-2, which only bind VEGF164, increased their expression about 2-folds only at P30, at levels similar to those observed for VEGF164.

  12. Diabetes and other vascular risk factors for dementia : Which factor matters most? A systematic review

    NARCIS (Netherlands)

    Kloppenborg, Raoul P.; van den Berg, Esther; Kappelle, L. Jaap; Biessels, Geert Jan

    2008-01-01

    Vascular risk factors, such as type 2 diabetes, hypertension, obesity and dyslipidaemia often co-occur. Each of these factors has been associated with an increased risk of dementia, but it is uncertain which factor imposes the greatest risk. Moreover, the effect of age at time of exposure may differ

  13. Cognitive impairment after cerebrovascular stroke: Relationship to vascular risk factors

    Directory of Open Access Journals (Sweden)

    Eman M Khedr

    2009-02-01

    Full Text Available Eman M Khedr1, Sherifa A Hamed1, Hala K El-Shereef2, Ola A Shawky1, Khalid A Mohamed1, Effat M Awad3, Mohamed A Ahmed2, Ghaydaa A Shehata1, Mahmoud A Eltahtawy41Department of Neurology and Psychiatry, 2Department of Internal Medicine, 3Department of Physiology, 4Department of Clinical Pathology, Assiut University, Faculty of Medicine, Assiut, EgyptBackground: Cognitive decline after cerebrovascular stroke has adverse outcome consequences. Since some vascular causes can be prevented and treated, the identification of stroke-related cognitive impairment is a challenge. Patients with cognitive impairment and vascular diseases exhibit higher homocysteine (Hcy concentrations. Whether Hcy is an independent risk factor for cognitive impairment after stoke is still in question. The objectives of this study were to determine: 1 the relative frequency of first-ever post-stroke dementia (PSD (three months after onset in a consecutive sample of our population, 2 the risk factors associated with PSD, and 3 the relationship between Hcy levels and PSD.Methods: Eighty-one inpatients with first-ever stroke were prospectively evaluated with a neuropsychological battery and event-related evoked potentials (P300 at onset and then after three months. A wide range of demographic, clinical, radiological and laboratory variables were examined. PSD was diagnosed if the clinical presentation fulfilled DSM-IV criteria of vascular dementia, the patient scored ≤21 on Mini Mental State Examination (MMSE and ≤67 points on Cognitive Abilities Screening Instruments (CASI.Results: PSD was diagnosed in 21%. PSD was significantly associated with increasing age, low levels of education, large sized and lacunar infarctions, severity of stroke, prolonged P300 latency, smoking, hypertension, and elevated Hcy levels. High Hcy levels increased the odds ratio of PSD after adjustment of significantly relevant variables including age, smoking, size of infarction, and carotid stenosis

  14. Effects of hyperthyroidism on expression of vascular endothelial growth factor (VEGF) and apoptosis in fetal adrenal glands.

    Science.gov (United States)

    Karaca, T; Hulya Uz, Y; Karabacak, R; Karaboga, I; Demirtas, S; Cagatay Cicek, A

    2015-11-26

    This study investigated the expression of vascular endothelial growth factor (VEGF), vascular density, and apoptosis in fetal rat adrenal glands with hyperthyroidism in late gestation. Twelve mature female Wistar albino rats with the same biological and physiological features were used for this study. Rats were divided into two groups: control and hyperthyroidism. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (250 μg/kg) before pregnancy for 21 days and during pregnancy. Rats in the control and hyperthyroidism groups were caged according to the number of male rats. Zero day of pregnancy (Day 0) was indicated when the animals were observed to have microscopic sperm in vaginal smears. Pregnant rats were sacrificed on the 20th day of pregnancy; blood from each animal was collected to determine the concentrations of maternal adrenocorticotropic hormone and thyroxine. Rat fetuses were then quickly removed from the uterus, and the adrenal glands of the fetuses were dissected. VEGF expression, vascular density, and apoptosis were analyzed in fetal rat adrenal glands. Maternal serum levels of the adrenocorticotropic hormone and free thyroxine were significantly higher in the hyperthyroidism group than in the control group. Immunohistochemistry revealed that the number of VEGF positive cells and vessel density significantly increased in the hyperthyroidism rat fetal adrenal group compared with the control group. Hyperthyroidism did not change the fetal and placental weights and the number of fetuses. This study demonstrates that hyperthyroidism may have an effect on the development of rat adrenal glands mediated by VEGF expression, angiogenesis, and apoptosis.

  15. In vitro effects of waterpipe smoke condensate on endothelial cell function: a potential risk factor for vascular disease.

    Science.gov (United States)

    Rammah, Mayyasa; Dandachi, Farah; Salman, Rola; Shihadeh, Alan; El-Sabban, Marwan

    2013-05-23

    Despite its increasing popularity, little is known about the health effects of waterpipe smoking (WPS), particularly on the cardiovascular system. To investigate the role of WPS as a risk factor for vascular disease, we evaluated its effect on endothelial cell function, which is an early event in vascular disease pathogenesis. We assessed the changes in cell viability, ROS generation, inflammatory and vasodilatory markers and in vitro angiogenesis of human aortic endothelial cells in response to waterpipe smoke condensate exposure. Mainstream waterpipe smoke condensate (WSC) was generated using a standard laboratory machine protocol. Compared to control, WSC induced cell cycle arrest, apoptosis, and oxidative stress in human primary endothelial cells. In addition, we assayed for impaired endothelium-dependent vasodilation and induced inflammation by studying the effect of WPS on the content and activity of AMPK, eNOS proteins and NF-κB p65 ser536 phosphorylation, respectively. WSC inhibited AMPK/eNOS phosphorylation and induced phosphorylation of p65. Moreover, we evaluated endothelial cells repair mechanism related properties that include migration/invasion and in vitro tube formation upon treatment with WSC. WSC reduced the motility and inhibited angiogenic potential of HAEC cells. WPS induced endothelial cell dysfunction as evident by exerting oxidative stress, inflammation, and impaired endothelial vasodilatory function and repair mechanisms. All together these data provide evidence for the potential contribution of WPS to endothelial dysfunction and thus to vascular disease. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  16. The original Pathologische Anatomie Leiden-Endothelium monoclonal antibody recognizes a vascular endothelial growth factor binding site within neuropilin-1.

    Science.gov (United States)

    Jaalouk, Diana E; Ozawa, Michael G; Sun, Jessica; Lahdenranta, Johanna; Schlingemann, Reinier O; Pasqualini, Renata; Arap, Wadih

    2007-10-15

    For two decades, the antigen recognized by the Pathologische Anatomie Leiden-Endothelium (PAL-E) monoclonal antibody, a standard vascular endothelial cell marker, has remained elusive. Here, we used a combinatorial phage display-based approach ("epitope mapping") to select peptides binding to the original PAL-E antibody. We found that a subset of the selected panel of peptides had motifs with strong homology to an exposed site within the b1 domain of human neuropilin-1 (NRP-1). We confirmed peptide binding by ELISA and by surface plasmon resonance. We also showed that the PAL-E antigen colocalizes with NRP-1 staining in endothelial cells. Crystal structure of the b1 domain in NRP-1 suggests that the PAL-E binding site overlaps with a vascular endothelial growth factor (VEGF) binding site. Taken together, these results indicate that NRP-1 is an endothelial cell antigen recognized by the true PAL-E antibody. The consistent biochemical, morphologic, and functional features between the PAL-E antigen and NRP-1 support our interpretation. Given that NRP-1 is a VEGF receptor, these results explain the attributes of the PAL-E antibody as a marker of vascular permeability and angiogenesis.

  17. Depressive symptoms, vascular risk factors, and Alzheimer's disease.

    Science.gov (United States)

    Luchsinger, José A; Honig, Lawrence S; Tang, Ming-Xin; Devanand, Devangere P

    2008-09-01

    Depressive symptoms in the elderly are associated with an increased Alzheimer's disease (AD) risk. We sought to determine whether the association between depressive symptoms and AD is explained by a history of vascular risk factors and stroke. Five hundred and twenty-six elderly persons from New York City without dementia at baseline were followed for a mean of 5 years. Depressive symptoms were assessed using the 17-item Hamilton Depression Rating Scale (HAM). Incident AD was ascertained using standard criteria. Diabetes, hypertension, heart disease, current smoking and stroke were ascertained by self-report. Proportional hazards regression was used to relate HAM scores to incident AD. HAM scores were higher in persons with hypertension, heart disease, and stroke, which in turn were related to higher AD risk. AD risk increased with increasing HAM scores as a continuous logarithmically transformed variable (HR for one point increase=1.4; 95% CI=1.1,1.8) and as a categorical variable (HR for HAM >or= 10=3.4; 95% CI=1.5,8.1; p for trend=0.004 with HAM=0 as the reference). These results were virtually unchanged after adjustment for vascular risk factors and stroke, individually (HR for HAM >or= 10=3.4; 95% CI=1.5,8.1; p for trend = 0.004), and in a composite measure (HR for HAM >or= 10=3.0; 95% CI=1.2,7.8; p for trend=0.02). The prospective relation between depressive symptoms and AD is not explained by a history of vascular risk factors and stroke, suggesting that other mechanisms may account for this association.

  18. 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.

  19. Vascular endothelial growth factor receptor-2 inhibitor cediranib causes regression of endometriotic lesions in a rat model

    Science.gov (United States)

    Liu, Fang; Wang, Li; Zhang, Xian-Xia; Min, Shu-Yun; Liu, Yi-Xuan; Zuo, Zhi; Jin, Zhi-Xing; Zhu, Zhi-Ling

    2015-01-01

    Vascular endothelial growth factor (VEGF) receptor-2 plays an essential role in angiogenesis, and it also expressed in the glandular epithelium and stromal cells of ectopic endometrium. Cediranib is a protein tyrosine kinase inhibitor that potently inhibits VEGF receptor-2, but there is no study about its effects on the endometriosis. We induced endometriosis on both sides of the abdominal wall in 20 female Sprague-Dawley rats and randomly divided them into 2 groups. They were administered: cediranib 4 mg/kg/day (group 1), equal saline (group 2) for 12 days. Then, the lesion volumes were calculated, and Masson trichrome was used to detect fibrosis. Angiogenesis was evaluated by CD-31 immunohistochemistry and serum VEGF levels. Proliferation was indicated by proliferating cell nuclear antigen immunohistochemistry. Apoptosis was measured by a TUNEL assay and cleaved caspase-3 immunohistochemistry. In the treatment group, the lesion volumes were smaller (P < 0.05), and the degree of fibrosis was greater. The microvessel density was lower (P < 0.05) than control, however, serum VEGF was up-regulated by a negative feedback mechanism (P < 0.01). In addition, proliferation was significantly suppressed (P < 0.01), and apoptosis in the lesions was more obvious in the treatment group. These data indicated that cediranib can inhibit development of endometriotic lesions in rats. PMID:25973002

  20. Vascular endothelial growth factor receptor-3 expression in mycosis fungoides

    DEFF Research Database (Denmark)

    Pedersen, Ida Holst; Willerslev-Olsen, Andreas; Vetter-Kauczok, Claudia

    2012-01-01

    Here, we have studied vascular endothelial growth factor receptor-3 (VEGFR-3) expression in mycosis fungoides (MF), the most common type of cutaneous T-cell lymphoma (CTCL). Immunohistochemistry revealed that in two-thirds of 34 patients, VEGFR-3 was expressed in situ by both tumor and stromal...... cells irrespective of the disease stage. The natural VEGFR-3 ligand, VEGF-C, partially protected malignant T-cell lines from growth inhibition by the histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA). Whereas the malignant T cells did not produce VEGF-C in vitro, its expression...

  1. Intrauterine growth restriction and placental angiogenesis

    Directory of Open Access Journals (Sweden)

    Harma Muge

    2010-04-01

    Full Text Available Abstract Background Vascular endothelial growth factor (VEGF, basic-fibroblast growth factor (b-FGF, and endothelial nitric oxide synthase (eNOS are factors that take part in placental angiogenesis. They are highly expressed during embryonic and fetal development, especially in the first trimester. In this study, we aimed to investigate the role of placental angiogenesis in the development of intrauterine growth restriction (IUGR by comparing the levels of expression of VEGF-A, b-FGF, and eNOS in normal-term pregnancy and IUGR placentas. Methods The expression of VEGF-A, b-FGF, and eNOS was studied using the avidin-biotin-peroxidase method in placental tissues diagnosed as normal (n = 55 and IUGR (n = 55. Results were evaluated in a semi-quantitative manner. Results The expression of all the markers was significantly higher (p Conclusion Increased expression of VEGF-A, b-FGF, and eNOS may be the result of inadequate uteroplacental perfusion, supporting the proposal that abnormal angiogenesis plays a role in the pathophysiology of IUGR.

  2. Grateloupia longifolia polysaccharide inhibits angiogenesis by downregulating tissue factor expression in HMEC-1 endothelial cells.

    Science.gov (United States)

    Zhang, Chao; Yang, Fan; Zhang, Xiong-Wen; Wang, Shun-Chun; Li, Mei-Hong; Lin, Li-Ping; Ding, Jian

    2006-07-01

    1. The antiangiogenic and antitumor properties of Grateloupia longifolia polysaccharide (GLP), a new type of polysaccharide isolated from the marine alga, were investigated with several in vitro and in vivo models. Possible mechanisms underlying its antiangiogenic activity were also assessed. 2. GLP dose-dependently inhibited proliferation of human microvascular endothelial cells (HMEC-1) and human umbilical vein endothelial cells (HUVEC), with IC50 values of 0.86 and 0.64 mg ml(-1), respectively. In tube formation and cell migration assays using HMEC-1 cells, noncytotoxic doses of GLP significantly inhibited formation of intact tube networks and reduced the number of migratory cells. Inhibition by GLP was VEGF-independent. 3. In the chick chorioallantoic membrane (CAM) assay, GLP (2.5 microg egg(-1)) reduced new vessel formation compared with the vehicle control. GLP (0.1 mg plug(-1)) also reduced the vessel density in Matrigel plugs implanted in mice. 4. The levels of pan and phosphorylated receptors for VEGF, VEGFR-1 (flt-1) and VEGFR-2 (KDR) were not significantly altered by 5 mg ml(-1) GLP treatment of HMEC-1, although tissue factor (TF) showed significant decreases at both mRNA and protein levels following GLP treatment. 5. In mice bearing sarcoma-180 cells, intravenous administration of GLP (200 mg kg(-1)) decreased tumor weight by 52% without obvious toxicity. Vascular density in sections of the tumor was reduced by 64% after GLP treatment. 6. Collectively, these results indicate that GLP has antitumor properties, associated at least, in part, with the antiangiogenesis induced by downregulation of TF.

  3. A nanomedicine approach to effectively inhibit contracture during bladder acellular matrix allograft-induced bladder regeneration by sustained delivery of vascular endothelial growth factor.

    Science.gov (United States)

    Xiong, Qianwei; Lin, Houwei; Hua, Xiaolin; Liu, Li; Sun, Ping; Zhao, Zhen; Shen, Xiaowei; Cui, Daxiang; Xu, Maosheng; Chen, Fang; Geng, Hongquan

    2015-01-01

    Macroscopic evidence of contracture has been identified as a major issue during the regeneration process. We hypothesize that lack of angiogenesis is the primary cause of contracture and explore a nanomedicine approach to achieve sustained release of vascular endothelial growth factor (VEGF) to stimulate angiogenesis. We evaluate the efficacy of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) for long-term (3 months) sustained release of VEGF in bladder acellular matrix allografts (BAMA) in a swine model. We anticipate that the sustained release of VEGF could stimulate angiogenesis along the regeneration process and thereby inhibit contracture. Bladder was replaced with BAMA (5×5 cm), modified with PLGA NPs encapsulated with VEGF in a pig model. The time points chosen for sampling were 1, 2, 4, and 12 weeks. The regenerated areas were then measured to obtain the contracture rate, and the extent of revascularization was calculated using histological and morphological features. In the control group of animals, the bladder was replaced with only BAMA. The in vivo release of VEGF was evident for ∼3 months, achieving the goal of long-acting sustained release, and successfully promoted the regeneration of blood vessels and smooth muscle fibers. In addition, less collagen deposition was observed in the experimental group compared with control. Most importantly, the inhibition of contracture was highly significant, and the ultimate contracture rate decreased by ∼57% in the experimental group compared with control. In isolated strips analysis, there were no significant differences between BAMA-regenerated (either VEGF added or not) and autogenous bladder. BAMA modified with VEGF-loaded PLGA-NPs can sustainably release VEGF in vivo (>3 months) to stimulate angiogenesis leading to the inhibition of contracture. This is the first study to report a viable nanomedicine-based strategy to overcome contracture during bladder regeneration induced by BAMA. Furthermore

  4. Modulatory effect of gastric pentadecapeptide BPC 157 on angiogenesis in muscle and tendon healing.

    Science.gov (United States)

    Brcic, L; Brcic, I; Staresinic, M; Novinscak, T; Sikiric, P; Seiwerth, S

    2009-12-01

    Angiogenesis is a natural and complex process controlled by angiogenic and angiostatic molecules, with a central role in healing process. One of the most important modulating factors in angiogenesis is the vascular endothelial growth factor (VEGF). Pentadecapeptide BPC 157 promotes healing demonstrating particular angiogenic/angiomodulatory potential. We correlated the angiogenic effect of BPC 157 with VEGF expression using in vitro (cell culture) and in vivo (crushed muscle and transected muscle and tendon) models. Results revealed that there is no direct angiogenic effect of BPC 157 on cell cultures. On the other hand, immunohistochemical analysis of muscle and tendon healing using VEGF, CD34 and FVIII antibodies showed adequately modulated angiogenesis in BPC 157 treated animals, resulting in a more adequate healing. Therefore the angiogenic potential of BPC 157 seems to be closely related to the healing process in vivo with BPC 157 stimulating angiogenesis by up-regulating VEGF expression.

  5. Adipose Extracellular Matrix/Stromal Vascular Fraction Gel Secretes Angiogenic Factors and Enhances Skin Wound Healing in a Murine Model

    Directory of Open Access Journals (Sweden)

    Mingliang Sun

    2017-01-01

    Full Text Available Mesenchymal stem cells are an attractive cell type for cytotherapy in wound healing. The authors recently developed a novel, adipose-tissue-derived, injectable extracellular matrix/stromal vascular fraction gel (ECM/SVF-gel for stem cell therapy. This study was designed to assess the therapeutic effects of ECM/SVF-gel on wound healing and potential mechanisms. ECM/SVF-gel was prepared for use in nude mouse excisional wound healing model. An SVF cell suspension and phosphate-buffered saline injection served as the control. The expression levels of vascular endothelial growth factor (VEGF, basic fibroblast growth factor (bFGF, and monocyte chemotactic protein-1 (MCP-1 in ECM/SVF-gel were analyzed at different time points. Angiogenesis (tube formation assays of ECM/SVF-gel extracts were evaluated, and vessels density in skin was determined. The ECM/SVF-gel extract promoted tube formation in vitro and increased the expression of the angiogenic factors VEGF and bFGF compared with those in the control. The expression of the inflammatory chemoattractant MCP-1 was high in ECM/SVF-gel at the early stage and decreased sharply during the late stage of wound healing. The potent angiogenic effects exerted by ECM/SVF-gel may contribute to the improvement of wound healing, and these effects could be related to the enhanced inflammatory response in ECM/SVF-gel during the early stage of wound healing.

  6. VEGF(165) and bFGF protein-based therapy in a slow release system to improve angiogenesis in a bioartificial dermal substitute in vitro and in vivo

    NARCIS (Netherlands)

    Wilcke, I.; Lohmeyer, J. A.; Liu, S.; Condurache, A.; Krueger, S.; Mailaender, P.; Machens, H. G.

    Background Angiogenesis can be enhanced by several growth factors, like vascular endothelial growth factor-165 (VEGF(165)) and basic fibroblast growth factor (bFGF). Delayed release of such growth factors could be provided by incorporation of growth factors in fibrin matrices. In this study, we

  7. CCL2-dependent infiltrating macrophages promote angiogenesis in progressive liver fibrosis

    NARCIS (Netherlands)

    Ehling, Josef; Bartneck, Matthias; Wei, Xiao; Gremse, Felix; Fech, Viktor; Möckel, Diana; Baeck, Christer; Hittatiya, Kanishka; Eulberg, Dirk; Luedde, Tom; Kiessling, Fabian; Trautwein, Christian; Lammers, Twan Gerardus Gertudis Maria; Tacke, Frank

    2014-01-01

    Objectives In chronic liver injury, angiogenesis, the formation of new blood vessels from pre-existing ones, may contribute to progressive hepatic fibrosis and to development of hepatocellular carcinoma. Although hypoxia-induced expression of vascular endothelial growth factor (VEGF) occurs in

  8. Kruppel-like factor 2 inhibit the angiogenesis of cultured human liver sinusoidal endothelial cells through the ERK1/2 signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Xiao-Qing, E-mail: zeng.xiaoqing@zs-hospital.sh.cn [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Li, Na, E-mail: Linala.2009@163.com [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Pan, Du-Yi, E-mail: lasikesmi@hotmail.com [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Miao, Qing, E-mail: sadsadvenus@163.com [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Ma, Gui-Fen, E-mail: ma.guifen@zs-hospital.sh.cn [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Liu, Yi-Mei, E-mail: liuyimei1988@163.com [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Tseng, Yu-Jen, E-mail: dianatseng14@gmail.com [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Li, Feng, E-mail: li.feng2@zs-hospital.sh.cn [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Xu, Li-Li, E-mail: xu.lili3@zs-hospital.sh.cn [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Chen, Shi-Yao, E-mail: chen.shiyao@zs-hospital.sh.cn [Department of Gastroenterology of Zhongshan Hospital, Fudan University, Shanghai (China); Institute of Endoscopic Research of Zhongshan Hospital, Fudan University, Shanghai (China)

    2015-09-04

    Kruppel-like factor 2 (KLF2) is a crucial anti-angiogenic factor. However, its precise role in hepatic angiogenesis induced by liver sinusoidal endothelial cells (LSECs) remain unclear. This study was aimed to evaluate the effect of KLF2 on angiogenesis of LSECs and to explore the corresponding mechanism. Cultured human LSECs were infected with different lentiviruses to overexpress or suppress KLF2 expression. The CCK-8 assay, transwell migration assay and tube formation test, were used to investigate the roles of KLF2 in the proliferation, migration and vessel tube formation of LSECs, respectively. The expression and phosphorylation of ERK1/2 were detected by western blot. We discovered that the up-regulation of KLF2 expression dramatically inhibited proliferation, migration and tube formation in treated LSECs. Correspondingly, down-regulation of KLF2 expression significantly promoted proliferation, migration and tube formation in treated LSECs. Additionally, KLF2 inhibited the phosphorylation of ERK1/2 pathway, followed by the function of KLF2 in the angiogenesis of LSECs disrupted. In conclusion, KLF2 suppressed the angiogenesis of LSECs through inhibition of cell proliferation, migration, and vessel tube formation. These functions of KLF2 may be mediated through the ERK1/2 signaling pathway. - Highlights: • Overexpression of KLF2 inhibits the proliferation and migration of LSECs. • Overexpression of KLF2 inhibits the angiogenesis of LSECs. • ERK1/2 signaling pathway involved in the anti-angiogenic process of KLF2 on LSECs.

  9. The Angiogenic Makeup of Human Hepatocellular Carcinoma Does Not Favor Vascular Endothelial Growth Factor/Angiopoletin-Driven Sprouting Neovascularization

    NARCIS (Netherlands)

    Zeng, Wenjiao; Gouw, Annette S. H.; van den Heuvel, Marius C.; Zwiers, Peter J.; Zondervan, Pieter E.; Poppema, Sibrand; Zhang, Nong; Platteel, Inge; de Jong, Koert P.; Molema, Grietje

    2008-01-01

    Quantitative data on the expression of multiple factors that control angiogenesis in hepatocellular carcinoma (HCC) are limited. A better understanding of the mechanisms underlying angiogenesis in HCC will improve the rational choice of anti-angiogenic treatment. We quantified gene and protein

  10. 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

    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...

  11. Curcumol Promotes Vascular Endothelial Growth Factor (VEGF)-Mediated Diabetic Wound Healing in Streptozotocin-Induced Hyperglycemic Rats.

    Science.gov (United States)

    Zhou, Jie; Ni, Maowei; Liu, Xia; Ren, Zeming; Zheng, Zhiguo

    2017-01-31

    BACKGROUND Wound healing in chronic diabetic mellitus is mainly associated with the management of angiogenesis. The angiogenic mechanism of vascular endothelial growth factor (VEGF) has been widely studied in the context of diabetic ulcers. The aim of this study was to investigate the wound-healing potential of curcumol in streptozotocin-induced diabetic rats. MATERIAL AND METHODS Sixty male SD (Sprague Dawley) rats were purchased and randomly assigned into four groups: a control group and a model group treated with blank ointment, a high-dose curcumol group, and a low-dose curcumol group. The number of animals in each group was 15. Diabetes was induced by an intraperitoneal injection of streptozotocin. Two cutaneous wounds were incised at the dorsal region of all the experimental animals. Wound healing was assessed for all animal groups by observing the rate of wound closure. The expression of VEGF at the wound sites was studied by immunohistochemical staining to evaluate the vascular endothelial cell reaction. VEGF protein and related mRNA levels were analyzed by Western blotting and RT-PCR (reverse transcription-polymerase chain reaction). RESULTS Curcumol treatment significantly increased the rates of wound closure in treated animals, and hence wound healing was drastically enhanced for treatment groups compared to control groups. Histological observations and related mRNA and protein levels showed a higher VEGF expression in the treatment groups. CONCLUSIONS Our analyses clearly suggested that the observed enhancement in wound healing as a result of curcumol administration was attributable to VEGF-mediated angiogenesis.

  12. CARACTERIZACIÓN DE LOS FACTORES DE RIESGO VASCULAR EN PACIENTES ADULTOS / Characterization of vascular risk factors in adult patients

    Directory of Open Access Journals (Sweden)

    Estrella M. Hernández Hurtado

    2013-07-01

    Full Text Available Resumen: Introducción: La elevada prevalencia de factores de riesgo vascular en la población y su relación con el desarrollo de la cardiopatía isquémica representan un problema de salud pública. Objetivo: Caracterizar estos factores en adultos. Método: Se realizó un estudio observacional, descriptivo, transversal en pacientes que asistieron a la consulta de riesgo vascular del municipio de Ranchuelo, en Villa Clara, entre abril de 2010 y abril de 2011. La información se procesó con el programa SPSS versión 15.0. Se estimaron estadígrafos de tendencia central y dispersión para variables cuantitativas, y las cualitativas se resumieron mediante frecuencias absolutas y porcentajes. Resultados: Los principales factores de riesgo identificados fueron: hipertensión arterial (85,7 %, obesidad (81,1 %, diabetes mellitus (61,9 % y hábito de fumar (52,4 %. El 42,9 % presentó cuatro factores de riesgo asociados al momento del diagnóstico. El hábito de fumar fue el que mostró asociación significativa con la cardiopatía isquémica (p=0.04. Conclusiones: Los principales factores de riesgo identificados fueron: hipertensión arterial, obesidad, diabetes mellitus y hábito de fumar. Predominó la tendencia de asociación entre ellos, y fue frecuente la presencia de varios factores en un mismo paciente. Se encontró una asociación significativa entre el hábito de fumar y la presencia de cardiopatía isquémica. / Abstract: Introduction: The high prevalence of vascular risk factors in the population and its relationship to the development of ischemic heart disease represent a public health problem. Objective: To characterize these risk factors in adults. Method: An observational, descriptive, transversal study was conducted in patients who were treated at the outpatient vascular risk consultation in the municipality of Ranchuelo, Villa Clara, from April 2010 to April 2011. The information was processed using SPSS software, version 15

  13. Xenon decreases cell migration and secretion of a pro-angiogenesis factor in breast adenocarcinoma cells: comparison with sevoflurane.

    Science.gov (United States)

    Ash, S A; Valchev, G I; Looney, M; Ni Mhathuna, A; Crowley, P D; Gallagher, H C; Buggy, D J

    2014-07-01

    While volatile agents have been implicated in metastasis-enhancing effects on cancer cells, the effects of xenon are unknown. We investigated xenon- and sevoflurane-mediated effects on migration and expression of angiogenesis biomarkers in human breast adenocarcinoma cells. MDA-MB-231 and MCF-7 cells were exposed to xenon 70% with O2 25%, CO2 5%; control gas containing O2 25%, CO2 5%, N2 70%; or sevoflurane 2.5 vol% administered in O2 60%, N2 37%, or control gas. Cell viability was determined by the MTT assay. Migration at 24 h was determined using the Oris™ Cell Migration Assay. Secretion of angiogenesis factors was measured using a membrane-based immunoassay array. Xenon reduced MDA-MB-231 migration to 59 (13%) after 1-h exposure (P=0.02), 64 (10%) after 3 h (P=0.01), and 71 (9%) after 5 h (P=0.04) compared with control gas, without affecting viability. Similarly, MCF-7 migration was significantly reduced at all timepoints [to 58 (12%) at 1 h, 65 (12%) at 3 h, and 65% (12%) at 5 h]. Sevoflurane did not affect migration when delivered in control gas. Glycine, an N-methyl-d-aspartate receptor co-agonist, antagonized the effects of xenon on migration. Expression of the pro-angiogenesis factor regulated on activation, normal T cell expressed and secreted (RANTES) was reduced in conditioned medium from xenon-exposed MDA-MB-231 cells compared with cells exposed to either control gas or sevoflurane [mean dot density 2.0 (0.2) compared with 3.0 (0.1) and 3.1 (0.3), respectively (P=0.02)]. Xenon, but not sevoflurane, inhibited migration in both oestrogen receptor positive and negative breast adenocarcinoma cells. Furthermore, xenon decreased release of the pro-angiogenic factor RANTES from MDA-MB-231 cells. © The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Angiogenesis, proteases and angiogenic factors during the inception of pregnancy. Crucial contributors or trivial bystanders?

    NARCIS (Netherlands)

    Plaisier, Geertruida Maria

    2008-01-01

    Vascularised, receptive endometrium is essential for implantation and for the success of the embryo-maternal interaction. Disturbances in vascular development may play an important role in frequently occurring pathologies during pregnancy, such as early pregnancy wastage, pre-eclampsia and

  15. CXCL12 enhances angiogenesis through CXCR7 activation in human umbilical vein endothelial cells

    OpenAIRE

    ZHANG Min; Qiu, Lisha; Zhang, Yanyan; Xu, Dongsheng; Zheng, Jialin C.; Jiang, Li

    2017-01-01

    Angiogenesis is the process by which new vessels form from existing vascular networks. Human umbilical vein endothelial cells (HUVECs) may contribute to the study of vascular repair and angiogenesis. The chemokine CXCL12 regulates multiple cell functions, including angiogenesis, mainly through its receptor CXCR4. In contrast to CXCL12/CXCR4, few studies have described roles for CXCR7 in vascular biology, and the downstream mechanism of CXCR7 in angiogenesis remains unclear. The results of the...

  16. MicroRNA expression profile in endometriosis: its relation to angiogenesis and fibrinolytic factors.

    Science.gov (United States)

    Braza-Boïls, Aitana; Marí-Alexandre, Josep; Gilabert, Juan; Sánchez-Izquierdo, Dolors; España, Francisco; Estellés, Amparo; Gilabert-Estellés, Juan

    2014-05-01

    Could an aberrant microRNA (miRNA) expression profile be responsible for the changes in the angiogenic and fibrinolytic states observed in endometriotic lesions? This study revealed characteristic miRNA expression profiles associated with endometriosis in endometrial tissue and endometriotic lesions from the same patient and their correlation with the most important angiogenic and fibrinolytic factors. WHAT IS ALREADY KNOWN?: An important role for dysregulated miRNA expression in the pathogenesis of endometriosis is well documented. However, to the best of our knowledge, there are no reports of the relationship between angiogenic and fibrinolytic factors and miRNAs when endometrial tissue and different types of endometriotic lesions from the same patient are compared. Case-control study that involved 51 women with endometriosis and 32 women without the disease (controls). The miRNA expression profiles were determined using the GeneChip miRNA 2.0 Affymetrix array platform, and the results were analysed using Partek Genomic Suite software. To validate the obtained results, 12 miRNAs differentially expressed were quantified by using miRCURY LNA™ Universal RT microRNA PCR. Levels of vascular endothelial growth factor (VEGF-A), thrombospondin-1 (TSP-1), urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) proteins were quantified by ELISA. Patient endometrial tissue showed significantly lower levels of miR-202-3p, miR-424-5p, miR-449b-3p and miR-556-3p, and higher levels of VEGF-A and uPA than healthy (control) endometrium. However, tissue affected by ovarian endometrioma showed significantly lower expression of miR-449b-3p than endometrium from both controls and patients, and higher levels of PAI-1 and the angiogenic inhibitor TSP-1. A significant inverse correlation between miR-424-5p and VEGF-A protein levels was observed in patient endometrium, and an inverse correlation between miR-449b-3p and TSP-1 protein levels was observed in

  17. Immunohistochemical expression of sex steroid hormone receptors, cell cycle regulators and angiogenesis factors in intraductal papillary mucinous neoplasms: an explorative study.

    Science.gov (United States)

    Georgiadou, Despoina; Sergentanis, Theodoros N; Sakellariou, Stratigoula; Filippakis, George M; Zagouri, Flora; Psaltopoulou, Theodora; Lazaris, Andreas C; Patsouris, Efstratios; Gounaris, Antonia; Zografos, George C

    2015-02-01

    The objectives of our explorative study were to (i) evaluate the immunohistochemical expression of sex steroid hormone receptors (estrogen receptor a [ERα], estrogen receptor β [ERβ], progesterone receptor [PR] and androgen receptor [AR]), angiogenesis factors (vascular endothelial growth factor [VEGF] and inhibitor of differentiation/DNA synthesis 1 [Id-1]) and cell-cycle regulators (cyclin D1, p16 and p27) in intraductal papillary mucinous neoplasms (IPMNs) in comparison to normal adjacent pancreatic tissues and (ii) assess their correlation with the grade and histological sub-type of those lesions. Paraffin-embedded specimens from 12 consecutive patients with IPMNs were immunostained for the studied markers and staining quantification was assessed by an image analysis system. AR H-score and cyclin D1 H-score were significantly higher in the IPMN lesions (0.86±0.33 vs. 0.57±0.12 in the normal tissue, p=0.010 and 0.47±0.23 vs. 0.21±0.20 in the normal tissue, p=0.019, respectively). No significant differences were noted regarding the expression of ERα, ERβ, PR, p16, p27, VEGF, Id-1 or MVD. Moreover, no significant associations were found between the expression of studied markers and grade or histological subtype. Our study showed higher expression of AR and cyclin D1 in IPMNs compared to normal pancreatic ducts without any association between AR and cyclin D1 expression and IPMNs' grade or subtype. Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. OVEREXPRESSION OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND THE DEVELOPMENT OF POST-TRANSPLANTATION CANCER

    Science.gov (United States)

    Basu, Aninda; Contreras, Alan G.; Datta, Dipak; Flynn, Evelyn; Zeng, Liling; Cohen, Herbert T.; Briscoe, David M.; Pal, Soumitro

    2009-01-01

    Cancer is an increasing and major problem following solid organ transplantation. In part, the increased cancer risk is associated with the use of immunosuppressive agents, especially calcineurin inhibitors. We propose that the effect of calcineurin inhibitors on the expression of vascular endothelial growth factor (VEGF) leads to an angiogenic milieu that favors tumor growth. Here, we used 786-0 human renal cancer cells to investigate the effect of Cyclosporine (CsA) on VEGF expression. Utilizing a full-length VEGF promoter-luciferase construct, we found that CsA markedly induced VEGF transcriptional activation through the PKC signaling pathway, specifically involving PKCζ and PKCδ isoforms. Moreover, CsA promoted the association of PKCζ and PKCδ with the transcription factor Sp1 as observed by immunoprecipitation assays. Using promoter deletion constructs, we found that CsA-mediated VEGF transcription was primarily Sp1-dependent. Furthermore, CsA-induced and PKC-Sp1-mediated VEGF transcriptional activation was partially inhibited by pVHL. CsA also promoted the progression of human renal tumors in vivo, where VEGF is overexpressed. Finally, to evaluate the in vivo significance of CsA-induced VEGF overexpression in terms of post-transplantation tumor development, we injected CT26 murine carcinoma cells (known to form angiogenic tumors) into mice with fully MHC mismatched cardiac transplants. We observed that therapeutic doses of CsA increased tumor size, VEGF mRNA expression, and also enhanced tumor angiogenesis. However, co-administration of a blocking anti-VEGF antibody inhibited this CsA-mediated tumor growth. Collectively, these findings define PKC-mediated VEGF transcriptional activation as a key component in the progression of CsA-induced post-transplantation cancer. PMID:18632621

  19. Vascular access complications and risk factors in hemodialysis ...

    African Journals Online (AJOL)

    Tarek A. Ghonemy

    2015-08-18

    Aug 18, 2015 ... Abstract Background: Morbidity related to vascular access is the leading cause of hospitalization for chronic hemodialysis patients and is associated with high cost. Since data on vascular access complications are scarce, this study was designed to focus on vascular access complications in hemodialysis ...

  20. Vascular access complications and risk factors in hemodialysis ...

    African Journals Online (AJOL)

    Background: Morbidity related to vascular access is the leading cause of hospitalization for chronic hemodialysis patients and is associated with high cost. Since data on vascular access complications are scarce, this study was designed to focus on vascular access complications in hemodialysis patients. Methods: 119 ...

  1. 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.

  2. Improvement of insulin sensitivity in response to exercise training in type 2 diabetes mellitus is associated with vascular endothelial growth factor A expression.

    Science.gov (United States)

    Wagner, Henrik; Fischer, Helene; Degerblad, Marie; Alvarsson, Michael; Gustafsson, Thomas

    2016-09-01

    Insulin sensitivity changes in response to exercise training demonstrate a large variation. Vascular endothelial growth factor A could promote increased insulin sensitivity through angiogenesis. We investigated associations between changes in expression of key genes and insulin sensitivity, aerobic capacity and glycaemic control following exercise training in diabetes mellitus type 2. Subjects with diabetes mellitus type 2 underwent 12 weeks of structured exercise. Euglycaemic clamp, exercise test and HbA1c were performed. Muscle biopsies were obtained for mRNA expression. A total of 16 subjects completed the study. Change in vascular endothelial growth factor A expression was positively associated with an increase in insulin sensitivity (p = 0.004) and with a decrease in HbA1c (p = 0.034). Vascular endothelial growth factor A receptor-1 expression showed similar associations. The variation in physical adaptation to exercise training in diabetes mellitus type 2 was associated with changes in expression of vascular endothelial growth factor A in muscle. This difference in induced gene expression could contribute to the variation in exercise training effects on insulin sensitivity. Measures of capillary blood flow need to be assessed in future studies. © The Author(s) 2016.

  3. Angiogenesis Inhibitors

    Science.gov (United States)

    ... blood vessels “feed” growing tumors with oxygen and nutrients , allowing the cancer cells to invade nearby tissue , to move throughout ... any angiogenesis inhibitors currently being used to treat cancer in humans? Yes. The U.S. Food and Drug Administration (FDA) has approved bevacizumab to ...

  4. Granulocyte-macrophage colony-stimulating factor increases tumor growth and angiogenesis directly by promoting endothelial cell function and indirectly by enhancing the mobilization and recruitment of proangiogenic granulocytes.

    Science.gov (United States)

    Zheng, Qiaowei; Li, Xueqian; Cheng, Xiaoliang; Cui, Ting; Zhuo, Yingcheng; Ma, Wenbin; Zhao, Xue; Zhao, Peipei; Liu, Xuanlin; Feng, Weiyi

    2017-02-01

    Granulocyte-macrophage colony-stimulating factor has been widely used as an adjuvant therapy for cancer patients exhibiting myelosuppression induced by chemotherapy or radiotherapy. However, the effects of granulocyte-macrophage colony-stimulating factor on tumor growth, as well as its precise mechanism, are still controversial due to inconsistent evidence. This study investigated the effect of exogenous granulocyte-macrophage colony-stimulating factor on the growth of B16 melanoma, S180 sarcoma, and U14 cervical carcinoma in mice. The angiogenesis and recruitment of bone-marrow-derived cells were analyzed in tumor tissues. Interactions among granulocyte-macrophage colony-stimulating factor, bone-marrow-derived cells, and B16 tumor cells were investigated in vitro. Proangiogenic types of bone-marrow-derived cells in blood were assessed both in vivo and in vitro. The results showed that granulocyte-macrophage colony-stimulating factor markedly facilitated the growth of B16 and S180 tumors, but not U14 tumors. Granulocyte-macrophage colony-stimulating factor increased the densities of blood vessels and the number of bone-marrow-derived cells in B16 tumor tissues. The granulocyte-macrophage colony-stimulating factor-induced enhancement of tumor cell proliferation was mediated by bone-marrow-derived cells in vitro. Meanwhile, a distinct synergistic effect on endothelial cell function between granulocyte-macrophage colony-stimulating factor and bone-marrow-derived cells was observed. After separating two types of bone-marrow-derived cells, granulocyte-macrophage colony-stimulating factor-induced enhancement of tumor growth and angiogenesis in vivo was mediated by proangiogenic cells in granulocytes, but not monocytes, with CD11b+, vascular endothelial growth factor receptor 2, and C-X-C chemokine receptor 4 granulocytes possibly involved. These data suggest that granulocyte-macrophage colony-stimulating factor contributes to the growth and angiogenesis of certain types

  5. 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.

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

    Science.gov (United States)

    Liu, Gang; Qutub, Amina A; Vempati, Prakash; Mac Gabhann, Feilim; Popel, Aleksander S

    2011-04-04

    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. 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. 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.

  7. Antiangiogenic therapy in lung cancer: focus on vascular endothelial growth factor pathway.

    LENUS (Irish Health Repository)

    Korpanty, Grzegorz

    2010-01-01

    Lung cancer (LC) is a leading cause of death worldwide. Recent advances in chemotherapeutic agents have not yielded any significant improvement in the prognosis of patients with LC. The five-year survival rate for all combined disease stages remains about 15%. For this reason, new therapies such as those that inhibit tumor angiogenesis or block activity of growth factor receptors are of special interest in this group of patients. In this review we will summarize the most recent clinical data on biologic therapies that inhibit tumor angiogenesis in LC, focusing on those that are most clinically relevant.

  8. COX-2 – A Novel Target for Reducing Tumor Angiogenesis and Metastasis | Center for Cancer Research

    Science.gov (United States)

    Angiogenesis is essential for tumor growth and metastasis, by supplying a steady stream of nutrients, removing waste, and providing tumor cells access to other sites in the body. The vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) play a key role in tumor-mediated angiogenesis, and this pathway is the target of monoclonal antibodies and tyrosine kinase inhibitors (TKIs) that have been approved to treat patients with cancer. Unfortunately, tumors can use alternative angiogenesis mechanisms to escape VEGF pathway blockade, but these alternate pathways are not well understood. Brad St. Croix, Ph.D., of CCR’s Mouse Cancer Genetics Program, along with Lihong Xu, Ph.D., a Postdoctoral Fellow in the St. Croix laboratory, and colleagues set out to identify VEGF-independent mediators of tumor angiogenesis.

  9. Wound healing gene therapy: cartilage regeneration induced by vascular endothelial growth factor plasmid

    Czech Academy of Sciences Publication Activity Database

    Kološtová, K.; Taltynov, O.; Pintérová, D.; Boubelík, M.; Raška, O.; Hozák, Pavel; Jirkovská, M.; Bobek, V.

    2012-01-01

    Roč. 33, č. 1 (2012), s. 68-74 ISSN 0196-0709 Institutional research plan: CEZ:AV0Z50520514 Keywords : BALB/c mouse strain * significant angiogenesis * cartilage repair * phVEGF(165) injection Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 1.228, year: 2012

  10. Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability.

    NARCIS (Netherlands)

    Pickkers, P.; Sprong, T.; Eijk, L.T. van; Hoeven, J.G. van der; Smits, P.; Deuren, M. van

    2005-01-01

    Meningococcal septic shock is an important cause of morbidity and mortality in children and young adults worldwide and is the prototypical gram-negative septic shock. One of the key factors in the development of shock is increased microvascular permeability. Vascular endothelial growth factor (VEGF)

  11. Transcription factor KLF6 upregulates expression of metalloprotease MMP14 and subsequent release of soluble endoglin during vascular injury.

    Science.gov (United States)

    Gallardo-Vara, Eunate; Blanco, Francisco J; Roqué, Mercè; Friedman, Scott L; Suzuki, Toru; Botella, Luisa M; Bernabeu, Carmelo

    2016-04-01

    After endothelial injury, the transcription factor Krüppel-like factor 6 (KLF6) translocates into the cell nucleus to regulate a variety of target genes involved in angiogenesis, vascular repair and remodeling, including components of the membrane transforming growth factor beta (TGF-β) receptor complex such as endoglin and activin receptor-like kinase 1. The membrane metalloproteinase 14 (MMP14 or MT1-MMP) targets endoglin to release soluble endoglin and is involved in vascular inflammation and endothelial tubulogenesis. However, little is known about the regulation of MMP14 expression during vascular wounding. In vitro denudation of monolayers of human endothelial cell monolayers leads to an increase in the KLF6 gene transcriptional rate, followed by an upregulation of MMP14 and release of soluble endoglin. Concomitant with this process, MMP14 co-localizes with endoglin in the sprouting endothelial cells surrounding the wound border. MMP14 expression at mRNA and protein levels is increased by ectopic KLF6 and downregulated by KLF6 suppression in cultured endothelial cells. Moreover, after wire-induced endothelial denudation, Klf6 (+/-) mice show lower levels of MMP14 in their vasculature compared with their wild-type siblings. Ectopic cellular expression of KLF6 results in an increased transcription rate of MMP14, and chromatin immunoprecipitation assays show that KLF6 interacts with MMP14 promoter in ECs, this interaction being enhanced during wound healing. Furthermore, KLF6 markedly increases the transcriptional activity of different reporter constructs of MMP14 gene promoter. These results suggest that KLF6 regulates MMP14 transcription and is a critical player of the gene expression network triggered during endothelial repair.

  12. 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....

  13. Repression of Vascular Endothelial Growth Factor Expression by the Runt-Related Transcription Factor 1 in Acute Myeloid Leukemia

    NARCIS (Netherlands)

    ter Elst, Arja; Ma, Bin; Scherpen, Frank J. G.; de Jonge, Hendrik J. M.; Douwes, Jenny; Wierenga, Albertus T. J.; Schuringa, Jan Jacob; Kamps, Willem A.; de Bont, Eveline S. J. M.

    2011-01-01

    VEGFA is considered one of the most important regulators of tumor-associated angiogenesis in cancer. In acute myeloid leukemia (AML) VEGFA is an independent prognostic factor for reduced overall and relapse-free survival. Transcriptional activation of the VEGFA promoter, a core mechanism for VEGFA

  14. 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.

  15. 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.

    Science.gov (United States)

    Woolf, Eric C; Curley, Kara L; Liu, Qingwei; Turner, Gregory H; Charlton, Julie A; Preul, Mark C; Scheck, Adrienne C

    2015-01-01

    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.

  16. Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer

    Directory of Open Access Journals (Sweden)

    Kim Wun-Jae

    2011-04-01

    Full Text Available Abstract Background Most bladder cancer patients experience lymphatic metastasis in the course of disease progression, yet the relationship between lymphangiogenesis and lymphatic metastasis is not well known. The aim of this study is to elucidate underlying mechanisms of how expanded lymphatic vessels and tumor microenvironment interacts each other and to find effective therapeutic options to inhibit lymphatic metastasis. Results The orthotopic urinary bladder cancer (OUBC model was generated by intravesical injection of MBT-2 cell lines. We investigated the angiogenesis, lymphangiogenesis, and CD11b+/CD68+ tumor-associated macrophages (TAM by using immunofluorescence staining. OUBC displayed a profound lymphangiogenesis and massive infiltration of TAM in primary tumor and lymphatic metastasis in lymph nodes. TAM flocked near lymphatic vessels and express higher levels of VEGF-C/D than CD11b- cells. Because VEGFR-3 was highly expressed in lymphatic vascular endothelial cells, TAM could assist lymphangiogenesis by paracrine manner in bladder tumor. VEGFR-3 expressing adenovirus was administered to block VEGF-C/D signaling pathway and clodronate liposome was used to deplete TAM. The blockade of VEGF-C/D with soluble VEGF receptor-3 markedly inhibited lymphangiogenesis and lymphatic metastasis in OUBC. In addition, the depletion of TAM with clodronate liposome exerted similar effects on OUBC. Conclusion VEGF-C/D are the main factors of lymphangiogenesis and lymphatic metastasis in bladder cancer. Moreover, TAM plays an important role in these processes by producing VEGF-C/D. The inhibition of lymphangiogenesis could provide another therapeutic target to inhibit lymphatic metastasis and recurrence in patients with invasive bladder cancer.

  17. Dynamic changes of serum vascular endothelial growth factor levels in a rat myocardial infarction model.

    Science.gov (United States)

    Yin, R; Feng, J; Yao, Z

    2000-09-01

    To investigate the dynamic changes of serum vascular endothelial growth factor (VEGF) levels in a rat model of acute myocardial infarction. Eighty-eight adult male Sprague-Dawley rats weighing approximately 270 g we used in this study. Eighty rats were subjected to left coronary artery ligation, with 8 rats for each different duration of infarct. Eight sham-operated animals in which the left coronary artery was surgically exposed without ligation were used as controls. Blood samples were drawn from the right atrium before (sham animals) and 1, 3, 6, 12, 24 h and 2, 3, 5, 7, 14 d after myocardial infarction. The concentrations of serum VEGF were measured by a sensitive enzyme-linked imosorbent assay with a rabbit polyclonal antibody specific for VEGF. In the 8 control animals, the mean concentration of serum VEGF was 66.99 +/- 17.83 pg/ml. Six hours after myocardial infarction, the level of serum VEGF significantly increased to 125.68 +/- 28.07 pg/ml (P < 0.01 vs x sham controls), and reached a peak (240.61 +/- 70.63 pg/ml. P < 0.01 vs x sham animals) at 24 h after ligation and then decreased gradually over the remaining 2 weeks. However, the level remained significantly elevated for 14 d (107.64 +/- 30.13 pg/ml, P < 0.01 vs x sham controls). The present study shows that the levels of serum VEGF are markedly increased until 14 d in the rat model of acute myocardial infarction. The increased serum VEGF level may play an important role in the angiogenesis associated with myocardial infarction.

  18. Effect of medical nutrition combined with exercise intervention on the placental ischemic hypoxic injury and serum angiogenesis factors in patients with gestational hypertension

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    Liang-Hui Hu

    2017-08-01

    Full Text Available Objective: To discuss the effect of medical nutrition combined with exercise intervention on the placental ischemic hypoxic injury and serum angiogenesis factors in patients with gestational hypertension. Methods: A total of 90 patients with gestational hypertension who received antenatal care and gave birth in our hospital between July 2014 and July 2016 were collected and divided into control group and observation group according to random number table, 45 cases in each group. Control group of patients received routine therapy, observation group of patients received routine therapy + nutrition combined with exercise intervention, and the ischemic hypoxic injury index expression in placenta tissue and serum angiogenesis factor levels before delivery were compared between two groups of patients. Results: After intervention, ischemic hypoxic injury index NO level in placental grinding fluid of observation group was higher than that of control group while ET-1, HIF-1α, Bax, Caspase-3 and MDA levels were lower than those of control group; serum angiogenesis factors TGFβ1, HGF, bFGF, VEGF and Ang-2 levels were significantly higher than those of control group while sFlt-1 level was lower than that of control group. Conclusion: The combination of medical nutrition and exercise can effectively reduce the placental ischemic hypoxic injury and reduce the angiogenesis in patients with gestational hypertension.

  19. Vascular Endothelial Growth Factor, Irradiation, and Axitinib Have Diverse Effects on Motility and Proliferation of Glioblastoma Multiforme Cells

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    Reinhardt Krcek

    2017-08-01

    Full Text Available Glioblastoma multiforme (GBM is the most common primary brain tumor. It is highly aggressive with an unfavorable prognosis for the patients despite therapies including surgery, irradiation, and chemotherapy. One important characteristic of highly vascularized GBM is the strong expression of vascular endothelial growth factor (VEGF. VEGF has become a new target in the treatment of GBM, and targeted therapies such as the VEGF-receptor blocker axitinib are in clinical trials. Most studies focus on VEGF-induced angiogenesis, but only very few investigations analyze autocrine or paracrine effects of VEGF on the tumor cells. In this study, we examined the impact of VEGF, irradiation, and axitinib on cell proliferation and cell motility in human GBM cell lines U-251 and U-373. VEGF receptor 2 was shown to be expressed within both cell lines by using PCR and immunochemistry. Moreover, we performed 24-h videography to analyze motility, and a viability assay for cell proliferation. We observed increasing effects of VEGF and irradiation on cell motility in both cell lines, as well as strong inhibiting effects on cellular motility by VEGF-receptor blockade using axitinib. Moreover, axitinib diminished irradiation induced accelerating effects. While VEGF stimulation or irradiation did not affect cell proliferation, axitinib significantly decreased cell proliferation in both cell lines. Therefore, the impairment of VEGF signaling might have a crucial role in the treatment of GBM.

  20. In vitro stimulation of vascular endothelial growth factor by borate-based glass fibers under dynamic flow conditions.

    Science.gov (United States)

    Chen, Sisi; Yang, Qingbo; Brow, Richard K; Liu, Kun; Brow, Katherine A; Ma, Yinfa; Shi, Honglan

    2017-04-01

    Bioactive borate glass has been recognized to have both hard and soft tissue repair and regeneration capabilities through stimulating both osteogenesis and angiogenesis. However, the underlying biochemical and cellular mechanisms remain unclear. In this study, dynamic flow culturing modules were designed to simulate the micro-environment near the vascular depletion and hyperplasia area in wound-healing regions, thus to better investigate the mechanisms underlying the biocompatibility and functionality of borate-based glass materials. Glass fibers were dosed either upstream or in contact with the pre-seeded cells in the dynamic flow module. Two types of borate glasses, doped with (1605) or without (13-93B3) CuO and ZnO, were studied along with the silicate-based glass, 45S5. Substantial fiber dissolution in cell culture medium was observed, leading to the release of ions (boron, sodium and potassium) and the deposition of a calcium phosphate phase. Different levels of vascular endothelial growth factor secretion were observed from cells exposed to these three glass fibers, and the copper/zinc containing borate 1605 fibers exhibited the most positive influence. These results indicate that dynamic studies of in vitro bioactivity provide useful information to understand the in vivo response to bioactive borate glasses. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. MDA-9/syntenin and IGFBP-2 promote angiogenesis in human melanoma.

    Science.gov (United States)

    Das, Swadesh K; Bhutia, Sujit K; Azab, Belal; Kegelman, Timothy P; Peachy, Leyla; Santhekadur, Prasanna K; Dasgupta, Santanu; Dash, Rupesh; Dent, Paul; Grant, Steven; Emdad, Luni; Pellecchia, Maurizio; Sarkar, Devanand; Fisher, Paul B

    2013-01-15

    Melanoma differentiation-associated gene-9 (mda-9/syntenin) encodes an adapter scaffold protein whose expression correlates with and mediates melanoma progression and metastasis. Tumor angiogenesis represents an integral component of cancer metastasis prompting us to investigate a possible role of mda-9/syntenin in inducing angiogenesis. Genetic (gain-of-function and loss-of-function) and pharmacologic approaches were used to modify mda-9/syntenin expression in normal immortal melanocytes, early radial growth phase melanoma, and metastatic melanoma cells. The consequence of modifying mda-9/syntenin expression on angiogenesis was evaluated using both in vitro and in vivo assays, including tube formation assays using human vascular endothelial cells, chorioallantoic membrane (CAM) assays and xenograft tumor animal models. Gain-of-function and loss-of-function experiments confirm that MDA-9/syntenin induces angiogenesis by augmenting expression of several proangiogenic factors/genes. Experimental evidence is provided for a model of angiogenesis induction by MDA-9/syntenin in which MDA-9/syntenin interacts with the extracellular matrix (ECM), activating Src and FAK resulting in activation by phosphorylation of Akt, which induces hypoxia inducible factor 1-α (HIF-1α). The HIF-1α activates transcription of insulin growth factor-binding protein-2 (IGFBP-2), which is secreted thereby promoting angiogenesis and further induces endothelial cells to produce and secrete VEGF-A augmenting tumor angiogenesis. Our studies delineate an unanticipated cell nonautonomous function of MDA-9/syntenin in the context of angiogenesis, which may directly contribute to its metastasis-promoting properties. As a result, targeting MDA-9/syntenin or its downstream-regulated molecules may provide a means of simultaneously impeding metastasis by both directly inhibiting tumor cell transformed properties (autonomous) and indirectly by blocking angiogenesis (nonautonomous).

  2. Assessment of angiogenic factor, vascular endothelial growth factor, serum and urine level changes in superficial bladder tumor immunotherapy by intravesical Bacillus Calmette-Guerin

    Directory of Open Access Journals (Sweden)

    Kerigh Behzad

    2010-01-01

    Full Text Available Background and Aim: Bladder tumor is one of the most common genitourinary tumors. Management of non-muscle invasive (NMI bladder tumors is primarily by transurethral resection (TURBT followed by intravesical immunotherapy or chemotherapy. Bacillus Calmette-Guerin (BCG is the most effective adjuvant therapy in NMI bladder tumor. Since angiogenesis is an essential factor in solid tumor progression and vascular endothelial growth factor (VEGF is an important factor in angiogenesis, the aim of this study is the assessment of angiogenic factor, VEGF, serum and urine level changes in superficial bladder tumor immunotherapy by intravesical BCG. Materials and Methods: A total of 23 patients with bladder transitional cell carcinoma (TCC in stage Ta/T1 or carcinoma insitu (CIS, low or high grade, which passed a 2-4 week period from TURBT participated in this study. Blood and urine samples were obtained at first and sixth sessions before instillation of BCG. Enzyme-linked immunosorbent assay (ELISA method was used to obtain VEGF level in samples. Results: Urine and serum VEGF levels did not change significantly before and after BCG therapy. Changes in VEGF level were significantly different neither in low grade against high grade tumors nor in stage T1 against stage Ta tumors. A significant difference in VEGF level was seen between low grade and high grade tumors in serum after BCG therapy (P=0.007; but not in urine samples. Conclusion: Although intravesical BCG possesses anti-angiogenic activity, it seems that it exerts its effect through pathways other than VEGF, especially in low grade tumors.

  3. Camel milk inhibits inflammatory angiogenesis via downregulation of proangiogenic and proinflammatory cytokines in mice.

    Science.gov (United States)

    Alhaider, Abdulqader A; Abdel Gader, Abdel Galil M; Almeshaal, Nawaf; Saraswati, Sarita

    2014-07-01

    Camel milk has traditionally been used to treat cancer, but this practice awaits scientific scrutiny, in particular its role in tumor angiogenesis, the key step involved in tumor growth and metastasis. We aimed to investigate the effects of camel milk on key components of inflammatory angiogenesis in sponge implant angiogenesis model. Polyester-polyurethane sponges, used as a framework for fibrovascular tissue growth, were implanted in Swiss albino mice and camel milk (25, 50 and 100 mg/kg/day) was administered for 14 days through installed cannula. The implants collected at day 14 post-implantation were processed for the assessment of hemoglobin (Hb), myeloperoxidase (MPO), N-acetylglucosaminidase (NAG), and collagen, which were used as indices for angiogenesis, neutrophil, and macrophage accumulation and extracellular matrix deposition, respectively. Relevant inflammatory, angiogenic, and fibrogenic cytokines were also determined. Camel milk treatment attenuated the main components of the fibrovascular tissue, wet weight, vascularization (Hb content), macrophage recruitment (NAG activity), collagen deposition and the levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, IL-17, tumor necrosis factor-α, and transforming growth factor-β. A regulatory function of camel milk on multiple parameters of the main components of inflammatory angiogenesis has been revealed, giving insight into the potential therapeutic benefit underlying the anti-cancer actions of camel milk. © 2013 APMIS. Published by John Wiley & Sons Ltd.

  4. TRAF6 inhibits proangiogenic signals in endothelial cells and regulates the expression of vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Bruneau, Sarah; Datta, Dipak; Flaxenburg, Jesse A.; Pal, Soumitro [Transplantation Research Center, Division of Nephrology, Department of Medicine, Children' s Hospital Boston, Boston, MA (United States); Department of Pediatrics, Harvard Medical School, Boston, MA (United States); Briscoe, David M., E-mail: david.briscoe@childrens.harvard.edu [Transplantation Research Center, Division of Nephrology, Department of Medicine, Children' s Hospital Boston, Boston, MA (United States); Department of Pediatrics, Harvard Medical School, Boston, MA (United States)

    2012-03-02

    Highlights: Black-Right-Pointing-Pointer TNF-receptor associated factors (TRAFs) function in the angiogenesis response. Black-Right-Pointing-Pointer TRAF6 regulates basal and inducible expression of VEGF in endothelial cells (EC). Black-Right-Pointing-Pointer TRAF6 is an endogenous inhibitor of EC proliferation and migration in EC. Black-Right-Pointing-Pointer TRAF6 inhibits VEGF expression in part via its ability to regulate Src signaling. -- Abstract: TNF-family molecules induce the expression Vascular Endothelial Growth Factor (VEGF) in endothelial cells (EC) and elicit signaling responses that result in angiogenesis. However, the role of TNF-receptor associated factors (TRAFs) as upstream regulators of VEGF expression or as mediators of angiogenesis is not known. In this study, HUVEC were cotransfected with a full-length VEGF promoter-luciferase construct and siRNAs to TRAF 1, -2, -3, -5, -6, and promoter activity was measured. Paradoxically, rather than inhibiting VEGF expression, we found that knockdown of TRAF6 resulted in a 4-6-fold increase in basal VEGF promoter activity compared to control siRNA-transfected EC (P < 0.0001). In addition, knockdown of TRAF 1, -2, -3 or -5 resulted in a slight increase or no change in VEGF promoter activation. Using [{sup 3}H]thymidine incorporation assays as well as the in vitro wound healing assay, we also found that basal rates of EC proliferation and migration were increased following TRAF6 knockdown; and this response was inhibited by the addition of a blocking anti-VEGF antibody into cell cultures. Using a limited protein array to gain insight into TRAF6-dependent intermediary signaling responses, we observed that TRAF6 knockdown resulted in an increase in the activity of Src family kinases. In addition, we found that treatment with AZD-0530, a pharmacological Src inhibitor, reduced the regulatory effect of TRAF6 knockdown on VEGF promoter activity. Collectively, these findings define a novel pro-angiogenic signaling

  5. Development of functional fibrous matrices for the controlled release of basic fibroblast growth factor to improve therapeutic angiogenesis.

    Science.gov (United States)

    Kim, Min Sup; Bhang, Suk-Ho; Yang, Hee Seok; Rim, Nae Gyune; Jun, Indong; Kim, Sun I; Kim, Byung-Soo; Shin, Heungsoo

    2010-10-01

    In this study, novel fibrous matrices were developed as a depot to store and liberate growth factors in a controlled manner. Specifically, heparin was covalently conjugated onto the surface of fibrous matrices (composites of poly[caprolactone] and gelatin crosslinked with genipin), and basic fibroblast growth factor (bFGF) was then reversibly immobilized. The immobilization of bFGF was controlled as a function of the amount of conjugated heparin. The sustained release of bFGF from the fibrous matrices was successfully achieved over 4 weeks whereas physical adsorption of bFGF released quickly. The bFGF released from the fibrous matrices significantly enhanced in vitro proliferation of human umbilical vein endothelial cells. From the in vivo study, the group implanted with a higher amount of immobilized bFGF significantly facilitated neo-blood vessel formation as compared with other implantation groups. These results indicate that the sustained release of bFGF is important for the formation of blood vessels and that our fibrous matrices could be useful for regulation of tissue damage requiring angiogenesis. Further, our system can be combined with other growth factors with heparin binding domains, representing a facile depot for spatiotemporal control over the delivery of bioactive molecules in regenerative medicine.

  6. Inhibition of angiogenesis by humulone, a bitter acid from beer hop.

    Science.gov (United States)

    Shimamura, M; Hazato, T; Ashino, H; Yamamoto, Y; Iwasaki, E; Tobe, H; Yamamoto, K; Yamamoto, S

    2001-11-23

    On the basis of our previous finding that humulone, a bitter acid from beer hop extract, was a potent inhibitor of bone resorption and inhibited the catalytic activity of cyclooxygenase-2 (COX-2) and more potently the transcription of the COX-2 gene, we examined the effect of humulone on angiogenesis, using chick embryo chorioallantoic membranes (CAMs) and vascular endothelial and tumor cells. Humulone significantly prevented in vivo angiogenesis in CAM in a dose-dependent manner with an ED(50) of 1.5 microg/CAM. Humulone also inhibited in vitro tube formation of vascular endothelial cells. Moreover, it suppressed the proliferation of endothelial cells and the production of vascular endothelial growth factor (VEGF), an angiogenic growth factor, in endothelial and tumor cells. Thus, humulone is a potent angiogenic inhibitor, and may be a novel powerful tool for the therapy of various angiogenic diseases involving solid tumor growth and metastasis. Copyright 2001 Academic Press.

  7. The relationship between lymphatic vascular density and vascular endothelial growth factor A (VEGF-A) expression with clinical-pathological features and survival in pancreatic adenocarcinomas.

    Science.gov (United States)

    Zorgetto, Verônica A; Silveira, Giórgia G; Oliveira-Costa, João Paulo; Soave, Danilo F; Soares, Fernando A; Ribeiro-Silva, Alfredo

    2013-10-18

    Pancreatic cancer is a rare tumor with an extremely low survival rate. Its known risk factors include the chronic use of tobacco and excessive alcohol consumption and the presence of chronic inflammatory diseases, such as pancreatitis and type 2 diabetes. Angiogenesis and lymphangiogenesis, which have been the focus of recent research, are considered prognostic factors for cancer development. Knowing the angiogenic and lymphangiogenic profiles of a tumor may provide new insights for designing treatments according to the different properties of the tumor. The aim of this study was to evaluate the density of blood and lymphatic vessels, and the expression of VEGF-A, in pancreatic adenocarcinomas, as well as the relationship between blood and lymphatic vascular density and the prognostically important clinical-pathological features of pancreatic tumors. Paraffin blocks containing tumor samples from 100 patients who were diagnosed with pancreatic cancer between 1990 and 2010 were used to construct a tissue microarray. VEGF expression was assessed in these samples by immunohistochemistry. To assess the lymphatic and vascular properties of the tumors, 63 cases that contained sufficient material were sectioned routinely. The sections were then stained with the D2-40 antibody to identify the lymphatic vessels and with a CD34 antibody to identify the blood vessels. The vessels were counted individually with the Leica Application Suite v4 program. All statistical analyses were performed using SPSS 18.0 (Chicago, IL, USA) software, and p values ≤ 0.05 were considered significant. In the Cox regression analysis, advanced age (p=0.03) and a history of type 2 diabetes (p=0.014) or chronic pancreatitis (p=0.02) were shown to be prognostic factors for pancreatic cancer. Blood vessel density (BVD) had no relationship with clinical-pathological features or death. Lymphatic vessel density (LVD) was inversely correlated with death (p=0.002), and by Kaplan-Meyer survival analysis, we

  8. MicroRNA-410 reduces the expression of vascular endothelial growth factor and inhibits oxygen-induced retinal neovascularization.

    Directory of Open Access Journals (Sweden)

    Na Chen

    Full Text Available Retinal neovascularization (RNV is an eye disease that can cause retinal detachment and even lead to blindness. RNV mainly occurs in the elderly population. The pathogenesis of RNV has been previously reported to be highly related to the expression of vascular endothelial growth factor A (VEGFA, basic fibroblast growth factor (bFGF and other angiogenic factors. It has also been reported that VEGFA and other factors associated with RNV could be regulated by certain microRNAs (miRNA, a group of small non-coding RNAs which are able to regulate the expression of many genes in vivo. Here, we demonstrate that the miRNA miR-410 is highly expressed in mice within two weeks after birth. miR-410 could suppress VEGFA expression through interaction with the 3'UTR of the VEGFA messenger RNA. Overexpressing a miR-410 mimic effectively suppresses VEGFA expression in various cell lines. Further experiments on oxygen-induced retinopathy (OIR in mice revealed that eye drops containing large amounts of miR-410 efficiently downregulate VEGFA expression, prevent retinal angiogenesis and effectively treat RNV. These results not only show the underlying mechanism of how miR-410 targets VEGFA but also provide a potential treatment strategy for RNV that might be used in the near future.

  9. Analysis of VEGF--a regulated gene expression in endothelial cells to identify genes linked to angiogenesis.

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    Corban G Rivera

    Full Text Available Angiogenesis is important for many physiological processes, diseases, and also regenerative medicine. Therapies that inhibit the vascular endothelial growth factor (VEGF pathway have been used in the clinic for cancer and macular degeneration. In cancer applications, these treatments suffer from a "tumor escape phenomenon" where alternative pathways are upregulated and angiogenesis continues. The redundancy of angiogenesis regulation indicates the need for additional studies and new drug targets. We aimed to (i identify novel and missing angiogenesis annotations and (ii verify their significance to angiogenesis. To achieve these goals, we integrated the human interactome with known angiogenesis-annotated proteins to identify a set of 202 angiogenesis-associated proteins. Across endothelial cell lines, we found that a significant fraction of these proteins had highly perturbed gene expression during angiogenesis. After treatment with VEGF-A, we found increasing expression of HIF-1α, APP, HIV-1 tat interactive protein 2, and MEF2C, while endoglin, liprin β1 and HIF-2α had decreasing expression across three endothelial cell lines. The analysis showed differential regulation of HIF-1α and HIF-2α. The data also provided additional evidence for the role of endothelial cells in Alzheimer's disease.

  10. Analysis of VEGF--a regulated gene expression in endothelial cells to identify genes linked to angiogenesis.

    Science.gov (United States)

    Rivera, Corban G; Mellberg, Sofie; Claesson-Welsh, Lena; Bader, Joel S; Popel, Aleksander S

    2011-01-01

    Angiogenesis is important for many physiological processes, diseases, and also regenerative medicine. Therapies that inhibit the vascular endothelial growth factor (VEGF) pathway have been used in the clinic for cancer and macular degeneration. In cancer applications, these treatments suffer from a "tumor escape phenomenon" where alternative pathways are upregulated and angiogenesis continues. The redundancy of angiogenesis regulation indicates the need for additional studies and new drug targets. We aimed to (i) identify novel and missing angiogenesis annotations and (ii) verify their significance to angiogenesis. To achieve these goals, we integrated the human interactome with known angiogenesis-annotated proteins to identify a set of 202 angiogenesis-associated proteins. Across endothelial cell lines, we found that a significant fraction of these proteins had highly perturbed gene expression during angiogenesis. After treatment with VEGF-A, we found increasing expression of HIF-1α, APP, HIV-1 tat interactive protein 2, and MEF2C, while endoglin, liprin β1 and HIF-2α had decreasing expression across three endothelial cell lines. The analysis showed differential regulation of HIF-1α and HIF-2α. The data also provided additional evidence for the role of endothelial cells in Alzheimer's disease.

  11. Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB

    Science.gov (United States)

    Banfi, Andrea; von Degenfeld, Georges; Gianni-Barrera, Roberto; Reginato, Silvia; Merchant, Milton J.; McDonald, Donald M.; Blau, Helen M.

    2012-01-01

    Therapeutic angiogenesis by delivery of vascular growth factors is an attractive strategy for treating debilitating occlusive vascular diseases, yet clinical trials have thus far failed to show efficacy. As a result, limb amputation remains a common outcome for muscle ischemia due to severe atherosclerotic disease, with an overall incidence of 100 per million people in the United States per year. A challenge has been that the angiogenic master regulator vascular endothelial growth factor (VEGF) induces dysfunctional vessels, if expressed outside of a narrow dosage window. We tested the hypothesis that codelivery of platelet-derived growth factor-BB (PDGF-BB), which recruits pericytes, could induce normal angiogenesis in skeletal muscle irrespective of VEGF levels. Coexpression of VEGF and PDGF-BB encoded by separate vectors in different cells or in the same cells only partially corrected aberrant angiogenesis. In marked contrast, coexpression of both factors in every cell at a fixed relative level via a single bicistronic vector led to robust, uniformly normal angiogenesis, even when VEGF expression was high and heterogeneous. Notably, in an ischemic hindlimb model, single-vector expression led to efficient growth of collateral arteries, revascularization, increased blood flow, and reduced tissue damage. Furthermore, these results were confirmed in a clinically applicable gene therapy approach by adenoviral-mediated delivery of the bicistronic vector. We conclude that coordinated expression of VEGF and PDGF-BB via a single vector constitutes a novel strategy for harnessing the potency of VEGF to induce safe and efficacious angiogenesis.—Banfi, A., von Degenfeld, G., Gianni-Barrera, R., Reginato, S., Merchant, M. J., McDonald, D. M., Blau, H. M. Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB. PMID:22391130

  12. Apparent diffusion coefficient correlation with oesophageal tumour stroma and angiogenesis.

    Science.gov (United States)

    Aoyagi, Tomoyoshi; Shuto, Kiyohiko; Okazumi, Shinichi; Hayano, Kohichi; Satoh, Asami; Saitoh, Hiroshige; Shimada, Hideaki; Nabeya, Yoshihiro; Kazama, Toshiki; Matsubara, Hisahiro

    2012-06-01

    Because diffusion-weighted imaging (DWI) can predict the prognosis of patients with oesophageal squamous cell carcinoma (ESCC), we hypothesised that apparent diffusion coefficient (ADC) values might be correlated with the collagen content and tumour angiogenesis. The purpose of this study was to determine the correlation between ADC values of ESCC before treatment and oesophageal tumour stroma and angiogenesis. Seventeen patients with ESCC were enrolled. The ADC values were calculated from the DWI score. Seventeen patients who had undergone oesophagectomy were analysed for tumour stroma, vascular endothelial growth factor (VEGF) and CD34. Tissue collagen was stained with azocarmine and aniline blue to quantitatively analyse the extracellular matrix in cancer stroma. Tissues were stained with VEGF and CD34 to analyse the angiogenesis. The ADC values decreased with stromal collagen growth. We found a negative correlation between the tumour ADC and the amount of stromal collagen (r = -0.729, P = 0.001), i.e. the ADC values decreased with growth of VEGF. We also found a negative correlation between the ADC of the tumours and the amount of VEGF (r = 0.538, P = 0.026). Our results indicated that the ADC value may be a novel prognostic factor and contribute to the treatment of oesophageal cancer. • Magnetic resonance apparent diffusion coefficient values inversely indicate tumour stromal collagen • There is also negative correlation between ADCs and vascular endothelial growth factor • ADC values may contribute to the treatment of oesophageal cancer.

  13. Apparent diffusion coefficient correlation with oesophageal tumour stroma and angiogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Aoyagi, Tomoyoshi; Shuto, Kiyohiko; Okazumi, Shinichi; Hayano, Kohichi; Satoh, Asami; Saitoh, Hiroshige; Shimada, Hideaki; Nabeya, Yoshihiro; Matsubara, Hisahiro [Chiba University, Department of Frontier Surgery, Graduate School of Medicine, Chiba (Japan); Kazama, Toshiki [Chiba University, Department of Radiology, Graduate School of Medicine, Chiba (Japan)

    2012-06-15

    Because diffusion-weighted imaging (DWI) can predict the prognosis of patients with oesophageal squamous cell carcinoma (ESCC), we hypothesised that apparent diffusion coefficient (ADC) values might be correlated with the collagen content and tumour angiogenesis. The purpose of this study was to determine the correlation between ADC values of ESCC before treatment and oesophageal tumour stroma and angiogenesis. Seventeen patients with ESCC were enrolled. The ADC values were calculated from the DWI score. Seventeen patients who had undergone oesophagectomy were analysed for tumour stroma, vascular endothelial growth factor (VEGF) and CD34. Tissue collagen was stained with azocarmine and aniline blue to quantitatively analyse the extracellular matrix in cancer stroma. Tissues were stained with VEGF and CD34 to analyse the angiogenesis. The ADC values decreased with stromal collagen growth. We found a negative correlation between the tumour ADC and the amount of stromal collagen (r = -0.729, P = 0.001), i.e. the ADC values decreased with growth of VEGF. We also found a negative correlation between the ADC of the tumours and the amount of VEGF (r = 0.538, P = 0.026). Our results indicated that the ADC value may be a novel prognostic factor and contribute to the treatment of oesophageal cancer. circle Magnetic resonance apparent diffusion coefficient values inversely indicate tumour stromal collagen circle There is also negative correlation between ADCs and vascular endothelial growth factor circle ADC values may contribute to the treatment of oesophageal cancer. (orig.)

  14. The impact of hyperbaric oxygen therapy on serological values of vascular endothelial growth factor (VEGF and basic fibroblast growth factor (bFGF

    Directory of Open Access Journals (Sweden)

    Ziebura Thomas

    2010-12-01

    Full Text Available Abstract Background Hyperbaric oxygen (HBO therapy is an effective adjunct treatment for ischemic disorders such as chronic infection or chronic wounds. It combines hyperoxic effects with the stimulating potential of post-therapeutic reactive hypoxia. As its crucial effects, stimulation of fibroblast growth, induction of collagen synthesis and the initiation of angiogenesis are discussed. Angiogenesis is a multistage process resulting in the growth of blood vessels. It includes degradation of extracellular matrix, proliferation and migration of different cell populations and finally formation of new vessel structures. This complex chain of procedures is orchestrated by different cytokines and growth factors. Crucial mediators of angiogenesis are basic fibroblast growth factor (bFGF and vascular endothelial growth factor (VEGF; their in-vivo function is still not fully understood. Methods Forty-three patients suffering from sudden sensorineural hearing loss or tinnitus were treated with HBO. The therapy included 10 sessions of 90 minutes each, one session a day. Serological levels of bFGF and VEGF were assessed by enzyme-linked immunosorbent assays performed according to the manufacturer's instructions on day 1, 2, 5 and 10 of HBO therapy and were compared to mean values of the control group, related to the patient's age and sex, and their development observed over the ten days of HBO. Results There was no sex- or age dependency of bFGF observed in the present study, whereas under HBO our results showed a significant mitigation of the bFGF concentration. In the present data, there was no connection between the VEGF concentration and the patients' ages. Women showed significantly higher levels of VEGF. There was no significant change of VEGF concentration or the VEGF/bFGF ratio during HBO. All scored results varied within the range of standard values as described in the current literature. Conclusions A significant effect of HBO on serum

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

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    Nadia Alfaidy

    2014-01-01

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

  16. Effects of hyperthyroidism on expression of vascular endothelial growth factor (VEGF and apoptosis in fetal adrenal glands

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    T. Karaca

    2015-11-01

    Full Text Available This study investigated the expression of vascular endothelial growth factor (VEGF, vascular density, and apoptosis in fetal rat adrenal glands with hyperthyroidism in late gestation. Twelve mature female Wistar albino rats with the same biological and physiological features were used for this study. Rats were divided into two groups: control and hyperthyroidism. Hyperthyroidism was induced by daily subcutaneous injections of L-thyroxine (250 μg/kg before pregnancy for 21 days and during pregnancy. Rats in the control and hyperthyroidism groups were caged according to the number of male rats. Zero day of pregnancy (Day 0 was indicated when the animals were observed to have microscopic sperm in vaginal smears. Pregnant rats were sacrificed on the 20th day of pregnancy; blood from each animal was collected to determine the concentrations of maternal adrenocorticotropic hormone and thyroxine. Rat fetuses were then quickly removed from the uterus, and the adrenal glands of the fetuses were dissected. VEGF expression, vascular density, and apoptosis were analyzed in fetal rat adrenal glands. Maternal serum levels of the adrenocorticotropic hormone and free thyroxine were significantly higher in the hyperthyroidism group than in the control group. Immunohistochemistry revealed that the number of VEGF positive cells and vessel density significantly increased in the hyperthyroidism rat fetal adrenal group compared with the control group. Hyperthyroidism did not change the fetal and placental weights and the number of fetuses. This study demonstrates that hyperthyroidism may have an effect on the development of rat adrenal glands mediated by VEGF expression, angiogenesis, and apoptosis. 

  17. Angiogenesis in cutaneous disease: part I.

    Science.gov (United States)

    Nguyen, Amy; Hoang, Van; Laquer, Vivian; Kelly, Kristen M

    2009-12-01

    Angiogenesis is an important process in normal physiology and disease pathogenesis. Angiogenesis is controlled in a healthy body by a system of angiogenic growth factors and angiogenesis inhibitors. When angiogenic growth factors are predominantly expressed, blood vessel growth occurs and disease may result. Successful therapies have been developed that target growth factors, their receptors, or the cascade pathways that are activated by growth factor/receptor interactions. There is good evidence that angiogenesis plays an important role in a wide range of cutaneous maladies, and angiogenesis-targeting therapies are playing an increasing role in the management of dermatologic disease. Cutaneous angiogenesis offers an exciting new arena for targeted dermatologic therapeutics. After completing this learning activity, participants should be able to distinguish angiogenic growth factors and inhibitors, recognize angiogenic mediating agents and compare their mechanisms of action, and apply the use of angiogenic mediating agents in clinical and research situations.

  18. A hypoxia-inducible factor (HIF)-3α splicing variant, HIF-3α4 impairs angiogenesis in hypervascular malignant meningiomas with epigenetically silenced HIF-3α4

    Energy Technology Data Exchange (ETDEWEB)

    Ando, Hitoshi [Department of Neurosurgery, Nagoya University School of Medicine, Nagoya (Japan); Department of Neurosurgery, Fukushima Medical University School of Medicine, Fukushima (Japan); Natsume, Atsushi, E-mail: anatsume@med.nagoya-u.ac.jp [Department of Neurosurgery, Nagoya University School of Medicine, Nagoya (Japan); Iwami, Kenichiro; Ohka, Fumiharu [Department of Neurosurgery, Nagoya University School of Medicine, Nagoya (Japan); Kuchimaru, Takahiro; Kizaka-Kondoh, Shinae [Department of Biomolecular Engineering, Tokyo Institute of Technology Graduate School of Bioscience and Biotechnology, Yokohama (Japan); Ito, Kengo [National Center for Geriatrics and Gerontology, Aichi (Japan); Saito, Kiyoshi [Department of Neurosurgery, Fukushima Medical University School of Medicine, Fukushima (Japan); Sugita, Sachi; Hoshino, Tsuneyoshi [MICRON Inc.Medical Facilities Support Department, Aichi (Japan); Wakabayashi, Toshihiko [Department of Neurosurgery, Nagoya University School of Medicine, Nagoya (Japan)

    2013-03-29

    Highlights: ► HIF-3α4 is silenced by DNA methylation in meningiomas. ► Induction of HIF-3α4 impaired angiogenesis in meningiomas. ► Induction of HIF-3α4 impaired proliferation and oxygen-dependent metabolism. -- Abstract: Hypoxia inducible factor is a dominant regulator of adaptive cellular responses to hypoxia and controls the expression of a large number of genes regulating angiogenesis as well as metabolism, cell survival, apoptosis, and other cellular functions in an oxygen level-dependent manner. When a neoplasm is able to induce angiogenesis, tumor progression occurs more rapidly because of the nutrients provided by the neovasculature. Meningioma is one of the most hypervascular brain tumors, making anti-angiogenic therapy an attractive novel therapy for these tumors. HIF-3α has been conventionally regarded as a dominant-negative regulator of HIF-1α, and although alternative HIF-3α splicing variants are extensively reported, their specific functions have not yet been determined. In this study, we found that the transcription of HIF-3α4 was silenced by the promoter DNA methylation in meningiomas, and inducible HIF-3α4 impaired angiogenesis, proliferation, and metabolism/oxidation in hypervascular meningiomas. Thus, HIF-3α4 could be a potential molecular target in meningiomas.

  19. Predisposing factors in posterior circulation infarcts: a vascular morphological assessment

    Energy Technology Data Exchange (ETDEWEB)

    Coban, Goekcen; Cifci, Egemen; Yildirim, Erkan; Agildere, Ahmet Muhtesem [Baskent University Faculty of Medicine, Department of Radiology, Konya (Turkey)

    2015-05-01

    The aim of the study is to assess the effect of shape, diameter, elongation and deviation criteria of basilar artery (BA), convergence angle and diameter variations of vertebral arteries, and concurrent chronic diseases on posterior circulation infarcts. Between January 2010 and May 2013, 186 patients who underwent brain and diffusion magnetic resonance imaging (MRI) with suspected cerebrovascular accident and were diagnosed with posterior circulation infarct and 120 infarct negative control subjects were included in this case-control retrospective study. Vertebral artery (VA) and BA diameter, right (R) and left (L) VA angles at the level of bifurcation, and BA elongation-deviation, and shape of BA were assessed in a total of 306 subjects. Ischemic lesions in the posterior circulation were classified according to their anatomical location and vascular perfusion areas. No significant difference was noted between the control and patient groups with respect to BA diameter (p = 0.676). The most effective risk factors for posterior circulation infarcts were as follows: BA elongation of 2 or 3, BA transverse location of 2 or 3, increase in left VA angle, and history of hypertension, hypercholesterolemia, and diabetes mellitus. Our results suggest that prominent elongation and deviation, C and J shape of BA, and increased L VA angle may be the predictors of at-risk patients in posterior circulation infarcts. Reporting marked morphological BA and VA variations detected at routine brain MRI will aid in selection of patients. Timely detection and treatment of at-risk patients may be life-saving. (orig.)

  20. Pharmacogenetics of Vascular Risk Factors in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Ramón Cacabelos

    2018-01-01

    Full Text Available Alzheimer’s disease (AD is a polygenic/complex disorder in which genomic, epigenomic, cerebrovascular, metabolic, and environmental factors converge to define a progressive neurodegenerative phenotype. Pharmacogenetics is a major determinant of therapeutic outcome in AD. Different categories of genes are potentially involved in the pharmacogenetic network responsible for drug efficacy and safety, including pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes. However, most drugs exert pleiotropic effects that are promiscuously regulated for different gene products. Only 20% of the Caucasian population are extensive metabolizers for tetragenic haplotypes integrating CYP2D6-CYP2C19-CYP2C9-CYP3A4/5 variants. Patients harboring CYP-related poor (PM and/or ultra-rapid (UM geno-phenotypes display more irregular profiles in drug metabolism than extensive (EM or intermediate (IM metabolizers. Among 111 pentagenic (APOE-APOB-APOC3-CETP-LPL haplotypes associated with lipid metabolism, carriers of the H26 haplotype (23-TT-CG-AG-CC exhibit the lowest cholesterol levels, and patients with the H104 haplotype (44-CC-CC-AA-CC are severely hypercholesterolemic. Furthermore, APOE, NOS3, ACE, AGT, and CYP variants influence the therapeutic response to hypotensive drugs in AD patients with hypertension. Consequently, the implementation of pharmacogenetic procedures may optimize therapeutics in AD patients under polypharmacy regimes for the treatment of concomitant vascular disorders.

  1. Functional role of inorganic trace elements in angiogenesis-Part II: Cr, Si, Zn, Cu, and S.

    Science.gov (United States)

    Saghiri, Mohammad Ali; Asatourian, Armen; Orangi, Jafar; Sorenson, Christine M; Sheibani, Nader

    2015-10-01

    Trace elements play critical roles in angiogenesis events. The effects of nitrogen, iron, selenium, phosphorus, gold, and calcium were discussed in part I. In part II, we evaluated the effect of chromium, silicon, zinc, copper, and sulfur on different aspects of angiogenesis, with critical roles in healing and regeneration processes, and undeniable roles in tumor growth and cancer therapy. This review is the second of series that serves as an overview of the role of inorganic elements in regulation of angiogenesis and vascular function. The methods of exposure, structure, mechanism, and potential activity of these trace elements are briefly discussed. An electronic search was performed on the role of these trace elements in angiogenesis from January 2005 to April 2014. The recent aspects of the relationship between five different trace elements and their role in regulation of angiogenesis, and homeostasis of pro- and anti-angiogenic factors were assessed. Many studies have investigated the effects and importance of these elements in angiogenesis events. Both stimulatory and inhibitory effects on angiogenesis are observed for the evaluated elements. Chromium can promote angiogenesis in pathological manners. Silicon as silica nanoparticles is anti-angiogenic, while in calcium silicate extracts and bioactive silicate glasses promote angiogenesis. Zinc is an anti-angiogenic agent acting on important genes and growth factors. Copper and sulfur compositions have pro-angiogenic functions by activating pro-angiogenic growth factors and promoting endothelial cells migration, growth, and tube formation. Thus, utilization of these elements may provide a unique opportunity to modulate angiogenesis under various setting. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  2. 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

  3. 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.

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

    Science.gov (United States)

    Simone, Valeria; Brunetti, Oronzo; Lupo, Luigi; Testini, Mario; Maiorano, Eugenio; Simone, Michele; Longo, Vito; Rolfo, Christian; Peeters, Marc; Scarpa, Aldo; Azzariti, Amalia; Russo, Antonio; Ribatti, Domenico; Silvestris, Nicola

    2017-02-15

    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.

  5. Leptin-induced transphosphorylation of vascular endothelial growth factor receptor increases Notch and stimulates endothelial cell angiogenic transformation.

    Science.gov (United States)

    Lanier, Viola; Gillespie, Corey; Leffers, Merle; Daley-Brown, Danielle; Milner, Joy; Lipsey, Crystal; Webb, Nia; Anderson, Leonard M; Newman, Gale; Waltenberger, Johannes; Gonzalez-Perez, Ruben Rene

    2016-10-01

    Leptin increases vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2), and Notch expression in cancer cells, and transphosphorylates VEGFR-2 in endothelial cells. However, the mechanisms involved in leptin's actions in endothelial cells are not completely known. Here we investigated whether a leptin-VEGFR-Notch axis is involved in these leptin's actions. To this end, human umbilical vein and porcine aortic endothelial cells (wild type and genetically modified to overexpress VEGFR-1 or -2) were cultured in the absence of VEGF and treated with leptin and inhibitors of Notch (gamma-secretase inhibitors: DAPT and S2188, and silencing RNA), VEGFR (kinase inhibitor: SU5416, and silencing RNA) and leptin receptor, OB-R (pegylated leptin peptide receptor antagonist 2: PEG-LPrA2). Interestingly, in the absence of VEGF, leptin induced the expression of several components of Notch signaling pathway in endothelial cells. Inhibition of VEGFR and Notch signaling significantly decreased leptin-induced S-phase progression, proliferation, and tube formation in endothelial cells. Moreover, leptin/OB-R induced transphosphorylation of VEGFR-1 and VEGFR-2 was essential for leptin's effects. These results unveil for the first time a novel mechanism by which leptin could induce angiogenic features via upregulation/trans-activation of VEGFR and downstream expression/activation of Notch in endothelial cells. Thus, high levels of leptin found in overweight and obese patients might lead to increased angiogenesis by activating VEGFR-Notch signaling crosstalk in endothelial cells. These observations might be highly relevant for obese patients with cancer, where leptin/VEGFR/Notch crosstalk could play an important role in cancer growth, and could be a new target for the control of tumor angiogenesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

  6. Prognostic significance of cellular vascular endothelial growth factor (VEGF expression in the course of chronic myeloid leukaemia

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    Vidović Ana

    2009-01-01

    Full Text Available Introduction. Increased angiogenesis in bone marrow is one of the characteristics of chronic myeloid leukaemia (CML, a clonal myeloproliferative disorder that expresses a chimeric bcr/abl protein. Vascular endothelial growth factor (VEGF is one of the most potent and a specific regulator of angiogenesis which principally targets endothelial cells and regulates several of their functions, including mitogenesis, permeability and migration. The impact of elevated VEGF expression on the course of chronic myeloid leukaemia is unknown. Objective. The aim of this study was the follow-up of VEGF expression during the course of CML. Methods. We studied VEGF expression of 85 CML patients (median age 50 years, range 16-75 years. At the commencement of the study, 29 patients were in chronic phase (CP, 25 in an accelerated phase (AP, and 31 in the blast crisis (BC. The temporal expression (percentage positivity per 1000 analysed cells VEGF proteins over the course of CML were studied using the immunohistochemical technique utilizing relevant monoclonal antibodies. It was correlated with the laboratory (Hb, WBC and platelet counts, and the percentage of blasts and clinical parameters (organomegaly, duration of CP, AP, and BC of disease progression. Results. The expression of VEGF protein was most pronounced in AP (ANOVA, p=0.033. The level of VEGF expression correlated inversely with the degree of splenomegaly (Pearson, r=-0.400, p=0.011. High expression of VEGF correlated with a shorter overall survival (log rank, p=0.042. Conclusion. Immunohistochemically confirmed significance of the expression of VEGF in dependence of the CML stage could be of clinical importance in deciding on the timing therapy. These data suggest that VEGF plays a role in the biology of CML and that VEGF inhibitors should be investigated in CML.

  7. Inhibition of vascular endothelial growth factor signaling facilitates liver repair from acute ethanol-induced injury in zebrafish

    Directory of Open Access Journals (Sweden)

    Changwen Zhang

    2016-11-01

    Full Text Available Alcoholic liver disease (ALD results from alcohol overconsumption and is among the leading causes of liver-related morbidity and mortality worldwide. Elevated expression of vascular endothelial growth factor (VEGF and its receptors has been observed in ALD, but how it contributes to ALD pathophysiology is unclear. Here, we investigated the impact of VEGF signaling inhibition on an established zebrafish model of acute alcoholic liver injury. Kdrl activity was blocked by chemical inhibitor treatment or by genetic mutation. Exposing 4-day-old zebrafish larvae to 2% ethanol for 24 h induced hepatic steatosis, angiogenesis and fibrogenesis. The liver started self-repair once ethanol was removed. Although inhibiting Kdrl did not block the initial activation of hepatic stellate cells during ethanol treatment, it suppressed their proliferation, extracellular matrix protein deposition and fibrogenic gene expression after ethanol exposure, thus enhancing the liver repair. It also ameliorated hepatic steatosis and attenuated hepatic angiogenesis that accelerated after the ethanol treatment. qPCR showed that hepatic stellate cells are the first liver cell type to increase the expression of VEGF ligand and receptor genes in response to ethanol exposure. Both hepatic stellate cells and endothelial cells, but not hepatic parenchymal cells, expressed kdrl upon ethanol exposure and were likely the direct targets of Kdrl inhibition. Ethanol-induced steatosis and fibrogenesis still occurred in cloche mutants that have hepatic stellate cells but lack hepatic endothelial cells, and Kdrl inhibition suppressed both phenotypes in the mutants. These results suggest that VEGF signaling mediates interactions between activated hepatic stellate cells and hepatocytes that lead to steatosis. Our study demonstrates the involvement of VEGF signaling in regulating sustained liver injuries after acute alcohol exposure. It also provides a proof of principle of using the

  8. Targeting Slit-Roundabout signaling inhibits tumor angiogenesis in chemical-induced squamous cell carcinogenesis.

    Science.gov (United States)

    Wang, Li-Jing; Zhao, Yuan; Han, Bing; Ma, Yu-Guang; Zhang, Jie; Yang, Ding-Ming; Mao, Jian-Wen; Tang, Fu-Tian; Li, Wei-Dong; Yang, Yang; Wang, Rui; Geng, Jian-Guo

    2008-03-01

    Slit is a secreted protein known to function through the Roundabout (Robo) receptor as a repellent for axon guidance and neuronal migration, and as an inhibitor in leukocyte chemotaxis. We have previously shown that Slit2 is also secreted by a variety of human cancer cells whereby it acts as a chemoattractant to vascular endothelial cells for tumor angiogenesis. We used a blocking antibody to investigate the role of Slit-Robo signaling in tumor angiogenesis during oral carcinogenesis. In this report we undertook a multistage model of 7,12-dimethyl-1,2-benzanthracene-induced squamous cell carcinoma in the hamster buccal pouch. R5, a monoclonal antibody against the first immunoglobulin domain of Robo1, was used to study whether R5 blocks the Slit-Robo interaction and furthermore inhibits tumor angiogenesis and growth in our model. In addition, the expression of Slit2, von Willebrand factor, and vascular endothelial growth factor were examined using human tissue of oral cheek mucosa with oral squamous cell carcinoma. Our data showed that Slit2 was expressed minimally in normal and hyperplastic mucosa, moderately in dysplastic mucosa, and highly in neoplastic mucosa obtained from hamster buccal pouch. We also found that increased Slit2 expression was associated with higher tumor angiogenesis, as reflected by increased vascular endothelial growth factor expression and microvessel density. A similar Slit2 expression profile was found in human tissue. Importantly, interruption of the Slit2-Robo interaction using R5 inhibited tumor angiogenesis and growth in our in vivo model, which indicates that Slit2-mediated tumor angiogenesis is a critical process underlying the carcinogenesis of chemical-induced squamous cell carcinoma. Therefore, targeting Slit-Robo signaling may offer a novel antiangiogenesis approach for oral cancer therapy.

  9. Autoantibodies in dilated cardiomyopathy induce vascular endothelial growth factor expression in cardiomyocytes

    Energy Technology Data Exchange (ETDEWEB)

    Saygili, Erol, E-mail: erol.saygili@med.uni-duesseldorf.de [Division of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf (Germany); Noor-Ebad, Fawad; Schröder, Jörg W.; Mischke, Karl [Department of Cardiology, University RWTH Aachen, Pauwelsstr. 30, D-52074 Aachen (Germany); Saygili, Esra [Clinic for Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf (Germany); Rackauskas, Gediminas [Department of Cardiovascular Medicine, Vilnius University Hospital Santariskiu Klinikos, Vilnius University (Lithuania); Marx, Nikolaus [Department of Cardiology, University RWTH Aachen, Pauwelsstr. 30, D-52074 Aachen (Germany); Kelm, Malte; Rana, Obaida R. [Division of Cardiology, Pulmonology, and Vascular Medicine, University Hospital Düsseldorf, Moorenstrasse 5, D-40225 Düsseldorf (Germany)

    2015-09-11

    Background: Autoantibodies have been identified as major predisposing factors for dilated cardiomyopathy (DCM). Patients with DCM show elevated serum levels of vascular endothelial growth factor (VEGF) whose source is unknown. Besides its well-investigated effects on angiogenesis, evidence is present that VEGF signaling is additionally involved in fibroblast proliferation and cardiomyocyte hypertrophy, hence in cardiac remodeling. Whether autoimmune effects in DCM impact cardiac VEGF signaling needs to be elucidated. Methods: Five DCM patients were treated by the immunoadsorption (IA) therapy on five consecutive days. The eluents from the IA columns were collected and prepared for cell culture. Cardiomyocytes from neonatal rats (NRCM) were incubated with increasing DCM-immunoglobulin-G (IgG) concentrations for 48 h. Polyclonal IgG (Venimmun N), which was used to restore IgG plasma levels in DCM patients after the IA therapy was additionally used for control cell culture purposes. Results: Elevated serum levels of VEGF decreased significantly after IA (Serum VEGF (ng/ml); DCM pre-IA: 45 ± 9.1 vs. DCM post–IA: 29 ± 6.7; P < 0.05). In cell culture, pretreatment of NRCM by DCM-IgG induced VEGF expression in a time and dose dependent manner. Biologically active VEGF that was secreted by NRCM significantly increased BNP mRNA levels in control cardiomyocytes and induced cell-proliferation of cultured cardiac fibroblast (Fibroblast proliferation; NRCM medium/HC-IgG: 1 ± 0.0 vs. NRCM medium/DCM-IgG 100 ng/ml: 5.6 ± 0.9; P < 0.05). Conclusion: The present study extends the knowledge about the possible link between autoimmune signaling in DCM and VEGF induction. Whether this observation plays a considerable role in cardiac remodeling during DCM development needs to be further elucidated. - Highlights: • Mechanisms of remodeling in dilated cardiomyopathy (DCM) are not fully understood. • Autoantibodies have been identified as major predisposing factors

  10. Late and early onset dementia: what is the role of vascular factors? A retrospective study.

    Science.gov (United States)

    Carotenuto, Anna; Rea, Raffaele; Colucci, Luisa; Ziello, Antonio Rosario; Molino, Ivana; Carpi, Sabrina; Traini, Enea; Amenta, Francesco; Fasanaro, Angiola Maria

    2012-11-15

    Neuropathology of Alzheimer's disease (AD) demonstrates that the common occurrence of vascular lesions and vascular factors is suggested to contribute significantly to the clinical progression of the disease. This study has assessed the presence of vascular brain lesions and risk factors in subjects with diagnosis of AD and their influence on the disease course both in Late Onset Dementia (LOD) and in Early Onset Dementia (EOD). MRI scans of 374 LOD and of 67 EOD patients were evaluated for the presence of vascular associated lesions and rated according to the age-related white matter changes (ARWMC) scale as "pure degenerative", "mixed" and "vascular" cases of dementia. Vascular risk factors burden (hypertension, diabetes, dyslipidemia, myocardial infarction) and disease progression were also assessed. 44% of LOD cases and 46% of EOD were classified as "mixed dementia cases". The vascular risk factors burden showed an increase from the pure degenerative to the pure vascular forms. Disease progression, calculated in two years using the Mini Mental State Evaluation (MMSE), Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scores, did not reveal differences among the three different classes of dementias. Vascular lesions are found in the majority of LOD cases and in about one half of EOD. This observation is consistent with the hypothesis of a synergistic effect of the degenerative and vascular factors on the development of cognitive dysfunction. The linear increase of the vascular burden supports the idea of a continuum spectrum between the pure degenerative and the pure vascular forms of adult-onset dementia disorders. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Cognitive impairment after cerebrovascular stroke: Relationship to vascular risk factors

    National Research Council Canada - National Science Library

    Khedr, Eman M; Hamed, Sherifa A; El-Shereef, Hala K; Shawky, Ola A; Mohamed, Khalid A; Awad, Effat M; Ahmed, Mohamed A; Shehata, Ghaydaa A; Eltahtawy, Mahmoud A

    2009-01-01

    Cognitive decline after cerebrovascular stroke has adverse outcome consequences. Since some vascular causes can be prevented and treated, the identification of stroke-related cognitive impairment is a challenge...

  12. Tympanomastoid cholesterol granulomas: Immunohistochemical evaluation of angiogenesis.

    Science.gov (United States)

    Iannella, Giannicola; Di Gioia, Cira; Carletti, Raffaella; Magliulo, Giuseppe

    2017-08-01

    This study investigates the immunohistochemical expression of vascular endothelial growth factor (VEGF) and CD34 in patients treated for middle ear and mastoid cholesterol granulomas to evaluate the angiogenesis and vascularization of this type of lesion. A correlation between the immunohistochemical data and the radiological and intraoperative evidence of temporal bone marrow invasion and blood source connection was performed to validate this hypothesis. Retrospective study. Immunohistochemical expression of VEGF and CD34 in a group of 16 patients surgically treated for cholesterol granuloma was examined. Middle ear cholesteatomas with normal middle ear mucosa and external auditory canal skin were used as the control groups. The radiological and intraoperative features of cholesterol granulomas were also examined. In endothelial cells, there was an increased expression of angiogenetic growth factor receptors in all the cholesterol granulomas in this study. The quantitative analysis of VEGF showed a mean value of 37.5, whereas the CD34 quantitative analysis gave a mean value of 6.8. Seven patients presented radiological or intraoperative evidence of bone marrow invasion, hematopoietic potentialities, or blood source connections that might support the bleeding theory. In all of these cases there was computed tomography or intraoperative evidence of bone erosion of the middle ear and/or temporal bone structures. The mean values of VEGF and CD34 were 41.1 and 7.7, respectively. High values of VEGF and CD34 are present in patients with cholesterol granulomas. Upregulation of VEGF and CD34 is indicative of a remarkable angiogenesis and a widespread vascular concentration in cholesterol granulomas. 3b. Laryngoscope, 127:E283-E290, 2017. © 2017 The American Laryngological, Rhinological and Otological Society, Inc.

  13. Small GTP-Binding Protein Rac Is an Essential Mediator of Vascular Endothelial Growth Factor-Induced Endothelial Fenestrations and Vascular Permeability

    DEFF Research Database (Denmark)

    Eriksson, A.; Cao, R.; Tritsaris, K.

    2003-01-01

    ), endothelial nitric oxide synthase (eNOS), and extracellular regulated kinase (Erk1/2). We further found that phosphatidylinositol-3-OH kinase (PI3K) acted upstream of Rac and Akt-eNOS in VEGF/VEGFR-2 signaling. Conclusions- Our findings indicate that the small GTP-binding protein Rac is a key component...... and vascular permeability but only partially inhibited angiogenesis. Studies on endothelial cell cultures further revealed that VEGF stimulated phosphorylation of VEGF receptor-2 (VEGFR-2), leading to activation of Rac as well as increased phosphorylation of phospholipase C (PLC ), protein kinase B (Akt...

  14. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia.

    Science.gov (United States)

    Iadecola, Costantino

    2010-09-01

    There is increasing evidence that cerebrovascular dysfunction plays a role not only in vascular causes of cognitive impairment but also in Alzheimer's disease (AD). Vascular risk factors and AD impair the structure and function of cerebral blood vessels and associated cells (neurovascular unit), effects mediated by vascular oxidative stress and inflammation. Injury to the neurovascular unit alters cerebral blood flow regulation, depletes vascular reserves, disrupts the blood-brain barrier, and reduces the brain's repair potential, effects that amplify the brain dysfunction and damage exerted by incident ischemia and coexisting neurodegeneration. Clinical-pathological studies support the notion that vascular lesions aggravate the deleterious effects of AD pathology by reducing the threshold for cognitive impairment and accelerating the pace of the dementia. In the absence of mechanism-based approaches to counteract cognitive dysfunction, targeting vascular risk factors and improving cerebrovascular health offers the opportunity to mitigate the impact of one of the most disabling human afflictions.

  15. Factors Associated with Amputation after Popliteal Vascular Injuries.

    Science.gov (United States)

    Keeley, Jessica; Koopmann, Matthew; Yan, Huan; DeVirgilio, Christian; Putnam, Brant; Y Kim, Dennis; Plurad, David

    2016-05-01

    Popliteal artery trauma has the highest rate of limb loss of all peripheral vascular injuries. The objectives of this study were to evaluate outcomes after popliteal vascular injury and to identify predictors of amputation. Retrospective data over a 14-year period were collected for patients with popliteal artery with or without vein injuries. Patient demographics, mechanism of injury, Injury Severity Score (ISS), Mangled Extremity Severity Score (MESS), and physiologic parameters were extracted. Time to operative intervention, operative time, type of vascular repair, need for concomitant orthopedic procedures, and outcomes including amputation rate, and in-hospital mortality were recorded. Fifty-one patients were found to have popliteal artery injuries, with a median age of 25 (range 10-70 years). The median ISS was 9, and the mean extremity Abbreviated Injury Severity score was 3. The mechanism of injury was blunt for 43% and penetrating for 57%. Fasciotomies were performed in 74% of patients and 64% of patients underwent combined orthopedic and vascular procedures. Overall, 66% of these patients had their vascular procedure performed first. Ten patients required amputation: 1 immediate and 9 after attempted limb salvage (20%). We found that those patients requiring amputation had a higher incidence of blunt trauma (80% vs. 35%, P = 0.014) and higher MESS score (7.1 vs. 4.7, P = 0.02). There was no difference in the incidence of amputation for those who underwent orthopedic fixation before vascular repair (P = 0.68). Popliteal vascular injuries continue to be associated with a high risk of amputation. Those patients undergoing attempted limb salvage should be revascularized expediently, but selected patients may undergo orthopedic stabilization before vascular repair without increased risk of limb loss. Copyright © 2016 Elsevier Inc. All rights reserved.

  16. Expression of Hypoxia-Inducible Factor (HIF-1a-Vascular Endothelial Growth Factor (VEGF-Inhibitory Growth Factor (ING-4- axis in sarcoidosis patients

    Directory of Open Access Journals (Sweden)

    Tzouvelekis Argyris

    2012-11-01

    Full Text Available Abstract Background Sarcoidosis is a granulomatous disorder of unknown etiology. The term of immunoangiostasis has been addressed by various studies as potentially involved in the disease pathogenesis. The aim of the study was to investigate the expression of the master regulator of angiogenesis hypoxia inducible factor (HIF-1a – vascular endothelial growth factor (VEGF- inhibitor of growth factor 4-(ING4 - axis within sarcoid granuloma. Methods A total of 37 patients with sarcoidosis stages II-III were recruited in our study. Tissue microarray technology coupled with immunohistochemistry analysis were applied to video-assisted thoracoscopic surgery (VATS lung biopsy samples collected from 37 sarcoidosis patients and 24 controls underwent surgery for benign lesions of the lung. Computerized image analysis was used to quantify immunohistochemistry results. qRT-PCR was used to assess HIF-1a and ING4 expression in 10 sarcoidosis mediastinal lymph node and 10 control lung samples. Results HIF-1a and VEGF-ING4 expression, both in protein and mRNA level, was found to be downregulated and upregulated, respectively, in sarcoidosis samples compared to controls. Immunohistochemistry coupled with computerized image analysis revealed minimal expression of HIF-1a within sarcoid granulomas whereas an abundant staining of ING4 and VEGF in epithelioid cells was also visualized. Conclusions Our data suggest an impairment of the HIF-1a – VEGF axis, potentialy arising by ING4 overexpression and ultimately resulting in angiostasis and monocyte recruitment within granulomas. The concept of immunoangiostasis as a possible protection mechanism against antigens of infectious origin needs further research to be verified.

  17. Enhancement of Gastric Ulcer Healing and Angiogenesis by Hepatocyte Growth Factor Gene Mediated by Attenuated Salmonella in Rats.

    Science.gov (United States)

    Ha, Xiaoqin; Peng, Junhua; Zhao, Hongbin; Deng, Zhiyun; Dong, Juzi; Fan, Hongyan; Zhao, Yong; Li, Bing; Feng, Qiangsheng; Yang, Zhihua

    2017-02-01

    The present study developed an oral hepatocyte growth factor (HGF) gene therapy strategy for gastric ulcers treatment. An attenuated Salmonella typhimurium that stably expressed high HGF (named as TPH) was constructed, and the antiulcerogenic effect of TPH was evaluated in a rat model of gastric ulcers that created by acetic acid subserosal injection. From day 5 after injection, TPH (1 × 10⁹ cfu), vehicle (TP, 1 × 10⁹ cfu), or sodium bicarbonate (model control) was administered orally every alternate day for three times. Then ulcer size was measured at day 21 after ulcer induction. The ulcer area in TPH-treated group was 10.56 ± 3.30 mm², which was smaller when compared with those in the TP-treated and model control groups (43.47 ± 4.18 and 56.25 ± 6.38 mm², respectively). A higher level of reepithelialization was found in TPH-treated group and the crawling length of gastric epithelial cells was significantly longer than in the other two groups (P ulcer granulation tissues of the TPH-treated rats was 39.9 vessels/mm², which was greater than in the TP-treated and model control rats, with a significant statistical difference. These results suggest that TPH treatment significantly accelerates the healing of gastric ulcers via stimulating proliferation of gastric epithelial cells and enhancing angiogenesis on gastric ulcer site.

  18. MicroRNA regulates vascular endothelial growth factor expression in chondrosarcoma cells.

    Science.gov (United States)

    Sun, Xiaojuan; Wei, Lei; Chen, Qian; Terek, Richard M

    2015-03-01

    Systemic treatments to prevent or treat chondrosarcoma metastasis are lacking and targeted therapy has yet to be developed. Hypoxia develops in tumors as they grow and hypoxia-related alterations in gene expression underlie some of the traits of cancer. One critical trait is the ability to induce sustained angiogenesis, which is usually related to expression of vascular endothelial growth factor (VEGF). A potential hypoxia-related mechanism resulting in altered gene expression involves microRNA. Little is known about microRNA expression in chondrosarcoma and its potential role in regulation of VEGF expression. Our purposes were (1) to determine if there is hypoxia-regulated microRNA overexpressed in chondrosarcoma; (2) if that contributes to increased VEGF expression; and (3) can VEGF expression be inhibited with a specific antagomir? MicroRNA expression was analyzed in two primary human chondrosarcomas and articular cartilage using array analysis and a cutoff of a fourfold difference in expression between tumor and normal tissue. The effects of hypoxia and hypoxia-inducible factor-1α (HIF-1α) transfection and silencing with siRNA on expression of candidate microRNAs were analyzed in chondrosarcoma cell line JJ. VEGF expression was measured with quantitative polymerase chain reaction and enzyme-linked immunosorbent assay after specific microRNA transfection and knockdown. miR-181a was identified by array analysis and confirmed with quantitative reverse transcription-polymerase chain reaction, which showed that miR-181a was overexpressed in both human chondrosarcomas (33- and 55-fold) and the JJ cell line (sixfold) compared with cartilage and chondrocytes, respectively. In vitro, hypoxia and HIF-1α transfection each further increased miR-181a expression twofold in JJ cells. miR-181a transfection of JJ cells doubled expression of VEGF mRNA and increased secreted VEGF protein by 46% in normoxia, an effect that could be either direct or indirect. Similar enhancement

  19. Granulocyte-Colony Stimulating Factor (G-CSF) Accelerates Wound Healing in Hemorrhagic Shock Rats by Enhancing Angiogenesis and Attenuating Apoptosis

    Science.gov (United States)

    Huang, Hong; Zhang, Qi; Liu, Jiejie; Hao, Haojie; Jiang, Chaoguang; Han, Weidong

    2017-01-01

    Background Following severe trauma, treatment of cutaneous injuries is often delayed by inadequate blood supply. The aim of the present study was to determine whether granulocyte-colony stimulating factor (G-CSF) protects endothelial cells (ECs) and enhances angiogenesis in a rat model of hemorrhagic shock (HS) combined with cutaneous injury after resuscitation. Material/Methods The HS rats with full-thickness defects were resuscitated and randomly divided into a G-CSF group (200 μg/kg body weight), a normal saline group, and a blank control group. Histological staining was to used estimate the recovery and apoptosis of skin. Apoptosis- and angiogenesis-related factors were analyzed by reverse transcription-polymerase chain reaction (RT-PCR) and Western blot (WB). Scratch assay, tube formation, and WB experiments were performed to verify the functional effects of G-CSF on HUVECs in vitro. Results H&E staining and Masson trichrome staining showed earlier inflammation resolution and collagen synthesis in the G-CSF-treated group. Angiogenesis-related factors were elevated at mRNA and protein levels. TUNEL staining suggested fewer apoptotic cells in the G-CSF group. The apoptotic-related factors were down-regulated and anti-apoptotic factors were up-regulated in the G-CSF-treated group. Scratch assay and tube formation experiments revealed that G-CSF facilitated migration ability and angiogenic potential of HUVECs. The angiogenic and anti-apoptotic effects were also enhanced in vitro. Conclusions Our results suggest that G-CSF after resuscitation attenuates local apoptosis and accelerates angiogenesis. These findings hold great promise for improving therapy for cutaneous injury in severe trauma and ischemia diseases. PMID:28559534

  20. Immunohistochemical expression of vascular endothelial growth factor in keratocystic odontogenic tumor, dentigerous cyst, and radicular cyst: A comparative study.

    Science.gov (United States)

    Khajuria, Nidhi; Metgud, Rashmi; Naik, Smitha; Lerra, Sahul; Tiwari, Priya; Mamta; Katakwar, Payal; Tak, Anirudh

    2016-01-01

    Cyst and tumors arise from tissue remains of odontogenesis, these interactions have been considered to play an important role in the tumorigenesis of odontogenic lesions. The connective tissue stroma has an essential role in the preservation of epithelial tissues and minor alterations in the epithelium are followed by corresponding changes in the stroma, such as angiogenesis. Vascular endothelial growth factor (VEGF) is considered the first factor which maintains its position as the most critical driver of vascular formation and is required to initiate the formation of immature vessels, with this aim, present study was executed to evaluate VEGF expression in kertocystic odontogenic tumor, dentigerous cyst and radicular cyst (RC). A retrospective study was carried out comprising a total of 31 cases; 13 cases of keratocystic odontogenic tumor (KCOT), nine cases of dentigerous cyst (DC) and nine cases of RC. The sections were stained immunohistochemically with VEGF antibody and were evaluated for the presence and intensity of the immuno reactive cells. Statistical analysis was carried out using Chi-square test to inter-compare the VEGF expression between KCOT, DC, and RC. VEGF expression in the epithelium and connective tissue was significantly higher in KCOT compared to dentigerous and RC. One case of KCOT with carcinomatous change also revealed positive results for the VEGF expression in the dysplastic epithelium, tumor islands, and connective tissue. The significant difference was observed on inter-comparison of the VEGF expression in the connective tissue of KCOT and DC, whereas no significant difference was observed in the VEGF expression in the connective tissue of KCOT and DC. The present study data supports the literature finding that angiogenesis can be important in the progression and enlargement of odontogenic cysts similarly to what occurs in neoplastic conditions and further it can be concluded that the higher positivity for VEGF of KCOT could help to

  1. Upregulation of angiogenesis in oral lichen planus.

    Science.gov (United States)

    Al-Hassiny, A; Friedlander, L T; Parachuru, V Pb; Seo, B; M Hussaini, H; Rich, A M

    2017-11-24

    Since angiogenesis is fundamental to the pathogenesis of many chronic inflammatory disorders this study investigated the expression of various vascular markers in oral lichen planus and non-specific oral mucosal inflammatory tissues. Archival specimens of oral lichen planus (n=15) and inflamed tissues (n=13) were stained using immunohistochemistry with antibodies to CD34, vascular endothelial growth factor, vascular endothelial growth factor receptor and vasohibin. Nine representative sites at the epithelial-connective tissue junction and through the fibrous connective tissue were selected and automated analysis techniques were used to determine the extent of positivity expressed as the percentage of positive cells. Significance was denoted when plichen planus samples compared with inflamed controls. A higher level of CD34 was observed in the deeper parts of the connective tissue of OLP (p=0.04), whereas VEGF and VEGFR2 expression was higher all through the tissues (respectively plichen planus in all sites evaluated (plichen planus compared with inflamed controls, with increased expression of pro-angiogenic factors and decreased anti-angiogenic expression. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  2. COMP-Angiopoietin-1 Promotes Cavernous Angiogenesis in a Type 2 Diabetic Rat Model

    OpenAIRE

    Kim, Sun-Ouck; Lee, Hyun-Suk; Ahn, Kyuyoun; Park, Kwangsung

    2013-01-01

    Cartilage oligomeric matrix protein-angiopoietin-1 (COMP-Ang1) is an angiogenic factor for vascular angiogenesis. The aim was to investigate the effect of an intracavernosal injection of COMP-Ang1 on cavernosal angiogenesis in a diabetic rat model. Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats made up the experimental group (1 yr old) and Long-Evans Tokushima Otsuka (LETO) rats made up the control group. The experimental group was divided into vehicle only, 10 ?g COMP-Ang1, and 20 ?g CO...

  3. VASCULAR ENDOTHELIAL GROWTH FACTORS IN HEART TRANSPLANT REJECTIONS

    Directory of Open Access Journals (Sweden)

    O. P. Shevchenko

    2015-01-01

    Full Text Available Aim: to determine the clinical significance of vascular endothelial growth factors VEGF-A, VEGF-D, PlGF-1 to assess the risk of cardiovascular complications in heart recipients. Materials and methods. 103 patients, aged 16 to 73 years, 85 males and 18 females. 65 recipients (47 men and 18 women had dilated cardiomyopathy, 38 – coronary heart disease (CHD. The concentration of VEGF-A, VEGF-D, PlGF-1 was measured using xMAP technology with sets of reagents Simplex ProcartaPlex™. Results. After HTx the level of VEGF-A significantly decreased, p = 0.001. There were no correlations between the levels of VEGF-A, VEGF-D and PlGF-1 with age, gender and diagnosis. After HTx VEGF-A level was higher in recipients with ACR than in those without it (p = 0.001. ACR frequency was significantly higher in patients with high VEGF-A level (≥316.5 pg/ml, RR = 5.8 ± 0.5, AUC = 0.779. After HTx PlGF-1 level was higher in recipients with ACR too (p = 0.039. ACR frequency was significantly higher in patients with high PlGF-1 level (≥5.33 pg/ml, RR = 1.8 ± 0.5, AUC = 0.65. There were no correlations between VEGF-D level with ACR and all three biomarkers with AMR. ACR frequency was significantly higher with both high VEGF-A and PlGF-1 levels (RR = 6.4. Conclusion. Serum levels of VEGF-A and PlGF-1 after HTx may be regarded as indicators of increased risk of ACR.

  4. Influence of vascular endothelial growth factor stimulation and serum deprivation on gene activation patterns of human adipose tissue-derived stromal cells

    DEFF Research Database (Denmark)

    Tratwal, Josefine; Mathiasen, Anders Bruun; Juhl, Morten

    2015-01-01

    INTRODUCTION: Stimulation of mesenchymal stromal cells and adipose tissue-derived stromal cells (ASCs) with vascular endothelial growth factor (VEGF) has been used in multiple animal studies and clinical trials for regenerative purposes. VEGF stimulation is believed to promote angiogenesis and VEGF...... stimulation is usually performed under serum deprivation. Potential regenerative molecular mechanisms are numerous and the role of contributing factors is uncertain. The aim of the current study was to investigate the effect of in vitro serum deprivation and VEGF stimulation on gene expression patterns...... of ASCs. METHODS: Gene expressions of ASCs cultured in complete medium, ASCs cultured in serum-deprived medium and ASCs stimulated with VEGF in serum-deprived medium were compared. ASC characteristics according to criteria set by the International Society of Cellular Therapy were confirmed by flow...

  5. Transcription of Inflammatory Cytokine TNFα is Upregulated in Retinal Angiogenesis under Hyperoxia

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    Yuxi Feng

    2016-07-01

    Full Text Available Background/Aims: Hypoxia induces angiogenesis while hyperoxia promotes vasoregression in the retina. We investigated herein the effect of prolonged hyperoxia on retinal angiogenesis and the underlying mechanism in an oxygen-induced retinopathy (OIR model. Methods: Vascular morphology was quantified in whole-mount retina from the mice subjected to the conventional OIR model (c-OIR or the OIR model with prolonged hyperoxia (p-OIR. Expressions of genes related to angiogenesis were determined by real-time PCR. Results: p-OIR retinas showed few intraretinal neovascular tufts at the border of avascular zones, lacking preretinal neovascularization, whereas c-OIR retinas had numerous preretinal neovascularizations. p-OIR retinas demonstrated outgrowth of capillaries in the deep layers despite persistent hyperoxia and possess a larger avascular zone compared with the c-OIR retinas. The capillaries in the p-OIR retinas were well-formed in contrast to those in the c-OIR retinas. p-OIR retinas expressed significantly higher TNFα (∼4 fold than c-OIR retinas. The expression of vascular endothelial growth factor, Erythropoietin, Angiopoietin 1 and 2 remained unchanged. Conclusion: Our data demonstrate that TNFα transcription is increased in hyperoxia-promoted retinal angiogenesis, implicating it, in association with low VEGF levels, as a possible proponent in retinal angiogenesis under hyperoxia.

  6. Low-Level Laser Therapy Promoted Aggressive Proliferation and Angiogenesis Through Decreasing of Transforming Growth Factor-β1 and Increasing of Akt/Hypoxia Inducible Factor-1α in Anaplastic Thyroid Cancer.

    Science.gov (United States)

    Rhee, Yun-Hee; Moon, Jeong-Hwan; Choi, Sun-Hyang; Ahn, Jin-Chul

    2016-06-01

    We assessed the cause of increased tumor after low-level laser therapy (LLLT) by histological analysis. LLLT is a nonthermal phototherapy used in several medical applications, including wound healing, reduction of pain, and amelioration of oral mucositis. We discovered by accident that LLLT increased tumor size while testing a photodynamic therapy (PDT) model for the treatment of thyroid cancer. Although therapeutic effects of LLLT on cancer or dysplastic cells have been studied, LLLT has been recently reported to stimulate the aggressiveness of the tumor. The anaplastic thyroid cancer cell line FRO was injected into thyroid glands of nude mice orthotopically and then laser irradiation was performed with 0, 15, and 30 J/cm(2) (100 mW/cm(2)) on the thyroid after 10 days. The tumor volume was measured for 4 weeks and the thyroid tissues underwent histological analysis. We observed that proliferation of FRO cells and macrophage infiltration was increased with energy delivery to the thyroid glands. We also assessed overproliferated FRO cells using an immunohistochemical staining with hypoxia inducible factor 1α (HIF-1α), p-Akt, vascular endothelial growth factor (VEGF), and transforming growth factor β1 (TGF-β1). HIF-1α and p-Akt were elevated after LLLT, which suggested that the phosphorylation of Akt by LLLT led to the activation of HIF-1α. Moreover, TGF-β1 expression was decreased after LLLT, which led to loss of cell cycle regulation. In conclusion, LLLT led to a decrease in TGF-β1 and increase of p-Akt/HIF-1α which resulted to overproliferation and angiogenesis of anaplastic thyroid carcinoma (ATC). Therefore, we suggest that LLLT can influence cancer aggressiveness associated with TGF-β1 and Akt/HIF-1α cascades in some poorly differentiated head and neck cancers.

  7. Procyanidins Mitigate Osteoarthritis Pathogenesis by, at Least in Part, Suppressing Vascular Endothelial Growth Factor Signaling

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    Angela Wang

    2016-12-01

    Full Text Available Procyanidins are a family of plant metabolites that have been suggested to mitigate osteoarthritis pathogenesis in mice. However, the underlying mechanism is largely unknown. This study aimed to determine whether procyanidins mitigate traumatic injury-induced osteoarthritis (OA disease progression, and whether procyanidins exert a chondroprotective effect by, at least in part, suppressing vascular endothelial growth factor signaling. Procyanidins (extracts from pine bark, orally administered to mice subjected to surgery for destabilization of the medial meniscus, significantly slowed OA disease progression. Real-time polymerase chain reaction revealed that procyanidin treatment reduced expression of vascular endothelial growth factor and effectors in OA pathogenesis that are regulated by vascular endothelial growth factor. Procyanidin-suppressed vascular endothelial growth factor expression was correlated with reduced phosphorylation of vascular endothelial growth factor receptor 2 in human OA primary chondrocytes. Moreover, components of procyanidins, procyanidin B2 and procyanidin B3 exerted effects similar to those of total procyanidins in mitigating the OA-related gene expression profile in the primary culture of human OA chondrocytes in the presence of vascular endothelial growth factor. Together, these findings suggest procyanidins mitigate OA pathogenesis, which is mediated, at least in part, by suppressing vascular endothelial growth factor signaling.

  8. Coronary Serum Obtained After Myocardial Infarction Induces Angiogenesis and Microvascular Obstruction Repair. Role of Hypoxia-inducible Factor-1A.

    Science.gov (United States)

    Ríos-Navarro, César; Hueso, Luisa; Miñana, Gema; Núñez, Julio; Ruiz-Saurí, Amparo; Sanz, María Jesús; Cànoves, Joaquin; Chorro, Francisco J; Piqueras, Laura; Bodí, Vicente

    2017-07-24

    Microvascular obstruction (MVO) exerts deleterious effects following acute myocardial infarction (AMI). We investigated coronary angiogenesis induced by coronary serum and the role of hypoxia-inducible factor-1A (HIF-1A) in MVO repair. Myocardial infarction was induced in swine by transitory 90-minute coronary occlusion. The pigs were divided into a control group and 4 AMI groups: no reperfusion, 1minute, 1 week and 1 month after reperfusion. Microvascular obstruction and microvessel density were quantified. The proangiogenic effect of coronary serum drawn from coronary sinus on endothelial cells was evaluated using an in vitro tubulogenesis assay. Circulating and myocardial HIF-1A levels and the effect of in vitro blockade of HIF-1A was assessed. Compared with control myocardium, microvessel density decreased at 90-minute ischemia, and MVO first occurred at 1minute after reperfusion. Both peaked at 1 week and almost completely resolved at 1 month. Coronary serum exerted a neoangiogenic effect on coronary endothelial cells in vitro, peaking at ischemia and 1minute postreperfusion (32 ± 4 and 41 ± 9 tubes vs control: 3 ± 3 tubes; P < .01). Hypoxia-inducible factor-1A increased in serum during ischemia (5-minute ischemia: 273 ± 52 pg/mL vs control: 148 ± 48 pg/mL; P < .01) being present on microvessels of all AMI groups (no reperfusion: 67% ± 5% vs control: 15% ± 17%; P < .01). In vitro blockade of HIF-1A reduced the angiogenic response induced by serum. Coronary serum represents a potent neoangiogenic stimulus even before reperfusion; HIF-1A might be crucial. Coronary neoangiogenesis induced by coronary serum can contribute to understanding the pathophysiology of AMI. Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

  9. Anti-tumor activity of a novel HS-mimetic-vascular endothelial growth factor binding small molecule.

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    Kazuyuki Sugahara

    Full Text Available The angiogenic process is controlled by variety of factors of which the vascular endothelial growth factor (VEGF pathway plays a major role. A series of heparan sulfate mimetic small molecules targeting VEGF/VEGFR pathway has been synthesized. Among them, compound 8 (2-butyl-5-chloro-3-(4-nitro-benzyl-3H-imidazole-4-carbaldehyde was identified as a significant binding molecule for the heparin-binding domain of VEGF, determined by high-throughput-surface plasmon resonance assay. The data predicted strong binding of compound 8 with VEGF which may prevent the binding of VEGF to its receptor. We compared the structure of compound 8 with heparan sulfate (HS, which have in common the functional ionic groups such as sulfate, nitro and carbaldehyde that can be located in similar positions of the disaccharide structure of HS. Molecular docking studies predicted that compound 8 binds at the heparin binding domain of VEGF through strong hydrogen bonding with Lys-30 and Gln-20 amino acid residues, and consistent with the prediction, compound 8 inhibited binding of VEGF to immobilized heparin. In vitro studies showed that compound 8 inhibits the VEGF-induced proliferation migration and tube formation of mouse vascular endothelial cells, and finally the invasion of a murine osteosarcoma cell line (LM8G7 which secrets high levels of VEGF. In vivo, these effects produce significant decrease of tumor burden in an experimental model of liver metastasis. Collectively, these data indicate that compound 8 may prevent tumor growth through a direct effect on tumor cell proliferation and by inhibition of endothelial cell migration and angiogenesis mediated by VEGF. In conclusion, compound 8 may normalize the tumor vasculature and microenvironment in tumors probably by inhibiting the binding of VEGF to its receptor.

  10. Impaired autonomic regulation of resistance arteries in mice with low vascular endothelial growth factor or upon vascular endothelial growth factor trap delivery

    DEFF Research Database (Denmark)

    Storkebaum, Erik; Ruiz de Almodovar, Carmen; Meens, Merlijn

    2010-01-01

    BACKGROUND: Control of peripheral resistance arteries by autonomic nerves is essential for the regulation of blood flow. The signals responsible for the maintenance of vascular neuroeffector mechanisms in the adult, however, remain largely unknown. METHODS AND RESULTS: Here, we report that VEGF( ...... for VEGF in the maintenance of arterial neuroeffector function and may help us better understand how VEGF inhibitors cause vascular regulation defects in cancer patients.......( partial differential/ partial differential) mice with low vascular endothelial growth factor (VEGF) levels suffer defects in the regulation of resistance arteries. These defects are due to dysfunction and structural remodeling of the neuroeffector junction, the equivalent of a synapse between autonomic...... nerve endings and vascular smooth muscle cells, and to an impaired contractile smooth muscle cell phenotype. Notably, short-term delivery of a VEGF inhibitor to healthy mice also resulted in functional and structural defects of neuroeffector junctions. CONCLUSIONS: These findings uncover a novel role...

  11. Vascular endothelial growth factor receptor 2 as a marker for malignant vascular tumors and mesothelioma: an immunohistochemical study of 262 vascular endothelial and 1640 nonvascular tumors.

    Science.gov (United States)

    Miettinen, Markku; Rikala, Maarit-Sarlomo; Rys, Janusz; Lasota, Jerzy; Wang, Zeng-Feng

    2012-04-01

    Vascular endothelial growth factor receptor 2 (VEGFR2) is a primary responder to vascular endothelial growth factor signal and thereby regulates endothelial migration and proliferation. This receptor is expressed in endothelial cells and in some vascular tumors, but many reports also detail its expression in carcinomas and lymphomas. VEGFR2 is a potential cell-type marker, and data on VEGFR2 expression may also have therapeutic significance in view of recent availability of VEGFR2 inhibitors. In this study, we immunohistochemically examined 262 vascular endothelial and 1640 nonvascular tumors and selected non-neoplastic tissues with a VEGFR2-specific rabbit monoclonal antibody 55B11. In early human embryo, VEFGR2 was expressed in endothelia of developing capillaries and in the thoracic duct, great vessels, hepatic sinusoids, epidermis, and mesothelia. In late first trimester fetus peripheral soft tissues, VEGFR2 was restricted to capillary endothelia, chondrocytes, and superficial portion of the epidermis. In normal adult tissues, it was restricted to endothelia and mesothelia. VEGFR2 was consistently expressed in angiosarcomas, Kaposi sarcomas, and retiform hemangioendotheliomas. It was detected in only half of epithelioid hemangioendotheliomas (15/27), usually focally. VEGFR2 was strongly expressed in most capillary hemangiomas and weakly or focally in cavernous, venous, and spindle cell hemangiomas and in lymphangiomas. Malignant epithelial mesothelioma was found to be a unique epithelial neoplasm with a strong and nearly consistent VEGFR2 expression, including membrane staining (35/38). Approximately 10% of squamous cell carcinomas and 23% of pulmonary adenocarcinomas contained focal positivity. The only nonendothelial mesenchymal tumors found to be VEGFR2 positive were biphasic synovial sarcoma (focal epithelial expression) and chordoma. All melanomas and lymphomas were negative. VEGFR2 is a promising marker for malignant vascular tumors and malignant

  12. Integrated approaches to spatiotemporally directing angiogenesis in host and engineered tissues.

    Science.gov (United States)

    Kant, Rajeev J; Coulombe, Kareen L K

    2018-03-15

    The field of tissue engineering has turned towards biomimicry to solve the problem of tissue oxygenation and nutrient/waste exchange through the development of vasculature. Induction of angiogenesis and subsequent development of a vascular bed in engineered tissues is actively being pursued through combinations of physical and chemical cues, notably through the presentation of topographies and growth factors. Presenting angiogenic signals in a spatiotemporal fashion is beginning to generate improved vascular networks, which will allow for the creation of large and dense engineered tissues. This review provides a brief background on the cells, mechanisms, and molecules driving vascular development (including angiogenesis), followed by how biomaterials and growth factors can be used to direct vessel formation and maturation. Techniques to accomplish spatiotemporal control of vascularization include incorporation or encapsulation of growth factors, topographical engineering, and 3D bioprinting. The vascularization of engineered tissues and their application in angiogenic therapy in vivo is reviewed herein with an emphasis on the most densely vascularized tissue of the human body - the heart. Vascularization is vital to wound healing and tissue regeneration, and development of hierarchical networks enables efficient nutrient transfer. In tissue engineering, vascularization is necessary to support physiologically dense engineered tissues, and thus the field seeks to induce vascular formation using biomaterials and chemical signals to provide appropriate, pro-angiogenic signals for cells. This review critically examines the materials and techniques used to generate scaffolds with spatiotemporal cues to direct vascularization in engineered and host tissues in vitro and in vivo. Assessment of the field's progress is intended to inspire vascular applications across all forms of tissue engineering with a specific focus on highlighting the nuances of cardiac tissue

  13. Proof-of-principle investigation of an algorithmic model of adenosine-mediated angiogenesis

    Directory of Open Access Journals (Sweden)

    Devaux Yvan

    2011-04-01

    Full Text Available Abstract Background We investigated an algorithmic approach to modelling angiogenesis controlled by vascular endothelial growth factor (VEGF, the anti-angiogenic soluble VEGF receptor 1 (sVEGFR-1 and adenosine (Ado. We explored its feasibility to test angiogenesis-relevant hypotheses. We illustrated its potential to investigate the role of Ado as an angiogenesis modulator by enhancing VEGF activity and antagonizing sVEGFR-1. Results We implemented an algorithmic model of angiogenesis consisting of the dynamic interaction of endothelial cells, VEGF, sVEGFR-1 and Ado entities. The model is based on a logic rule-based methodology in which the local behaviour of the cells and molecules is encoded using if-then rules. The model shows how Ado may enhance angiogenesis through activating and inhibiting effects on VEGF and sVEGFR-1 respectively. Despite the relative simplicity of the model, it recapitulated basic features observed in in vitro models. However, observed disagreements between our models and in vitro data suggest possible knowledge gaps and may guide future experimental directions. Conclusions The proposed model can support the exploration of hypotheses about the role of different molecular entities and experimental conditions in angiogenesis. Future expansions can also be applied to assist research planning in this and other biomedical domains.

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

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    Jertta-Riina Sarkanen

    2011-01-01

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

  15. Digital Microscopy Assessment of Angiogenesis in Different Breast Cancer Compartments

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    Anca Haisan

    2013-01-01

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

  16. Time Course of Flow-Mediated Dilation and Vascular Endothelial Growth Factor following Acute Stroke.

    Science.gov (United States)

    Billinger, Sandra A; Sisante, Jason-Flor V; Whitaker, Alicen A; Abraham, Michael G

    2017-11-30

    People after stroke demonstrate alterations in vascular endothelial function measured by flow-mediated dilation. Limited information is available in the literature on possible protective factors following stroke. The aims of the secondary analysis were (1) to characterize the time course of vascular endothelial function using flow-mediated dilation at 72 hours after stroke and 1 week later during inpatient stroke rehabilitation and (2) to determine whether flow-mediated dilation was related to vascular endothelial growth factor, brain-derived neurotrophic factor, or estimated prestroke peak oxygen uptake. Flow-mediated dilation using Doppler ultrasound was assessed in bilateral brachial arteries at the defined time points. Flow-mediated dilation and blood draws occurred on the same day between 7:30 am and 9:00 am following an overnight fast. Enzyme-linked immunosorbent assay was used to quantify plasma vascular endothelial growth factor and brain-derived neurotrophic factor values. A nonexercise estimate was used to calculate prestroke peak oxygen uptake. We have shown that between-limb differences are evident within 72 hours after stroke and remain 1 week later during inpatient rehabilitation. Higher values for vascular endothelial growth factor were associated with increased flow-mediated dilation at both time points. Higher estimated prestroke peak oxygen uptake was related to flow-mediated dilation. Brain-derived neurotrophic factor was not related to any outcome measures. Unique vascular adaptations start early after stroke in the stroke-affected limb and remain through inpatient stroke rehabilitation. Vascular endothelial growth factor and prestroke physical activity may have a protective role in vascular function following stroke. Future work should focus on mechanistic pathways for preservation of vascular health. Copyright © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.

  17. Vascular endothelial growth factor receptor-1 in human cancer: concise review and rationale for development of IMC-18F1 (Human antibody targeting vascular endothelial growth factor receptor-1).

    Science.gov (United States)

    Schwartz, Jonathan D; Rowinsky, Eric K; Youssoufian, Hagop; Pytowski, Bronislaw; Wu, Yan

    2010-02-15

    The human vascular endothelial growth factor receptor-1 (VEGFR-1, or Flt-1) is widely expressed in normal and pathologic tissue and contributes to the pathogenesis of both neoplastic and inflammatory diseases. In human cancer, VEGFR-1 mediated signaling is responsible for both direct tumor activation and angiogenesis. VEGFR-1 mediated activation of nonmalignant supporting cells, particularly stromal, dendritic, hematopoietic cells, and macrophages, is also likely important for cancer pathogenesis. VEGFR-1 is also hypothesized to enable the development of cancer metastases by means of activation and premetastatic localization in distant organs of bone marrow-derived hematopoietic progenitor cells, which express VEGFR-1. IMC-18F1 is a fully human IgG(1) antibody that binds to VEGFR-1 and has been associated with the inhibition of cancer growth in multiple in vitro and human tumor xenograft models. The preliminary results of phase 1 investigations have also indicated a favorable safety profile for IMC-18F1 at doses that confer antibody concentrations that are associated with relevant antitumor activity in preclinical models. (c) 2010 American Cancer Society.

  18. Chemical allergens stimulate human epidermal keratinocytes to produce lymphangiogenic vascular endothelial growth factor

    Energy Technology Data Exchange (ETDEWEB)

    Bae, Ok-Nam [College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791 (Korea, Republic of); Ahn, Seyeon; Jin, Sun Hee; Hong, Soo Hyun; Lee, Jinyoung [College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742 (Korea, Republic of); Kim, Eun-Sun [College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 426-791 (Korea, Republic of); Jeong, Tae Cheon [College of Pharmacy, Yeungnam University, Gyeongsan 712-749 (Korea, Republic of); Chun, Young-Jin [College of Pharmacy, Chung-Ang University, Seoul 156-756 (Korea, Republic of); Lee, Ai-Young, E-mail: leeay@duih.org [Department of Dermatology, Dongguk University Ilsan Hospital, Goyang 410-773 (Korea, Republic of); Noh, Minsoo, E-mail: minsoo@alum.mit.edu [College of Pharmacy, Natural Products Research Institute, Seoul National University, Seoul 151-742 (Korea, Republic of)

    2015-03-01

    Allergic contact dermatitis (ACD) is a cell-mediated immune response that involves skin sensitization in response to contact with various allergens. Angiogenesis and lymphangiogenesis both play roles in the allergic sensitization process. Epidermal keratinocytes can produce vascular endothelial growth factor (VEGF) in response to UV irradiation and during wound healing. However, the effect of haptenic chemical allergens on the VEGF production of human keratinocytes, which is the primary contact site of toxic allergens, has not been thoroughly researched. We systematically investigated whether immune-regulatory cytokines and chemical allergens would lead to the production of VEGF in normal human keratinocytes (NHKs) in culture. VEGF production significantly increased when NHKs were treated with IFNγ, IL-1α, IL-4, IL-6, IL-17A, IL-22 or TNFα. Among the human sensitizers listed in the OECD Test Guideline (TG) 429, we found that CMI/MI, DNCB, 4-phenylenediamine, cobalt chloride, 2-mercaptobenzothiazole, citral, HCA, cinnamic alcohol, imidazolidinyl urea and nickel chloride all significantly upregulated VEGF production in NHKs. In addition, common human haptenic allergens such as avobenzone, formaldehyde and urushiol, also induced the keratinocyte-derived VEGF production. VEGF upregulation by pro-inflammatory stimuli, IFNγ, DNCB or formaldehyde is preceded by the production of IL-8, an acute inflammatory phase cytokine. Lymphangiogenic VEGF-C gene transcription was significantly increased when NHKs were treated with formaldehyde, DNCB or urushiol, while transcription of VEGF-A and VEGF-B did not change. Therefore, the chemical allergen-induced VEGF upregulation is mainly due to the increase in lymphangiogenic VEGF-C transcription in NHKs. These results suggest that keratinocyte-derived VEGF may regulate the lymphangiogenic process during the skin sensitization process of ACD. - Highlights: • Pro-inflammatory cytokines induced VEGF production in normal human

  19. Elevated TATA-binding protein expression drives vascular endothelial growth factor expression in colon cancer

    Science.gov (United States)

    Johnson, Sandra A.S.; Lin, Justin J.; Walkey, Christopher J.; Leathers, Michael P.; Coarfa, Cristian; Johnson, Deborah L.

    2017-01-01

    The TATA-binding protein (TBP) plays a central role in eukaryotic gene transcription. Given its key function in transcription initiation, TBP was initially thought to be an invariant protein. However, studies showed that TBP expression is upregulated by oncogenic signaling pathways. Furthermore, depending on the cell type, small increases in cellular TBP amounts can induce changes in cellular growth properties towards a transformed phenotype. Here we sought to identify the specific TBP-regulated gene targets that drive its ability to induce tumorigenesis. Using microarray analysis, our results reveal that increases in cellular TBP concentrations produce selective alterations in gene expression that include an enrichment for genes involved in angiogenesis. Accordingly, we find that TBP levels modulate VEGFA expression, the master regulator of angiogenesis. Increases in cellular TBP amounts induce VEGFA expression and secretion to enhance cell migration and tumor vascularization. TBP mediates changes in VEGFA transcription requiring its recruitment at a hypoxia-insensitive proximal TSS, revealing a mechanism for VEGF regulation under non-stress conditions. The results are clinically relevant as TBP expression is significantly increased in both colon adenocarcinomas as well as adenomas relative to normal tissue. Furthermore, TBP expression is positively correlated with VEGFA expression. Collectively, these studies support the idea that increases in TBP expression contribute to enhanced VEGFA transcription early in colorectal cancer development to drive tumorigenesis. PMID:28415573

  20. SMART risk factor screening in patients at high vascular risk

    NARCIS (Netherlands)

    Brouwer, B.G.

    2008-01-01

    Studies presented in this thesis focused on the relationship between the presence of coronary heart disease and intra-abdominal fat, and the relationship between leisure-time physical activity and the presence of metabolic syndrome, incidence of type 2 diabetes and recurrence of vascular events in

  1. Quantitative estimates of vascularity in a collagen-based cell scaffold containing basic fibroblast growth factor by non-invasive near-infrared spectroscopy for regenerative medicine

    Science.gov (United States)

    Kushibiki, Toshihiro; Awazu, Kunio

    2008-04-01

    Successful tissue regeneration required both cells with high proliferative and differentiation potential and an environment permissive for regeneration. These conditions can be achieved by providing cell scaffolds and growth factors that induce angiogenesis and cell proliferation. Angiogenenis within cell scaffolds is typically determined by histological examination with immunohistochemical markers for endothelium. Unfortunately, this approach requires removal of tissue and the scaffold. In this study, we examined the hemoglobin content of implanted collagen-based cell scaffolds containing basic fibroblast growth factor (bFGF) in vivo by non-invasive near infrared spectroscopy (NIRS). We also compared the hemoglobin levels measured by NIRS to the hemoglobin content measured with a conventional biological assay. Non-invasive NIRS recordings were performed with a custom-built near-infrared spectrometer using light guide-coupled reflectance measurements. NIRS recordings revealed that absorbance increased after implantation of collagen scaffolds containing bFGF. This result correlated (R2=0.93) with our subsequent conventional hemoglobin assay. The NIRS technique provides a non-invasive method for measuring the degree of vascularization in cell scaffolds. This technique may be advantageous for monitoring angiogenesis within different cell scaffolds, a prerequisite for effective tissue regeneration.

  2. Candesartan Induces a Prolonged Proangiogenic Effect and Augments Endothelium-Mediated Neuroprotection after Oxygen and Glucose Deprivation: Role of Vascular Endothelial Growth Factors A and B

    Science.gov (United States)

    Soliman, Sahar; Ishrat, Tauheed; Pillai, Anilkumar; Somanath, Payaningal R.; Ergul, Adviye

    2014-01-01

    Angiogenesis is a key component of recovery after stroke. Angiotensin II receptor blocker (ARB) treatment improves neurobehavioral outcome and is associated with enhanced angiogenesis after stroke. The purpose of this study is to investigate the temporal pattern of the ARB proangiogenic effect in the ischemic brain and its association with vascular endothelial growth factors VEGF-A and VEGF-B. Wistar rats were exposed to 90-minute middle cerebral artery occlusion and treated with candesartan (1 mg/kg) at reperfusion. The proangiogenic potential of the cerebrospinal fluid was determined at 8, 24, 48, and 72 hours using an in vitro Matrigel tube formation assay. In addition, the expression of VEGF-A and VEGF-B was measured in brain homogenates using Western blotting at the same time points. A single candesartan dose induced a prolonged proangiogenic effect and a prolonged upregulation of VEGF-A and VEGF-B in vivo. In the ischemic hemisphere, candesartan treatment was associated with stabilization of hypoxia-inducible factor-1α and preservation of angiopoietin-1. The effect of ARB treatment on endothelial cells was studied in vitro. Our results identified brain endothelial cells as one target for the action of ARBs and a source of the upregulated VEGF-A and VEGF-B, which exerted an autocrine angiogenic response, in addition to a paracrine neuroprotective effect. Taken together, this study highlights the potential usefulness of augmenting the endogenous restorative capacity of the brain through the administration of ARBs. PMID:24681872

  3. 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.

  4. Diabetes and Wound Angiogenesis

    Directory of Open Access Journals (Sweden)

    Uzoagu A. Okonkwo

    2017-07-01

    Full Text Available Diabetes Mellitus Type II (DM2 is a growing international health concern with no end in sight. Complications of DM2 involve a myriad of comorbidities including the serious complications of poor wound healing, chronic ulceration, and resultant limb amputation. In skin wound healing, which has definite, orderly phases, diabetes leads to improper function at all stages. While the etiology of chronic, non-healing diabetic wounds is multi-faceted, the progression to a non-healing phenotype is closely linked to poor vascular networks. This review focuses on diabetic wound healing, paying special attention to the aberrations that have been described in the proliferative, remodeling, and maturation phases of wound angiogenesis. Additionally, this review considers therapeutics that may offer promise to better wound healing outcomes.

  5. Inhibition of Angiogenesis In Vitro by Chebulagic Acid: A COX-LOX Dual Inhibitor

    Directory of Open Access Journals (Sweden)

    A. P. Athira

    2013-01-01

    Full Text Available Angiogenesis is a crucial step in the growth of cancer and its metastasis. It is regulated by several endogenous factors which may stimulate or inhibit the new blood vessel growth. Besides these endogenous factors, several exogenous factors including some natural compounds are known to modulate angiogenesis. Angiogenesis being a potential target for drugs against a number of pathological conditions, search for compounds from natural sources that can affect angiogenesis is of great interest. The objective of our present study was to understand the effect of chebulagic acid, a COX-LOX dual inhibitor isolated from the fruits of Terminalia chebula Retz., on angiogenesis. The model systems used were rat aortic rings and human umbilical vein endothelial cells. The results showed that chebulagic acid exerts an antiangiogenic effect. This was evidenced from decreased sprouting in rat aortic rings and decrease in biochemical markers in endothelial cells treated with chebulagic acid. It downregulated the production of CD31, E-selectin, and vascular endothelial growth factor in human umbilical vein endothelial cells in culture (HUVEC. Further studies to understand the molecular mechanism of action of chebulagic acid revealed that CA exerts its anti angiogenic effect by modulating VE cadherin-β catenin signalling in human umbilical vein endothelial cells.

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

    Energy Technology Data Exchange (ETDEWEB)

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

    2016-02-19

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

  7. 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

  8. Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A.

    Directory of Open Access Journals (Sweden)

    Stephanie Jamison

    Full Text Available Evidence is accumulating that activation of the pancreatic endoplasmic reticulum kinase (PERK in response to endoplasmic reticulum (ER stress adapts tumor cells to the tumor microenvironment and enhances tumor angiogenesis by inducing vascular endothelial growth factor A (VEGF-A. Recent studies suggest that VEGF-A can act directly on certain tumor cell types in an autocrine manner, via binding to VEGF receptor 2 (VEGFR2, to promote tumor cell migration and invasion. Although several reports show that PERK activation increases VEGF-A expression in medulloblastoma, the most common solid malignancy of childhood, the role that either PERK or VEGF-A plays in medulloblastoma remains elusive. In this study, we mimicked the moderate enhancement of PERK activity observed in tumor patients using a genetic approach and a pharmacologic approach, and found that moderate activation of PERK signaling facilitated medulloblastoma cell migration and invasion and increased the production of VEGF-A. Moreover, using the VEGFR2 inhibitor SU5416 and the VEGF-A neutralizing antibody to block VEGF-A/VEGFR2 signaling, our results suggested that tumor cell-derived VEGF-A promoted medulloblastoma cell migration and invasion through VEGFR2 signaling, and that both VEGF-A and VEGFR2 were required for the promoting effects of PERK activation on medulloblastoma cell migration and invasion. Thus, these findings suggest that moderate PERK activation promotes medulloblastoma cell migration and invasion through enhancement of VEGF-A/VEGFR2 signaling.

  9. Pancreatic Endoplasmic Reticulum Kinase Activation Promotes Medulloblastoma Cell Migration and Invasion through Induction of Vascular Endothelial Growth Factor A

    Science.gov (United States)

    Jamison, Stephanie; Lin, Yifeng; Lin, Wensheng

    2015-01-01

    Evidence is accumulating that activation of the pancreatic endoplasmic reticulum kinase (PERK) in response to endoplasmic reticulum (ER) stress adapts tumor cells to the tumor microenvironment and enhances tumor angiogenesis by inducing vascular endothelial growth factor A (VEGF-A). Recent studies suggest that VEGF-A can act directly on certain tumor cell types in an autocrine manner, via binding to VEGF receptor 2 (VEGFR2), to promote tumor cell migration and invasion. Although several reports show that PERK activation increases VEGF-A expression in medulloblastoma, the most common solid malignancy of childhood, the role that either PERK or VEGF-A plays in medulloblastoma remains elusive. In this study, we mimicked the moderate enhancement of PERK activity observed in tumor patients using a genetic approach and a pharmacologic approach, and found that moderate activation of PERK signaling facilitated medulloblastoma cell migration and invasion and increased the production of VEGF-A. Moreover, using the VEGFR2 inhibitor SU5416 and the VEGF-A neutralizing antibody to block VEGF-A/VEGFR2 signaling, our results suggested that tumor cell-derived VEGF-A promoted medulloblastoma cell migration and invasion through VEGFR2 signaling, and that both VEGF-A and VEGFR2 were required for the promoting effects of PERK activation on medulloblastoma cell migration and invasion. Thus, these findings suggest that moderate PERK activation promotes medulloblastoma cell migration and invasion through enhancement of VEGF-A/VEGFR2 signaling. PMID:25794107

  10. Angiogenesis in cutaneous disease: Part II

    OpenAIRE

    Laquer, V; Hoang, V.; Nguyen, A; Kelly, KM

    2009-01-01

    This review will discuss the role of angiogenesis in specific cutaneous diseases. Scientific evidence now points to the role of angiogenesis in tumor development and many other cutaneous disorders. Angiogenesis is a complex process that involves angiogenic growth factors and inhibitors, many of which could be a potential target for pharmacologic intervention. Antiangiogenic agents have recently been applied to dermatologic diseases with promising efficacy. Learning objectives: After completin...

  11. Diagnostic Power of Vascular Endothelial Growth Factor and Macrophage Colony-Stimulating Factor in Breast Cancer Patients Based on ROC Analysis

    Directory of Open Access Journals (Sweden)

    Monika Zajkowska

    2016-01-01

    Full Text Available Breast cancer (BC is the most common malignancy in women. Vascular endothelial growth factor (VEGF has been described as an important regulator of angiogenesis which plays a vital role in the progression of tumor. Macrophage colony-stimulating factor (M-CSF is a cytokine whose functions include regulation of hematopoietic lineages cells growth, proliferation, and differentiation. We investigated the diagnostic significance of these parameters in comparison to CA15-3 in BC patients and in relation to the control group (benign breast tumor and healthy women. Plasma levels of the tested parameters were determined by ELISA and CA15-3 was determined by CMIA. VEGF was shown to be comparable to CA15-3 values of sensitivity in BC group and, what is more important, higher values in early stages of BC. VEGF was also the only parameter which has statistically significant AUC in all stages of cancer. M-CSF has been shown to be comparable to CA15-3 and VEGF, specificity, and AUC values only in stages III and IV of BC. These results indicate the usefulness and high diagnostic power of VEGF in the detection of BC. Also, it occurred to be the best candidate for cancer diagnostics in stages I and II of BC and in the differentiation between BC and benign cases.

  12. Hepatocyte growth factor increases vascular endothelial growth factor-A production in human synovial fibroblasts through c-Met receptor pathway.

    Directory of Open Access Journals (Sweden)

    Yu-Min Lin

    Full Text Available BACKGROUND: Angiogenesis is essential for the progression of osteoarthritis (OA. Hepatocyte growth factor (HGF is an angiogenic mediator, and it shows elevated levels in regions of OA. However, the relationship between HGF and vascular endothelial growth factor (VEGF-A in OA synovial fibroblasts (OASFs is mostly unknown. METHODOLOGY/PRINCIPAL FINDINGS: Here we found that stimulation of OASFs with HGF induced concentration- and time-dependent increases in VEGF-A expression. Pretreatment with PI3K inhibitor (Ly294002, Akt inhibitor, or mTORC1 inhibitor (rapamycin blocked the HGF-induced VEGF-A production. Treatment of cells with HGF also increased PI3K, Akt, and mTORC1 phosphorylation. Furthermore, HGF increased the stability and activity of HIF-1 protein. Moreover, the use of pharmacological inhibitors or genetic inhibition revealed that c-Met, PI3K, Akt, and mTORC1 signaling pathways were potentially required for HGF-induced HIF-1α activation. CONCLUSIONS/SIGNIFICANCE: Taken together, our results provide evidence that HGF enhances VEGF-A expression in OASFs by an HIF-1α-dependent mechanism involving the activation of c-Met/PI3K/Akt and mTORC1 pathways.

  13. Acclimatization to 4100 m does not change capillary density or mRNA expression of potential angiogenesis regulatory factors in human skeletal muscle

    DEFF Research Database (Denmark)

    Lundby, Carsten; Pilegaard, Henriette; Andersen, Jesper L.

    2004-01-01

    Increased skeletal muscle capillary density would be a logical adaptive mechanism to chronic hypoxic exposure. However, animal studies have yielded conflicting results, and human studies are sparse. Neoformation of capillaries is dependent on endothelial growth factors such as vascular endothelial...

  14. A Novel Vascular Endothelial Growth Factor Receptor Participates in White Spot Syndrome Virus Infection in Litopenaeus vannamei

    Directory of Open Access Journals (Sweden)

    Shihao Li

    2017-11-01

    Full Text Available Vascular endothelial growth factor (VEGF signaling pathway is known to play key roles in endothelial cell proliferation, migration, angiogenesis, vascular permeability, inhibition of apoptosis, and virus infection. In the present study, a novel VEGFR gene (LvVEGFR2 was identified and characterized from Litopenaeus vannamei. The deduced amino acid sequence of LvVEGFR2 possessed typical features of VEGFRs reported in other species, including six IG-like domains, a transmembrane motif, a protein kinase (PK domain, and one tyrosine-PK active site. The transcripts of LvVEGFR2 were mainly detected in hemocytes and lymphoid organ (Oka. Subcellular localization analysis showed that LvVEGFR2 was a membrane protein. Its expression level was obviously upregulated in hemocytes and Oka of the shrimp after white spot syndrome virus (WSSV infection. Knockdown of LvVEGFR2 gene expression by double-strand RNA mediated interference could lead to a decrease of virus copy number in WSSV-infected shrimp. The interaction between LvVEGFR2 and different LvVEGFs (LvVEGF1, LvVEGF2, and LvVEGF3 in shrimp was analyzed at the transcription level and protein level, respectively. Knockdown of LvVEGF2 or LvVEGF3 could downregulate the expression level of LvVEGFR2, and injection of the recombinant LvVEGF2 or LvVEGF3 could upregulate the expression level of LvVEGFR2. Yeast two-hybrid analysis showed that LvVEGFR2 could interact with LvVEGF2 and LvVEGF3 directly. The study improved our understanding on the VEGF signaling pathway of shrimp and its role during WSSV infection.

  15. Review of the role of the plasminogen activator system and vascular endothelial growth factor in subfertility.

    NARCIS (Netherlands)

    Ebisch, I.M.W.; Thomas, C.M.G.; Wetzels, A.M.M.; Willemsen, W.N.P.; Sweep, F.C.; Steegers-Theunissen, R.P.M.

    2008-01-01

    OBJECTIVE: To assess the importance of the plasminogen activator (PA) system and vascular endothelial growth factor (VEGF) in subfertility. DESIGN: Review. SETTING: Two university IVF centers. INTERVENTION(S): Systematic literature search (MEDLINE, Science Direct, and bibliographies of published

  16. Redox-sensitive transcription factor Nrf2 regulates vascular smooth muscle cell migration and neointimal hyperplasia.

    Science.gov (United States)

    Ashino, Takashi; Yamamoto, Masayuki; Yoshida, Takemi; Numazawa, Satoshi

    2013-04-01

    Reactive oxygen species are important mediators for platelet-derived growth factor (PDGF) signaling in vascular smooth muscle cells, whereas excess reactive oxygen species-induced oxidative stress contributes to the development and progression of vascular diseases, such as atherosclerosis. Activation of the redox-sensitive transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2), is pivotal in cellular defense against oxidative stress by transcriptional upregulation of antioxidant proteins. This study aimed to elucidate the role of Nrf2 in PDGF-mediated vascular smooth muscle cell migration and neointimal hyperplasia. PDGF promoted nuclear translocation of Nrf2, followed by the induction of target genes, including NAD(P)H:quinone oxidoreductase-1, heme oxygenase-1, and thioredoxin-1. Nrf2 depletion by small interfering RNA enhanced PDGF-promoted Rac1 activation and reactive oxygen species production and persistently phosphorylated downstream extracellular signal-regulated kinase-1/2. Nrf2 depletion enhanced vascular smooth muscle cell migration in response to PDGF and wound scratch. In vivo, Nrf2-deficient mice showed enhanced neointimal hyperplasia in a wire injury model. These findings suggest that the Nrf2 system is important for PDGF-stimulated vascular smooth muscle cell migration by regulating reactive oxygen species elimination, which may contribute to neointimal hyperplasia after vascular injury. Our findings provide insight into the Nrf2 system as a novel therapeutic target for vascular remodeling and atherosclerosis.

  17. Tibial dyschondroplasia is highly associated with suppression of tibial angiogenesis through regulating the HIF-1α/VEGF/VEGFR signaling pathway in chickens.

    Science.gov (United States)

    Huang, Shu-Cheng; Rehman, Mujeeb Ur; Lan, Yan-Fang; Qiu, Gang; Zhang, Hui; Iqbal, Muhammad Kashif; Luo, Hou-Qiang; Mehmood, Khalid; Zhang, Li-Hong; Li, Jia-Kui

    2017-08-22

    Tibial dyschondroplasia (TD) is an intractable poultry problem that is characterized by the appearance of non-vascularized and non-mineralized cartilage masses in tibial growth plates (TGPs). However, the role of angiogenesis inhibition in the occurrence of TD remains unknown. In this study, we found that, compared to low-altitude Arbor Acres chickens (AACs), high-altitude Tibetan chickens showed higher tibial vascular distributions that were accompanied by up-regulation of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor A (VEGFA) and VEGF receptors. These observations provide insights into hypoxia-induced angiogenesis, which may be related to the absence of TD in high-altitude native Tibetan chickens. Importantly, hypoxia experiments also showed that during hypoxia, tibial angiogenesis was enhanced, which was due to pro-angiogenic factor up-regulation (including VEGFA, VEGFR1, VEGFR2, and IL-8), in AACs. Moreover, we observed that thiram-induced TD could strongly inhibit tibial angiogenesis in the hypertrophic zone through coordinated down-regulation of HIF-1α and pro-angiogenic factors, leading to a disruption in the blood supply to the TGP. Taken together, these findings reveal that the occurrence of TD is highly associated with inhibition of tibial angiogenesis through down-regulated expression of HIF-1α, VEGFA and VEGF receptors, which results in suppression of TGP development.

  18. Cellular proliferation and angiogenesis in nasal polyps of young adult and geriatric patients.

    Science.gov (United States)

    Shin, Jae Min; Byun, Jang Yul; Baek, Byoung Joon; Lee, Jae Yong

    2015-06-01

    Cellular proliferation and angiogenesis are associated with pathophysiology of nasal polyposis (NP). In a previous report, we showed that patient age is a predictive factor of surgical outcomes among patients with chronic rhinosinusitis and NP, and that geriatric patients exhibit better outcomes than pediatric and adult patients. We postulated that better outcomes in the geriatric population may be secondary to decreased proliferation and angiogenesis within polyps. Therefore, we evaluated the cellular proliferation and angiogenesis in young adult and geriatric patients with NP. This was a prospective case-control study. Twenty patients were divided into 2 groups according to age (20 to 30 years vs ≥65 years of age). NP tissues were sampled during endoscopic sinus surgery and processed for immunohistochemistry. Cellular proliferation was evaluated with proliferating cell nuclear antigen and Ki67, and angiogenesis was assessed with vascular endothelial growth factor. We also compared objective surgical outcomes using endoscopy scores. Immunohistochemical analysis revealed significantly higher expression and positive reactivity of proliferating cell nuclear antigen and Ki67 in the polyps of young adults than in those of geriatric patients, whereas the expression of vascular endothelial growth factor was similar between the 2 groups. Endoscopy scores were better in the geriatric group. Geriatric patients have a lower cellular proliferative ability than young adults, and angiogenesis does not significantly differ between the 2 age groups. Cellular proliferation seems to be the cause of the different surgical outcomes between the 2 age groups, whereas angiogenesis has no significant influence on the postoperative course. © 2015 ARS-AAOA, LLC.

  19. Up-regulation of intestinal vascular endothelial growth factor by Afa/Dr diffusely adhering Escherichia coli.

    Directory of Open Access Journals (Sweden)

    Gaëlle Cane

    Full Text Available BACKGROUND: Angiogenesis has been recently described as a novel component of inflammatory bowel disease pathogenesis. The level of vascular endothelial growth factor (VEGF has been found increased in Crohn's disease and ulcerative colitis mucosa. To question whether a pro-inflammatory Escherichia coli could regulate the expression of VEGF in human intestinal epithelial cells, we examine the response of cultured human colonic T84 cells to infection by E. coli strain C1845 that belongs to the typical Afa/Dr diffusely adhering E. coli family (Afa/Dr DAEC. METHODOLOGY: VEGF mRNA expression was examined by Northern blotting and q-PCR. VEGF protein levels were assayed by ELISA and its bioactivity was analysed in endothelial cells. The bacterial factor involved in VEGF induction was identified using recombinant E. coli expressing Dr adhesin, purified Dr adhesin and lipopolysaccharide. The signaling pathway activated for the up-regulation of VEGF was identified using a blocking monoclonal anti-DAF antibody, Western blot analysis and specific pharmacological inhibitors. PRINCIPAL FINDINGS: C1845 bacteria induce the production of VEGF protein which is bioactive. VEGF is induced by adhering C1845 in both a time- and bacteria concentration-dependent manner. This phenomenon is not cell line dependent since we reproduced this observation in intestinal LS174, Caco2/TC7 and INT407 cells. Up-regulation of VEGF production requires: (1 the interaction of the bacterial F1845 adhesin with the brush border-associated decay accelerating factor (DAF, CD55 acting as a bacterial receptor, and (2 the activation of a Src protein kinase upstream of the activation of the Erk and Akt signaling pathways. CONCLUSIONS: Results demonstrate that a Afa/Dr DAEC strain induces an adhesin-dependent activation of DAF signaling that leads to the up-regulation of bioactive VEGF in cultured human intestinal cells. Thus, these results suggest a link between an entero-adherent, pro

  20. Effects of Hypothyroidism Treatment on the Level of Vascular Endothelial Growth Factor

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    O.M. Didushko

    2015-11-01

    Full Text Available The objective of the investigation is identifying the level of vascular endothelial growth factor in patients with primary hypothyroidism and influence of complex treatment on its levels. Materials and methods. One hundred and thirty three patients with primary hypothyroidism were examined. All patients were grouped into group 1 containing 32 patients with hypothyroidism resulted from autoimmune thyroiditis (AIT without obesity; group 2 involving 34 obese patients with autoimmune thyroiditis and hypothyroidism; group 3 including 34 patients with manifested hypothyroidism without obesity and Group 4, encompassing the rest 33 obese patients with post-operative hypothyroidism. Results. Patients’ data have shown significant increase of vascular endothelial growth factor levels in all groups, but the most expressed changes of vascular endothelial growth factor secretion have been noticed in obese patients with hypothyroidism resulting from autoimmune thyroidism. The possibility to increase the efficacy of treating such patients by means of complex use of LT4, enalapril and atorvastatin for six months has been discussed. Such complex use of LT4, enalapril and atorvastatin enhances the therapeutic effect of the background therapy and decreases the overproduction of vascular endothelial growth factor. Conclusions. With manifested hypothyroidism, levels of vascular endothelial growth factor in blood plasma are significantly higher in both obese and not obese patients. The highest indices have been found in obese patients with manifested hypothyroidism resulting from autoimmune thyroidism. Complex use of LT4, enalapril and atorvastatin for six months decreases vascular endothelial growth factor overproduction.

  1. Placenta growth factor-1 antagonizes VEGF-induced angiogenesis and tumor growth by the formation of functionally inactive PIGF-1/VEGF heterodimers

    DEFF Research Database (Denmark)

    Eriksson, A.; Cao, R.; Pawliuk, R.

    2002-01-01

    , the biological function of its related homolog, placenta growth factor (PlGF), is poorly understood. Here we demonstrate that PlGF-1, an alternatively spliced isoform of the PlGF gene, antagonizes VEGF-induced angiogenesis when both factors are coexpressed in murine fibrosarcoma cells. Overexpression of PlGF-1...... signaling pathways. Further, PlGF-1 inhibits the growth of a murine fibrosarcoma by approximately 90% when PlGF-1-expressing tumor cells are implanted in syngeneic mice. In contrast, overexpression of human VEGF in murine tumor cells causes accelerated and exponential growth of primary fibrosarcomas...

  2. Sustained-released mixture of vascular endothelial growth factor 165 and fibrin glue strengthens healing of ileal anastomoses in a rabbit model with intraperitoneal infection.

    Science.gov (United States)

    Li, Zhanwu; Wang, Wenjun; Wang, Xiaozhou; Jiang, Lei; Wang, Fengyi; Liu, Qiang

    2017-09-01

    To investigate the effects of a sustained-released mixture of vascular endothelial growth factor 165 (VEGF165) and fibrin glue (FG) local administration on postoperative rabbit ileal anastomoses. One hundred twenty-eight male and female New Zealand white rabbits underwent intraperitoneal infection subsequent ileal anastomosis surgery were divided randomly into 4 groups, including 32 animals in each, applied with saline solution, FG, rhVEGF165 and a mixture of rhVEGF165 with FG (VEGF + FG) on the anastomoses, respectively. The incidences of anastomotic leakage were observed. Histopathological examination for inflammatory infiltration, fibroblast proliferation, and capillary vascular proliferation were performed. Then, bursting pressure and hydroxyproline concentrations were assessed in anastomoses sits on postoperative days 3, 5, 7, and 14. Rabbits in VEGF + FG group had the lowest incidence of leakage (P < 0.05). Histological evaluations revealed that granulation tissue was formed on days 5 after anastomosis; fibroblast proliferation and capillary vascular proliferation were significantly increased on days 7 and 14 in VEGF + FG group. Furthermore, there was a statistically significant difference in the mean bursting pressures between VEGF + FG group and other groups on days 7 and 14 (P < 0.05), and rabbits in VEGF + FG group exhibited a higher concentration than VEGF group (P < 0.05) and FG group (P < 0.05) on day 14. Administration of VEGF165 mixed with FG to ileal anastomosis accelerates wound healing and enhances the anastomosis by increased angiogenesis.

  3. 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.

  4. Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164.

    Science.gov (United States)

    Sacchi, Veronica; Mittermayr, Rainer; Hartinger, Joachim; Martino, Mikaël M; Lorentz, Kristen M; Wolbank, Susanne; Hofmann, Anna; Largo, Remo A; Marschall, Jeffrey S; Groppa, Elena; Gianni-Barrera, Roberto; Ehrbar, Martin; Hubbell, Jeffrey A; Redl, Heinz; Banfi, Andrea

    2014-05-13

    Clinical trials of therapeutic angiogenesis by vascular endothelial growth factor (VEGF) gene delivery failed to show efficacy. Major challenges include the need to precisely control in vivo distribution of growth factor dose and duration of expression. Recombinant VEGF protein delivery could overcome these issues, but rapid in vivo clearance prevents the stabilization of induced angiogenesis. Here, we developed an optimized fibrin platform for controlled delivery of recombinant VEGF, to robustly induce normal, stable, and functional angiogenesis. Murine VEGF164 was fused to a sequence derived from α2-plasmin inhibitor (α2-PI1-8) that is a substrate for the coagulation factor fXIIIa, to allow its covalent cross-linking into fibrin hydrogels and release only by enzymatic cleavage. An α2-PI1-8-fused variant of the fibrinolysis inhibitor aprotinin was used to control the hydrogel degradation rate, which determines both the duration and effective dose of factor release. An optimized aprotinin-α2-PI1-8 concentration ensured ideal degradation over 4 wk. Under these conditions, fibrin-α2-PI1-8-VEGF164 allowed exquisitely dose-dependent angiogenesis: concentrations ≥25 μg/mL caused widespread aberrant vascular structures, but a 500-fold concentration range (0.01-5.0 μg/mL) induced exclusively normal, mature, nonleaky, and perfused capillaries, which were stable after 3 mo. Optimized delivery of fibrin-α2-PI1-8-VEGF164 was therapeutically effective both in ischemic hind limb and wound-healing models, significantly improving angiogenesis, tissue perfusion, and healing rate. In conclusion, this optimized platform ensured (i) controlled and highly tunable delivery of VEGF protein in ischemic tissue and (ii) stable and functional angiogenesis without introducing genetic material and with a limited and controllable duration of treatment. These findings suggest a strategy to improve safety and efficacy of therapeutic angiogenesis.

  5. Water extract of Cinnamomum cassia suppresses angiogenesis through inhibition of VEGF receptor 2 phosphorylation.

    Science.gov (United States)

    Kim, Eok-Cheon; Kim, Hye Jin; Kim, Tack-Joong

    2015-01-01

    Angiogenesis, the process of new blood vessel formation, has been a major target for cancer therapy. Antiangiogenic herbal medicines are useful in the treatment of cancer. In this study, we found that a water extract of Cinnamomum cassia (CCWE) was a potent inhibitor of angiogenesis. In cultured human umbilical vein endothelial cells, CCWE suppressed vascular endothelial growth factor (VEGF)-induced proliferation, migration, invasion, tube formation, and intracellular signaling events such as phosphorylation of ERK, p38 and VEGFR2, and activation of matrix metalloproteinase. Furthermore, CCWE inhibited VEGF-induced vessel sprouting of rat aorta ex vivo. These findings might be of particular interest for drug development because VEGF signaling is a potential target for treatment of angiogenesis-associated diseases.

  6. Anemia and elevated systemic levels of vascular endothelial growth factor (VEGF)

    Energy Technology Data Exchange (ETDEWEB)

    Dunst, J.; Becker, A.; Lautenschlaeger, C.; Markau, S.; Becker, H.; Fischer, K.; Haensgen, G. [Martin-Luther Univ. Halle-Wittenberg (Germany)

    2002-08-01

    Background: Tissue hypoxia is a major stimulus for the up-regulation of vascular endothelial growth factor (VEGF). Anemia might theoretically impact on angiogenesis via impairment of tissue oxygenation. We have investigated this hypothesis in patients with solid cancers and benign diseases. Patients and methods: 49 patients with untreated locoregionally confined solid cancers of the head and neck, cervix, rectum and lung and 59 additional patients with non-malignant diseases (36 normemic patients without serious diseases and 23 patients with renal anemia) were enrolled and the impact of anemia on plasma VEGF levels were determined. VEGF was measured with a commercially available sandwich enzyme immunoassay technique. Results: Plasma levels of VEGF were 16.2{+-}12.7 pg/ml in 36 normemic patients without malignant disease, 49,2{+-}34.5 pg/ml in 49 patients with cancers (p<0.001), and 89.9{+-}67.8 pg/ml in 23 patients with renal anemia (p=0.001). VEGF levels in cancer patients were significantly correlated with hemoglobin (hb) levels and platelet counts (each p=0.001), but not with type of tumor, stage, histology or age. Patients with cancers had higher plasma levels of VEGF than patients with non-malignant diseases in case of hb{>=}12 g/dl (33.1{+-}17.5 vs. 16.6{+-}13.0 pg/ml, p<0.001) and in case of hb between 11.0 and 11.9 g/dl (56.1{+-}26.4 vs 18.5{+-}14.5 pg/ml, p=0.038). In case of a hb<11 g/dl, plasma VEGF levels were significantly elevated in patients with and without cancers (67.0{+-}47.5 vs 88.9{+-}68.8 pg/ml, n.s.). In a multivariate model, a significant association between low hb levels and increased plasma levels of VEGF was confirmed. In 16 patients with renal anemia, changes in hb under erythropoietin treatment were inversely correlated with changes in plasma VEGF levels with decreasing VEGF after increase in hb (p=0.01). Conclusions: Anemic patients have elevated levels of VEGF. The data suggest that anemia might impact on the progression of

  7. Vascular injury triggers Krüppel-like factor 6 mobilization and cooperation with specificity protein 1 to promote endothelial activation through upregulation of the activin receptor-like kinase 1 gene.

    Science.gov (United States)

    Garrido-Martín, Eva M; Blanco, Francisco J; Roquè, Mercé; Novensà, Laura; Tarocchi, Mirko; Lang, Ursula E; Suzuki, Toru; Friedman, Scott L; Botella, Luisa M; Bernabéu, Carmelo

    2013-01-04

    Activin receptor-like kinase-1 (ALK1) is an endothelial transforming growth factor β receptor involved in angiogenesis. ALK1 expression is high in the embryo vasculature, becoming less detectable in the quiescent endothelium of adult stages. However, ALK1 expression becomes rapidly increased after angiogenic stimuli such as vascular injury. To characterize the molecular mechanisms underlying the regulation of ALK1 on vascular injury. Alk1 becomes strongly upregulated in endothelial (EC) and vascular smooth muscle cells of mouse femoral arteries after wire-induced endothelial denudation. In vitro denudation of monolayers of human umbilical vein ECs also leads to an increase in ALK1. Interestingly, a key factor in tissue remodeling, Krüppel-like factor 6 (KLF6) translocates to the cell nucleus during wound healing, concomitantly with an increase in the ALK1 gene transcriptional rate. KLF6 knock down in human umbilical vein ECs promotes ALK1 mRNA downregulation. Moreover, Klf6(+/-) mice have lower levels of Alk1 in their vasculature compared with their wild-type siblings. Chromatin immunoprecipitation assays show that KLF6 interacts with ALK1 promoter in ECs, and this interaction is enhanced during wound healing. We demonstrate that KLF6 is transactivating ALK1 gene, and this transactivation occurs by a synergistic cooperative mechanism with specificity protein 1. Finally, Alk1 levels in vascular smooth muscle cells are not directly upregulated in response to damage, but in response to soluble factors, such as interleukin 6, released from ECs after injury. ALK1 is upregulated in ECs during vascular injury by a synergistic cooperative mechanism between KLF6 and specificity protein 1, and in vascular smooth muscle cells by an EC-vascular smooth muscle cell paracrine communication during vascular remodeling.

  8. Copper Oxide Nanoparticles Reduce Vasculogenesis in Transgenic Zebrafish Through Down-Regulation of Vascular Endothelial Growth Factor Expression and Induction of Apoptosis.

    Science.gov (United States)

    Chang, Jie; Ichihara, Gaku; Shimada, Yasuhito; Tada-Oikawa, Saeko; Kuroyanagi, Junya; Zhang, Beibei; Suzuki, Yuka; Sehsah, Radwa; Kato, Masashi; Tanaka, Toshio; Ichihara, Sahoko

    2015-03-01

    The present study investigated the effects of exposure to metal oxide nanoparticles on vasculogenesis/angiogenesis using transgenic zebrafish. The study also examined the potential mechanisms involved in those effects using human umbilical vein endothelial cells (HUVEC). TG (nacre/fli1:EGFP) zebrafish were exposed to nano-sized titanium dioxide (TiO2), silica dioxide (SiO2), and copper oxide (CuO) particles at 0.01, 1 and 100 µg/ml concentrations from 1 to 5 dpf (day-post-fertilization). Angiogenesis was evaluated morphologically at the end of exposure. Exposure to CuO nanoparticles reduced the number of transversely-running subintestinal vessels in TG zebrafish. Exposure to CuO nanoparticles down-regulated the expression of vascular endothelial growth factor (VEGF) and VEGF receptor in endothelial cells sorted by Fluorescence Activated Cell Sorter (FACS). Exposure of HUVEC to CuO nanoparticles reduced cell viability and increased apoptotic index in a dose-dependent manner. The results suggested that CuO nanoparticles inhibit vasculogenesis through reduction of VEGF expression and induction of apoptosis.

  9. Cediranib, an oral inhibitor of vascular endothelial growth factor receptor kinases, is an active drug in recurrent epithelial ovarian, fallopian tube, and peritoneal cancer.

    Science.gov (United States)

    Matulonis, Ursula A; Berlin, Suzanne; Ivy, Percy; Tyburski, Karin; Krasner, Carolyn; Zarwan, Corrine; Berkenblit, Anna; Campos, Susana; Horowitz, Neil; Cannistra, Stephen A; Lee, Hang; Lee, Julie; Roche, Maria; Hill, Margaret; Whalen, Christin; Sullivan, Laura; Tran, Chau; Humphreys, Benjamin D; Penson, Richard T

    2009-11-20

    Angiogenesis is important for epithelial ovarian cancer (EOC) growth, and blocking angiogenesis can lead to EOC regression. Cediranib is an oral tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptor (VEGFR) -1, VEGFR-2, VEGFR-3, and c-kit. We conducted a phase II study of cediranib for recurrent EOC or peritoneal or fallopian tube cancer; cediranib was administered as a daily oral dose, and the original dose was 45 mg daily. Because of toxicities observed in the first 11 patients, the dose was lowered to 30 mg. Eligibility included 16 weeks, or CA-125 nonprogression > 16 weeks), which was the primary end point, was 30%; eight patients (17%; 95% CI, 7.6% to 30.8%) had a PR, six patients (13%; 95% CI, 4.8% to 25.7%) had SD, and there were no CRs. Eleven patients (23%) were removed from study because of toxicities before two cycles. Grade 3 toxicities (> 20% of patients) included hypertension (46%), fatigue (24%), and diarrhea (13%). Grade 2 hypothyroidism occurred in 43% of patients. Grade 4 toxicities included CNS hemorrhage (n = 1), hypertriglyceridemia/hypercholesterolemia/elevated lipase (n = 1), and dehydration/elevated creatinine (n = 1). No bowel perforations or fistulas occurred. Median PFS was 5.2 months, and median OS has not been reached; median follow-up time is 10.7 months. Cediranib has activity in recurrent EOC, tubal cancer, and peritoneal cancer with predictable toxicities observed with other TKIs.

  10. Retinal and choroidal angiogenesis: a review of new targets.

    Science.gov (United States)

    Cabral, Thiago; Mello, Luiz Guilherme M; Lima, Luiz H; Polido, Júlia; Regatieri, Caio V; Belfort, Rubens; Mahajan, Vinit B

    2017-01-01

    Retinal and choroidal neovascularization are a major cause of significant visual impairment, worldwide. Understanding the various factors involved in the accompanying physiopathology is vital for development of novel treatments, and most important, for preserving patient vision. The intraocular use of anti-vascular endothelial growth factor therapeutics has improved management of the retinal and choroidal neovascularization but some patients do not respond, suggesting other vascular mediators may also contribute to ocular angiogenesis. Several recent studies examined possible new targets for future anti-angiogenic therapies. Potential targets of retinal and choroidal neovascularization therapy include members of the platelet-derived growth factor family, vascular endothelial growth factor sub-family, epidermal growth factor family, fibroblast growth factor family, transforming growth factor-β superfamily (TGF-β1, activins, follistatin and bone morphogenetic proteins), angiopoietin-like family, galectins family, integrin superfamily, as well as pigment epithelium derived factor, hepatocyte growth factor, angiopoietins, endothelins, hypoxia-inducible factors, insulin-like growth factors, cytokines, matrix metalloproteinases and their inhibitors and glycosylation proteins. This review highlights current antiangiogenic therapies under development, and discusses future retinal and choroidal pro- and anti-angiogenic targets as wells as the importance of developing of new drugs.

  11. Long-lasting fibrin matrices ensure stable and functional angiogenesis by highly tunable, sustained delivery of recombinant VEGF164

    OpenAIRE

    Sacchi, Veronica; Mittermayr, Rainer; Hartinger, Joachim; Martino, Mikaël M.; Lorentz, Kristen M.; Wolbank, Susanne; Hofmann, Anna; Largo, Remo A.; Marschall, Jeffrey S.; Groppa, Elena; Gianni-Barrera, Roberto; Ehrbar, Martin; Hubbell, Jeffrey A.; Redl, Heinz; Banfi, Andrea

    2014-01-01

    Inducing the growth of new blood vessels by specific factors is an attractive strategy to restore blood flow in ischemic tissues. Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis, yet clinical trials of VEGF gene delivery failed. Major challenges include the need to control the tissue distribution of factor dose and the duration of expression. Here, we developed a highly tunable fibrin-based platform to precisely control the dose and duration of VEGF protein d...

  12. Evolutionary emergence of angiogenesis in avascular tumors using a spatial public goods game.

    Directory of Open Access Journals (Sweden)

    Javad Salimi Sartakhti

    Full Text Available Natural selection in cancer often results in the emergence of increasingly malignant tumor cells that display many if not all of the hallmarks of cancer. One of the most important traits acquired during cancer progression is angiogenesis. Tumor cells capable of secreting pro-angiogenic factors can be seen as cooperators where the improved oxygenation, nutrient delivery and waste disposal resulting from angiogenesis could be seen as a public good. Under this view, the relatively costly secretion of molecular signals required to orchestrate angiogenesis would be undertaken exclusively by cooperating tumor cells but the benefits of angiogenesis would be felt by neighboring tumor cells regardless of their contribution to the process. In this work we detail a mathematical model to better understand how clones capable of secreting pro-angiogenic factors can emerge in a tumor made of non-cooperative tumor cells. Given the importance of the spatial configuration of the tumor in determining the efficacy of the secretion of pro-angiogenic factors as well as the benefits of angiogenesis we have developed a spatial game theoretic approach where interactions and public good diffusion are described by graphs. The results show that structure of the population affects the evolutionary dynamics of the pro-angiogenic clone. Specifically, when the benefit of angiogenesis is represented by sigmoid function with regards to the number of pro-angiogenic clones then the probability of the coexistence of pro-angiogenic and angiogenesis-neutral clones increases. Our results demonstrate that pro-angiogenic clone equilibrates into clusters that appear from surrounding vascular tissues towards the center of tumor. These clusters appear notably less dense after anti-angiogenic therapy.

  13. Role of angiogenesis in endometrial repair of patients with severe intrauterine adhesion

    OpenAIRE

    Chen, Yuqing; Chang, Yajie; Yao, Shuzhong

    2013-01-01

    Objective: To detect vascular endothelial growth factor (VEGF) expression and micro-vessel density (MVD) in patients with severe intrauterine adhesion before and after therapy, and to preliminarily explore the role of angiogenesis in the therapy of severe intrauterine adhesion. Methods: A total of 36 patients with severe intrauterine adhesion were prospectively recruited into the treatment group. In the control group, 20 patients with normal uterine were recruited. Patients with severe intrau...

  14. Enhanced expression of fibroblast growth factors and receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease.

    NARCIS (Netherlands)

    Kranenburg, A.R.; Boer, W.I.; Krieken, J.H.J.M. van; Mooi, W.J.; Walters, J.E.; Saxena, P.R.; Sterk, P.J.; Sharma, H.S.

    2002-01-01

    Important characteristics of chronic obstructive pulmonary disease (COPD) include airway and vascular remodeling, the molecular mechanisms of which are poorly understood. We assessed the role of fibroblast growth factors (FGF) in pulmonary vascular remodeling by examining the expression pattern of

  15. Enhanced expression of fibroblast growth factors and receptor FGFR-1 during vascular remodeling in chronic obstructive pulmonary disease

    NARCIS (Netherlands)

    A.R. Kranenburg (Andor); W.I. de Boer (Pim); J.H.J.M. van Krieken (Han); W.J. Mooi (Wolter); J.E. Walters (Jane); P.R. Saxena (Pramod Ranjan); P.J. Sterk (Peter); H.S. Sharma (Hari)

    2002-01-01

    textabstractImportant characteristics of chronic obstructive pulmonary disease (COPD) include airway and vascular remodeling, the molecular mechanisms of which are poorly understood. We assessed the role of fibroblast growth factors (FGF) in pulmonary vascular remodeling by

  16. Angiogenesis: a potentially critical part of remodelling in chronic airway diseases?

    Science.gov (United States)

    Walters, Eugene Haydn; Reid, David; Soltani, Amir; Ward, Chris

    2008-04-01

    Angiogenesis is a prominent feature of the structural tissue remodelling that occurs in the chronic airway diseases of asthma, Bronchiolitis Obliterans Syndrome (BOS, post-lung transplantation), and in smoking-related Chronic Obstructive Pulmonary Disease (COPD). For each, we have explored the relationship between angiogenesis and underlying chronic inflammatory processes--are the hypervascular changes secondary to inflammation, or do they occur in parallel? What are the likely growth factors which stimulate the angiogenic process? We discuss the relationships that have been studied between angiogenesis and the physiological impairment of airflow obstruction. The pattern that emerges is complex and variable. In asthma, there is strong evidence to suggest that Vascular Endothelial Growth Factor (VEGF) and its receptor system is upregulated in the airway. Local production of VEGF has also been implicated as a major driver of angiogenesis in the airway component of COPD, though paradoxically emphysema seems to be due to lack of VEGF in the lung parenchyma. In BOS, the evidence suggests that VEGF is lacking in the airway: other mediators and especially C-X-C chemokines such as Interleukin (IL)-8, are likely to be more important in angiogenesis. The physiological consequences of angiogenesis are likely to be important in asthma (especially during acute episodes of deterioration), and probably also in COPD, although data is equivocal. In BOS, increased airway vascularity appears to occur early, but is not progressive. In terms of therapy, evidence for anti-angiogenic effectiveness is strongest for Inhaled Corticosteroid (ICS) and Long Acting Beta-Agonists (LABA) in asthma.

  17. The regulation of angiogenesis in neuroblastoma.

    Science.gov (United States)

    Chlenski, Alexandre; Liu, Shuqing; Cohn, Susan L

    2003-07-18

    Angiogenesis is required for the growth and metastasis of malignant tumors, and high vascular density has been correlated with aggressive tumor growth in many types of cancer. This process is regulated by the local balance of stimulatory and inhibitory molecules produced by tumor cells, stromal cells, and the organ-specific environment. In neuroblastoma, a pediatric malignancy that is characterized by a broad spectrum of clinical behavior, angiogenesis also appears to play an important role in determining tumor phenotype. The nature of the angiogenic balance in neuroblastoma is complex, and a spectrum of angiogenesis stimulators and inhibitors has been detected in neuroblastoma tumors. This review summarizes our current understanding of the regulation of angiogenesis in neuroblastoma.

  18. Characterization of Angiogenesis and Lymphangiogenesis in Human Minor Salivary Glands with Sjögren's Syndrome.

    Science.gov (United States)

    McCall, Andrew D; Baker, Olga J

    2015-05-01

    Angiogenesis has been proposed to play a role in the inflammation observed in Sjögren's Syndrome (SS). However, no studies have validated the degree of angiogenesis in salivary glands with SS. Therefore, the goal of this study was to determine the presence and localization of angiogenesis and lymphangiogenesis in salivary glands with SS. We used frozen tissue sections from human minor salivary glands (hMSG) with and without SS in our analyses. To investigate signs of angiogenesis, hMSG tissue lysates were used to detect levels of the pro-angiogenic protein vascular endothelial growth factor (VEGF) by western blot analyses. Additionally, we labeled blood vessels using antibodies specific to platelet endothelial cell adhesion molecule-1 (PECAM-1) and von Willebrand Factor (vWF) to determine blood vessel organization and volume fraction using fluorescence microscopy. Lymphatic vessel organization and volume fraction were determined using antibodies specific to lymphatic vessel endothelial hyaluronan receptor (LYVE-1). Our results suggest that expression levels of VEGF are decreased in hMSG with SS as compared with controls. Interestingly, there were no significant differences in blood or lymphatic vessel organization or volume fraction between hMSG with and without SS, suggesting that angiogenesis and lymphangiogenesis have little impact on the progression of SS. © The Author(s) 2015.

  19. Azaspirene: a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton produced by the fungus Neosartorya sp.

    Science.gov (United States)

    Asami, Yukihiro; Kakeya, Hideaki; Onose, Rie; Yoshida, Arika; Matsuzaki, Hiroshi; Osada, Hiroyuki

    2002-08-22

    [structure: see text] Azaspirene isolated from the fungus Neosartorya sp. is a novel angiogenesis inhibitor with a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton. Azaspirene inhibits the endothelial migration induced by vascular endothelial growth factor (ED100 = 27.1 microM).

  20. Molecular Analysis of Vascular Endothelial Growth Factor (VEGF) Receptors in EUS-guided Samples Obtained from Patients with Pancreatic Adenocarcinoma.

    Science.gov (United States)

    Costache, Madalin Ionut; Iordache, Sevastita; Costache, Cornelia Alexandra; Dragos, Ene; Dragos, Alexandru; Saftoiu, Adrian

    2017-03-01

    Vascular endothelial growth factor (VEGF) and its receptors (VEGF-R1 and VEGF-R2) are the most important angiogenesis stimulating factors in pancreatic cancer. This study aims to assess VEGF-R1 and VEGF-R2 gene expression in EUS-FNA samples and identify prognostic markers in pancreatic adenocarcinoma. This was a retrospective study of prospectively collected data of 88 consecutive patients, with clinical and imaging suspicion of pancreatic neoplasms, based on samples obtained through endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). EUS had an accuracy of 93.2% for the diagnosis of pancreatic cancer. Based on real-time qPCR analysis, VEGF-R1 and VEGF-R2 expressions were present in 90% and 65% of the analysed malignant samples, respectively; 89% of the patients died during the study, with a median survival rate of only 9 months. The survival was correlated with the initial stage and with the presence of VEGF-R1 and VEGF-R2 gene expression. We found that there are significant correlations between death/survival and T stage, N stage, resectability status, VEGF-R1, VEGF-R2 and VEGF-R1/VEGF-R2 coexpression. Using a Cox model regression our study demonstrates that VEGF-R1/VEGF-R2 coexpression might be considered as a poor prognostic factor in pancreatic cancer. EUS is a very effective technique for the diagnosis and staging of pancreatic adenocarcinoma in patients with clinical and imaging suspicion of pancreatic neoplasm, with an accuracy of 93.2%. Furthermore, the role of molecular analysis of EUS-guided FNA samples was established by the assessment of VEGF-R1, VEGF-R2 gene expression, which might be considered prognostic markers in pancreatic cancer.

  1. Trefoil Factor-3 (TFF3 Stimulates De Novo Angiogenesis in Mammary Carcinoma both Directly and Indirectly via IL-8/CXCR2.

    Directory of Open Access Journals (Sweden)

    Wai-Hoe Lau

    Full Text Available Mammary carcinoma cells produce pro-angiogenic factors to stimulate angiogenesis and tumor growth. Trefoil factor-3 (TFF3 is an oncogene secreted from mammary carcinoma cells and associated with poor prognosis. Herein, we demonstrate that TFF3 produced in mammary carcinoma cells functions as a promoter of tumor angiogenesis. Forced expression of TFF3 in mammary carcinoma cells promoted proliferation, survival, invasion and in vitro tubule formation of human umbilical vein endothelial cells (HUVEC. MCF7-TFF3 cells with forced expression of TFF3 generated tumors with enhanced microvessel density as compared to tumors formed by vector control cells. Depletion of TFF3 in mammary carcinoma cells by siRNA concordantly decreased the angiogenic behavior of HUVEC. Forced expression of TFF3 in mammary carcinoma cells stimulated IL-8 transcription and subsequently enhanced IL-8 expression in both mammary carcinoma cells and HUVEC. Depletion of IL-8 in mammary carcinoma cells with forced expression of TFF3, or antibody inhibition of IL-8, partially abrogated mammary carcinoma cell TFF3-stimulated HUVEC angiogenic behavior in vitro, as did inhibition of the IL-8 receptor, CXCR2. Depletion of STAT3 by siRNA in MCF-7 cells with forced expression of TFF3 partially diminished the angiogenic capability of TFF3 on stimulation of cellular processes of HUVEC. Exogenous recombinant hTFF3 also directly promoted the angiogenic behavior of HUVEC. Hence, TFF3 is a potent angiogenic factor and functions as a promoter of de novo angiogenesis in mammary carcinoma, which may co-coordinate with the growth promoting and metastatic actions of TFF3 in mammary carcinoma to enhance tumor progression.

  2. Molecular MRI of neurovascular inflammation and angiogenesis

    OpenAIRE

    Deddens, L.H.

    2013-01-01

    This thesis describes the use of different MR contrast agent platforms for the direct detection of pathology-induced upregulation of intraluminally-expressed vascular entities by molecular MRI. We particularly focused on the in vivo target specificity and MR sensitivity of the agents. The biological targets of our molecular MRI approaches were associated with two types of vascular events that are critically involved in many pathologies; i.e., angiogenesis and neurovascular inflammation. In Ch...

  3. Anti-vascular endothelial growth factor for diabetic macular oedema.

    Science.gov (United States)

    Virgili, Gianni; Parravano, Mariacristina; Menchini, Francesca; Evans, Jennifer R

    2014-10-24

    Diabetic macular oedema (DMO) is a common complication of diabetic retinopathy. Although grid or focal laser photocoagulation has been shown to reduce the risk of visual loss in DMO, or clinically significant macular oedema (CSMO), vision is rarely improved. Antiangiogenic therapy with anti-vascular endothelial growth factor (anti-VEGF) modalities is used to try to improve vision in people with DMO. To investigate the effects in preserving and improving vision and acceptability, including the safety, compliance with therapy and quality of life, of antiangiogenic therapy with anti-VEGF modalities for the treatment of DMO. We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (2014, Issue 3), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to April 2014), EMBASE (January 1980 to April 2014), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to April 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 28 April 2014. We included randomised controlled trials (RCTs) comparing any antiangiogenic drugs with an anti-VEGF mechanism of action versus another treatment, sham treatment or no treatment in people with DMO. We used standard methodological procedures expected by The Cochrane Collaboration. The risk ratios (RR) for visual loss and visual gain of three or more lines of logMAR visual acuity were estimated at one year of follow-up (plus or minus six months) after treatment initiation. Eighteen studies provided data on four comparisons of interest in this review. Participants in the trials had central

  4. Frequency of and predictive factors for vascular invasion after radiofrequency ablation for hepatocellular carcinoma.

    Science.gov (United States)

    Asaoka, Yoshinari; Tateishi, Ryosuke; Nakagomi, Ryo; Kondo, Mayuko; Fujiwara, Naoto; Minami, Tatsuya; Sato, Masaya; Uchino, Koji; Enooku, Kenichiro; Nakagawa, Hayato; Kondo, Yuji; Shiina, Shuichiro; Yoshida, Haruhiko; Koike, Kazuhiko

    2014-01-01

    Vascular invasion in patients with hepatocellular carcinoma (HCC) is representative of advanced disease with an extremely poor prognosis. The detailed course of its development has not been fully elucidated. We enrolled 1057 consecutive patients with HCC who had been treated with curative intent by radiofrequency ablation (RFA) as an initial therapy from 1999 to 2008 at our department. We analyzed the incidence rate of and predictive factors for vascular invasion. The survival rate after detection of vascular invasion was also analyzed. During a mean follow-up period of 4.5 years, 6075 nodules including primary and recurrent lesions were treated by RFA. Vascular invasion was observed in 97 patients. The rate of vascular invasion associated with site of original RFA procedure was 0.66% on a nodule basis. The incidence rates of vascular invasion on a patient basis at 1, 3, and 5 years were 1.1%, 5.9%, and 10.4%, respectively. Univariate analysis revealed that tumor size, tumor number, alpha-fetoprotein (AFP), des-gamma-carboxy prothrombin (DCP), and Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein were significant risk predictors of vascular invasion. In multivariate analysis, DCP was the most significant predictor for vascular invasion (compared with a DCP of ≤100 mAu/mL, the hazard ratio was 1.95 when DCP was 101-200 mAu/mL and 3.22 when DCP was >200 mAu/mL). The median survival time after development of vascular invasion was only 6 months. Vascular invasion occurs during the clinical course of patients initially treated with curative intent. High-risk patients may be identified using tumor markers.

  5. Frequency of and predictive factors for vascular invasion after radiofrequency ablation for hepatocellular carcinoma.

    Directory of Open Access Journals (Sweden)

    Yoshinari Asaoka

    Full Text Available BACKGROUND: Vascular invasion in patients with hepatocellular carcinoma (HCC is representative of advanced disease with an extremely poor prognosis. The detailed course of its development has not been fully elucidated. METHODS: We enrolled 1057 consecutive patients with HCC who had been treated with curative intent by radiofrequency ablation (RFA as an initial therapy from 1999 to 2008 at our department. We analyzed the incidence rate of and predictive factors for vascular invasion. The survival rate after detection of vascular invasion was also analyzed. RESULTS: During a mean follow-up period of 4.5 years, 6075 nodules including primary and recurrent lesions were treated by RFA. Vascular invasion was observed in 97 patients. The rate of vascular invasion associated with site of original RFA procedure was 0.66% on a nodule basis. The incidence rates of vascular invasion on a patient basis at 1, 3, and 5 years were 1.1%, 5.9%, and 10.4%, respectively. Univariate analysis revealed that tumor size, tumor number, alpha-fetoprotein (AFP, des-gamma-carboxy prothrombin (DCP, and Lens culinaris agglutinin-reactive fraction of alpha-fetoprotein were significant risk predictors of vascular invasion. In multivariate analysis, DCP was the most significant predictor for vascular invasion (compared with a DCP of ≤100 mAu/mL, the hazard ratio was 1.95 when DCP was 101-200 mAu/mL and 3.22 when DCP was >200 mAu/mL. The median survival time after development of vascular invasion was only 6 months. CONCLUSION: Vascular invasion occurs during the clinical course of patients initially treated with curative intent. High-risk patients may be identified using tumor markers.

  6. 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.

  7. 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

  8. Differential and synergistic effects of mechanical stimulation and growth factor presentation on vascular wall function

    Science.gov (United States)

    Liang, Mao-Shih; Koobatian, Maxwell T.; Lei, Pedro; Swartz, Daniel D.; Andreadis, Stelios T.

    2013-01-01

    We investigated the hypothesis that immobilizing TGF-β1 within fibrin hydrogels may act in synergy with cyclic mechanical stimulation to enhance the properties of vascular grafts. To this end, we engineered a fusion TGF-β1 protein that can covalently anchor to fibrin during polymerization upon the action of factor XIII. We also developed a 24-well based bioreactor in which vascular constructs can be mechanically stimulated by distending the silastic mandrel in the middle of each well. TGF-β1 was either conjugated to fibrin or supplied in the culture medium and the fibrin based constructs were cultured statically for a week followed by cyclic distention for another week. The tissues were examined for myogenic differentiation, vascular reactivity, mechanical properties and ECM content. Our results showed that some aspects of vascular function were differentially affected by growth factor presentation vs. pulsatile force application, while others were synergistically enhanced by both. Overall, this two-prong biomimetic approach improved ECM secretion, vascular reactivity and mechanical properties of vascular constructs. These findings may be applied in other tissue engineering applications such as cartilage, tendon or cardiac regeneration where growth factors TGF-β1 and mechano-stimulation play critical roles. PMID:23810080

  9. Prognostic impact of placenta growth factor and vascular endothelial growth factor A in patients with breast cancer

    DEFF Research Database (Denmark)

    Maae, Else; Olsen, Dorte Aalund; Steffensen, Karina Dahl

    2012-01-01

    such as ischemic heart disease, arthritis and tumor growth. Angiogenesis is a complex process with several growth factors involved. Because PlGF modulates VEGF-A responses, we investigated their mutual relationship and impact on breast cancer prognosis. Quantitative PlGF and VEGF-A levels were measured in 229...... tumor tissue specimen from primarily operated patients with unilateral breast cancer. Non-malignant breast tissue was also dissected near the tumor and quantitative measurements were available for 211 patients. PlGF and VEGF-A protein levels in homogenized tissue lysates were analyzed using the Luminex...

  10. A mathematical model of tumour angiogenesis incorporating cellular traction and viscoelastic effects.

    Science.gov (United States)

    Holmes, M J; Sleeman, B D

    2000-01-21

    Angiogenesis is defined as the outgrowth and formation of new vessels from a pre-existing vascular network (Rakusan, In: Cardiac Growth and Regeneration. Annals of the New York Academy of Sciences, 1995), and is of fundamental importance in understanding the processes by which a tumour achieves vascularization. Diffusible substances, collectively called tumour angiogenesis factors are released from the tumour to elicit a variety of responses from the surrounding tissues, most importantly the migration of endothelial cells (lining neighbouring vessels) towards the tumour. To facilitate locomotion, the cells exert appreciable traction forces upon the interstitial extracellular matrix which, in turn, influences the resulting direction of their migration. In this paper, we examine the role played by cellular traction during cell migration and the corresponding viscoelastic effects of the extracellular matrix. Copyright 2000 Academic Press.

  11. The inclusion of cognition in vascular risk factor clinical practice guidelines

    Science.gov (United States)

    Rockwood, Kenneth; Middleton, Laura E; Moorhouse, Paige K; Skoog, Ingmar; Black, Sandra E

    2009-01-01

    Background: People with vascular risk factors are at increased risk for cognitive impairment as well as vascular disease. The objective of this study was to evaluate whether vascular risk factor clinical practice guidelines consider cognition as an outcome or in connection with treatment compliance. Methods: Articles from PubMed, EMBASE, and the Cochrane Library were assessed by at least two reviewers and were included if: (1) Either hypertension, high cholesterol, diabetes, or atrial fibrillation was targeted; (2) The guideline was directed at physicians; (3) Adult patients (aged 19 years or older) were targeted; and (4) The guideline was published in English. Of 91 guidelines, most were excluded because they were duplicates, older versions, or focused on single outcomes. Results: Of the 20 clinical practice guidelines that met inclusion criteria, five mentioned cognition. Of these five, four described potential treatment benefits but only two mentioned that cognition may affect compliance. No guidelines adequately described how to screen for cognitive impairment. Conclusion: Despite evidence that links cognitive impairment to vascular risk factors, only a minority of clinical practice guidelines for the treatment of vascular risk factors consider cognition as either an adverse outcome or as a factor to consider in treatment. PMID:19966911

  12. [Histocompatibility of nano-hydroxyapatite/poly-co-glycolic acid tissue engineering bone modified by mesenchymal stem cells with vascular endothelial frowth factor].

    Science.gov (United States)

    Zhang, Minglei; Wang, Dapeng; Yin, Ruofeng

    2015-10-06

    To explorec Histocompatibility of nano-hydroxyapatite/poly-co-glycolic acid tissue engineering bone modified by mesenchymal stem cells with vascular endothelial frowth factor transinfected. Rat bone marrow mesenchymal stem cells (BMSCs) was separated, using BMSCs as target cells, and then vascular endothelial growth factor (VEGF) gene was transfected. Composite bone marrow mesenchymal stem cells and cells transfected with nano-hydroxyapatite (HA)/polylactic-co-glycolic acid (PLGA). The composition of cell and scaffold was observed. The blank plasmid transfection was 39.1%, 40.1% in VEGF group. The cell adhesion and growth was found on the scaffold pore wall after 5 days, and the number of adherent cells in the nano-HA/PLGA composite scaffold material basically had no significant difference in both. Although the nano-HA/PLGA scaffold material is still not fully meet the requirements of the matrix material for bone tissue engineering, but good biocompatibility, structure is its rich microporous satisfaction in material mechanics, toughening, enhanced obviously. Composition scaffold with BMSCs transfected by VEGF plasmid, the ability of angiogenesis is promoted.

  13. Serum concentration of vascular endothelial growth factor and depth of trophoblastic invasion in ampullary ectopic pregnancy.

    Science.gov (United States)

    Cabar, Fábio Roberto; Teshima, Décio Roberto Kamio; Pereira, Pedro Paulo; Antonangelo, Leila; Schultz, Regina; Francisco, Rossana Pulcineli

    2016-12-01

    To evaluate the association between the depth of trophoblastic infiltration and serum vascular endothelial growth factorconcentration in patients with an ampullary pregnancy. This prospective cross-sectionalstudy involved 34 patients with an ampullary ectopic pregnancy who underwent salpingectomy between 2012 and 2013. Maternal serum vascular endothelial growth factor concentrations were measured using Luminex technology. Trophoblastic invasion was classified histologically as follows: stage I, limited to the tubal mucosa; stage II, reaching the muscle layer; and stage III,involving the full thickness. The qualitative data were compared using Fisher's exact test. The nonparametric Kruskal-Wallis and Mann-Whitney tests were used to evaluate differences in serum vascular endothelial growth factor among the degrees of trophoblastic invasion. ROC curves were constructed to determine vascular endothelial growth factor cut-off values that predict the degree of tubal invasion based on the best sensitivity and specificity. Eight patients had stage I trophoblastic invasion, seven had stage II, and 19 had stage III. The median serum vascular endothelial growth factorconcentration was 69.88 pg/mL for stage I, 14.53 pg/mL for stage II and 9.08 pg/mL for stage III, with a significant difference between stages I and III. Based on the ROC curve, a serum vascular endothelial growth factor concentration of 25.9 pg/mL best differentiated stage I from stages II and III with asensitivity of 75.0%, specificity of 76.9%, and area under the curve of 0.798. The depth of trophoblastic penetration into the tubal wall isassociated with serum vascular endothelial growth factor concentration in ampullary pregnancies.

  14. Risk Factors and Mediators of the Vascular Dysfunction Associated with Hypertension in Pregnancy

    Science.gov (United States)

    Sheppard, Stephanie J.; Khalil, Raouf A.

    2010-01-01

    Normal pregnancy is associated with significant hemodynamic changes and vasodilation in the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. Hypertension in pregnancy (HTN-Preg) and preeclampsia (PE) are major complications and life-threatening conditions to both the mother and fetus. PE is precipitated by various genetic, dietary and environmental factors. Although the initiating events of PE are unclear, inadequate invasion of cytotrophoblasts into the uterine artery is thought to reduce uteroplacental perfusion pressure and lead to placental ischemia/hypoxia. Placental hypoxia induces the release of biologically active factors such as growth factor inhibitors, anti-angiogenic proteins, inflammatory cytokines, reactive oxygen species, hypoxia-inducible factors, and antibodies to vascular angiotensin II receptor. These bioactive factors affect the production/activity of various vascular mediators in the endothelium, smooth muscle and extracellular matrix, leading to severe vasoconstriction and HTN. As an endothelial cell disorder, PE is associated with decreased vasodilator mediators such as nitric oxide, prostacyclin and hyperpolarizing factor and increased vasoconstrictor mediators such as endothelin, angiotensin II and thromboxane A2. PE also involves enhanced mechanisms of vascular smooth muscle contraction including intracellular free Ca2+ concentration ([Ca2+]i), and [Ca2+]i sensitization pathways such as protein kinase C, Rho-kinase and mitogen-activated protein kinase. Changes in extracellular matrix composition and matrix metalloproteases activity also promote vascular remodeling and further vasoconstriction in the uterine and systemic circulation. Characterization of the predisposing risk factors, the biologically active factors, and the vascular mediators associated with PE holds the promise for early detection, and should help design specific genetic and pharmacological tools for the management

  15. Immunohistochemical expression of vascular endothelial growth factor and matrix metalloproteinase-9 in radicular and residual radicular cysts

    Directory of Open Access Journals (Sweden)

    Patrícia Alvarez Ruiz

    2010-12-01

    Full Text Available OBJECTIVE: This study assessed and compared the immunoexpression of vascular endothelial growth factor (VEGF and matrix metalloproteinase-9 (MMP-9 in radicular cysts (RCs and residual radicular cysts (RRCs, relating them to the angiogenic index and the intensity of the inflammatory infiltrate. MATERIAL AND METHODS: Twenty RCs and 10 RRCs were evaluated by immunohistochemistry using anti-VEGF and anti-MMP-9 antibodies. The angiogenic index was determined by microvessel count (MVC using anti-von Willebrand factor antibody. RESULTS: The expression of both VEGF and MMP-9 was higher in RCs than in RRCs. RCs and RRCs presented strong epithelial expression of VEGF, irrespective of the intensity of the inflammatory infiltrate. Lesions with strong expression of MMP-9 showed significantly higher number of immunopositive cells for VEGF (p<0.05 and higher MVC (p<0.05. Lesions with dense inflammatory infiltrate exhibited significantly higher MVC (p<0.05 and higher number of immunopositive cells for VEGF (p<0.05. There was a positive correlation between both MVC (p<0.05 and the quantity of immunopositive cells for VEGF (p<0.05, with intensity of the inflammatory infiltrate. In addition, it was observed a positive correlation between the number of immunopositive cells for VEGF and MVC (p<0.05. CONCLUSIONS: VEGF and MMP-9 might play important roles in the angiogenesis in RCs and RRCs. In these lesions, the expression of these molecules and the MVC is closely related to the intensity of the inflammatory infiltrate. The expression of VEGF in the epithelial lining of RCs and RRCs might be important for the enlargement of these lesions.

  16. Elevated Vascular Endothelial Growth Factor (VEGF) levels in the blood serum of dogs with malignant neoplasms of the oral cavity.

    Science.gov (United States)

    Sobczyńska-Rak, Aleksandra; Polkowska, Izabela; Silmanowicz, Piotr

    2014-09-01

    Angiogenesis plays an essential role in the development of a neoplastic tumour by conditioning both its growth and the formation of metastases. The induction of blood vessel growth occurs under the influence of proangiogenic factors, among which Vascular Endothelial Growth Factor (VEGF) seems to be the most important. The aim of this research was to study the level of VEGF measured by ELISA in the serum of dogs with neoplasms of the oral cavity. The study material comprised samples of neoplastic tissue from 17 operated dogs and the serum of the examined animals as well as of dogs from the control group. The tissue samples were taken from dogs of different breeds, aged 6-14 years. The tumour type was determined in accordance with the applicable WHO classification. Blood samples taken from sick dogs and from animals of the control group were centrifuged, and immunoenzymatic labelling of VEGF was performed in the obtained serum using ELISA and R&D system reagents (Quantikine Canine VEGF). All stages of VEGF labelling were performed according to the recommendation of the test manufacturer. The median of VEGF in the serum of the dogs with neoplasms of the oral cavity was 40.64 pg/mL. The lowest value of 14.26 pg/mL was observed in the case of fibrosarcoma, and the highest value of 99.19 pg/mL in the case of squamous cell carcinoma. The VEGF median in the control group amounted to 11.14 pg/mL whereas the VEGF value in the groups of animals diagnosed with benign tumours ranged between 2.30 and 19.74 pg/mL. Elevated VEGF in the blood serum, in comparison with the benign tumour group and the control group, was observed in all examined neoplasms of the oral cavity. It was suggested that overexpression of VEGF can have a prognostic value and is useful in the early detection of neoplasms.

  17. Immunohistochemical expression of vascular endothelial growth factor and matrix metalloproteinase-9 in radicular and residual radicular cysts.

    Science.gov (United States)

    Ruiz, Patrícia Alvarez; Toledo, Orlando Ayrton de; Nonaka, Cassiano Francisco Weege; Pinto, Leão Pereira; Souza, Lélia Batista de

    2010-12-01

    This study assessed and compared the immunoexpression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in radicular cysts (RCs) and residual radicular cysts (RRCs), relating them to the angiogenic index and the intensity of the inflammatory infiltrate. Twenty RCs and 10 RRCs were evaluated by immunohistochemistry using anti-VEGF and anti-MMP-9 antibodies. The angiogenic index was determined by microvessel count (MVC) using anti-von Willebrand factor antibody. The expression of both VEGF and MMP-9 was higher in RCs than in RRCs. RCs and RRCs presented strong epithelial expression of VEGF, irrespective of the intensity of the inflammatory infiltrate. Lesions with strong expression of MMP-9 showed significantly higher number of immunopositive cells for VEGF (p<0.05) and higher MVC (p<0.05). Lesions with dense inflammatory infiltrate exhibited significantly higher MVC (p<0.05) and higher number of immunopositive cells for VEGF (p<0.05). There was a positive correlation between both MVC (p<0.05) and the quantity of immunopositive cells for VEGF (p<0.05), with intensity of the inflammatory infiltrate. In addition, it was observed a positive correlation between the number of immunopositive cells for VEGF and MVC (p<0.05). VEGF and MMP-9 might play important roles in the angiogenesis in RCs and RRCs. In these lesions, the expression of these molecules and the MVC is closely related to the intensity of the inflammatory infiltrate. The expression of VEGF in the epithelial lining of RCs and RRCs might be important for the enlargement of these lesions.

  18. Genetic variability of vascular endothelial growth factor and prognosis of head and neck cancer in a Brazilian population

    Directory of Open Access Journals (Sweden)

    M.T. Ruiz

    2010-02-01

    Full Text Available Vascular endothelial growth factor (VEGF is one of the most potent endothelial cell mitogens and plays a critical role in angiogenesis. Polymorphisms in this gene have been evaluated in patients with several types of cancer. The objectives of this study were to determine if there was an association of the -1154G/A polymorphism of the VEGF gene with head and neck cancer and the interaction of this polymorphism with lifestyle and demographic factors. Additionally, the distribution of the VEGF genotype was investigated with respect to the clinicopathological features of head and neck cancer patients. The study included 100 patients with histopathological diagnosis of head and neck squamous cell carcinoma. Patients with treated tumors were excluded. A total of 176 individuals 40 years or older were included in the control group and individuals with a family history of neoplasias were excluded. Analysis was performed after extraction of genomic DNA using the real-time PCR technique. No statistically significant differences between allelic and genotype frequencies of -1154G/A VEGF polymorphism were identified between healthy individuals and patients. The real-time PCR analyses showed a G allele frequency of 0.72 and 0.74 for patients and the control group, respectively. The A allele showed a frequency of 0.28 for head and neck cancer patients and 0.26 for the control group. However, analysis of the clinicopathological features showed a decreased frequency of the A allele polymorphism in patients with advanced (T3 and T4 tumors (OR = 0.36; 95%CI = 0.14-0.93; P = 0.0345. The -1154A allele of the VEGF gene may decrease the risk of tumor growth and be a possible biomarker for head and neck cancer. This polymorphism is associated with increased VEGF production and may have a prognostic importance.

  19. Amphiregulin enhances VEGF-A production in human chondrosarcoma cells and promotes angiogenesis by inhibiting miR-206 via FAK/c-Src/PKCδ pathway.

    Science.gov (United States)

    Wang, Chao-Qun; Huang, Yu-Wen; Wang, Shih-Wei; Huang, Yuan-Li; Tsai, Chun-Hao; Zhao, Yong-Ming; Huang, Bi-Fei; Xu, Guo-Hong; Fong, Yi-Chin; Tang, Chih-Hsin

    2017-01-28

    Chondrosarcoma is the second most common primary malignancy of bone after myeloma and osteosarcoma. Chondrosarcoma development may be linked to angiogenesis, which is principally elicited by vascular endothelial growth factor-A (VEGF-A). The expression of VEGF-A has been recognized as a prognostic marker in angiogenesis. Amphiregulin (AR), an epidermal growth factor receptor ligand, promotes tumor proliferation, metastasis and angiogenesis. However, the role of AR in VEGF-A expression and angiogenesis in human chondrosarcoma remains largely unknown. This current study shows that AR promoted VEGF-A production and induced angiogenesis of human endothelial progenitor cells. Moreover, AR-enhanced VEGF-A expression and angiogenesis involved the FAK, c-Src and PKCδ signaling pathways, while miR-206 expression was negatively mediated by AR via the FAK, c-Src and PKCδ pathways. Our results illustrate the clinical significance between AR, VEGF-A and miR-206, as well as tumor stage, in human chondrosarcoma. AR may represent a novel therapeutic target in the metastasis and angiogenesis of chondrosarcoma. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Development and Characterization of a Camelid Single Domain Antibody–Urease Conjugate That Targets Vascular Endothelial Growth Factor Receptor 2

    Directory of Open Access Journals (Sweden)

    Baomin Tian

    2017-08-01

    Full Text Available Angiogenesis is the process of new blood vessel formation and is essential for a tumor to grow beyond a certain size. Tumors secrete the pro-angiogenic factor vascular endothelial growth factor, which acts upon local endothelial cells by binding to vascular endothelial growth factor receptors (VEGFRs. In this study, we describe the development and characterization of V21-DOS47, an immunoconjugate that targets VEGFR2. V21-DOS47 is composed of a camelid single domain anti-VEGFR2 antibody (V21 and the enzyme urease. The conjugate specifically binds to VEGFR2 and urease converts endogenous urea into ammonia, which is toxic to tumor cells. Previously, we developed a similar antibody–urease conjugate, L-DOS47, which is currently in clinical trials for non-small cell lung cancer. Although V21-DOS47 was designed from parameters learned from the generation of L-DOS47, additional optimization was required to produce V21-DOS47. In this study, we describe the expression and purification of two versions of the V21 antibody: V21H1 and V21H4. Each was conjugated to urease using a different chemical cross-linker. The conjugates were characterized by a panel of analytical techniques, including SDS-PAGE, size exclusion chromatography, Western blotting, and LC-MSE peptide mapping. Binding characteristics were determined by ELISA and flow cytometry assays. To improve the stability of the conjugates at physiologic pH, the pIs of the V21 antibodies were adjusted by adding several amino acid residues to the C-terminus. For V21H4, a terminal cysteine was also added for use in the conjugation chemistry. The modified V21 antibodies were expressed in the E. coli BL21 (DE3 pT7 system. V21H1 was conjugated to urease using the heterobifunctional cross-linker succinimidyl-[(N-maleimidopropionamido-diethyleneglycol] ester (SM(PEG2, which targets lysine resides in the antibody. V21H4 was conjugated to urease using the homobifunctional cross-linker, 1,8-bis

  1. Disruption of Angiogenesis by Anthocyanin-Rich Extracts of Hibiscus sabdariffa

    Science.gov (United States)

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

    2017-01-01

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

  2. 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.

  3. Inhibition of choroidal angiogenesis by calcium dobesilate in normal Wistar and diabetic GK rats.

    Science.gov (United States)

    Lameynardie, Stéphane; Chiavaroli, Carlo; Travo, Pierre; Garay, Ricardo P; Parés-Herbuté, Núria

    2005-03-07

    Calcium dobesilate reduces vascular endothelial growth factor (VEGF) over-expression in diabetic rat retina, but its effect on intraocular angiogenesis is unknown. Therefore, we tested calcium dobesilate for its in vitro and ex vivo effects on choroidal explant angiogenesis in spontaneously diabetic Goto-Kakizaki (GK) rats. Choroidal explants were cultured in gels of collagen. Budded microvessels numbers and VEGF formation were taken as markers of angiogenesis. Ex vivo studies were performed in GK rats orally given 100 mg/kg/day calcium dobesilate for 10 days. In vitro, calcium dobesilate dose- and time-dependently inhibited both microvessel formation and VEGF production, at concentrations >or=25 mug/ml (i.e. >or=60 microM), with complete inhibition at 100 microg/ml. Oral treatment of diabetic GK rats with calcium dobesilate induced a significant reduction of choroidal angiogenesis ex vivo (38.8% after 3 days of culture). In conclusion, calcium dobesilate inhibited choroidal explant angiogenesis both in vitro and ex vivo. This effect may be due, at least in part, to inhibition of VEGF production. Antiangiogenesis by calcium dobesilate can be involved in its therapeutic benefit in diabetic retinopathy.

  4. In Silico Discovery of Potential VEGFR-2 Inhibitors from Natural Derivatives for Anti-Angiogenesis Therapy

    Directory of Open Access Journals (Sweden)

    Jing Li

    2014-09-01

    Full Text Available Angiogenesis is the growth of new capillaries from existing blood vessels that supply oxygen and nutrients and provide gateways for immune surveillance. Abnormal vessel growth in term of excessive angiogenesis is a hallmark of cancer, inflammatory and eye diseases. VEGFR-2 (vascular endothelial growth factor receptor 2 dominating the process of angiogenesis has led to approval of therapeutic inhibitors and is becoming a promising target for anti-angiogenic drugs. Notwithstanding these successes, the clinical use of current VEGFR-2 blockers is more challenging than anticipated. Taking axitinib as a reference drug, in our study we found three potent VEGFR-2 inhibitors (ZINC08254217, ZINC08254138, and ZINC03838680 from natural derivatives. Each of the three inhibitors acquired a better grid score than axitinib (−62.11 when docked to VEGFR-2. Molecular dynamics simulations demonstrated that ZINC08254217– and ZINC08254138–VEGFR-2 complexes were more stable than axitinib. Similar to bind free energy for axitinib (−54.68 kcal/mol, such for ZINC03838680, ZINC08254217, and ZINC08254138 was −49.37, −43.32, and −32.73 kcal/mol respectively. These results suggested these three compounds could be candidate drugs against angiogenesis, with comparable VEGFR-2 binding affinity of axitinib. Hence findings in our study are able to provide valuable information on discovery of effective anti-angiogenesis therapy.

  5. Stimulatory effects of the flavanol (-)-epicatechin on cardiac angiogenesis: additive effects with exercise.

    Science.gov (United States)

    Ramirez-Sanchez, Israel; Nogueira, Leonardo; Moreno, Aldo; Murphy, Ann; Taub, Pam; Perkins, Guy; Ceballos, Guillermo M; Hogan, Michael; Malek, Moh; Villarreal, Francisco

    2012-11-01

    The consumption of moderate amounts of cocoa products has been associated with reductions in the incidence of cardiovascular diseases. In animal studies, the flavanol (-)-epicatechin (Epi) yields cardioprotection. The effects may be partly due to its capacity to stimulate endothelial nitric oxide synthase (eNOS). The sustained activation of eNOS, as observed with exercise, can serve as a trigger of muscle angiogenesis via the activation of vascular endothelial growth factor (VEGF)-related events. Experiments were pursued to examine the potential of Epi to stimulate myocardial angiogenesis and determine the effects that its combined use with exercise (Ex) may trigger. Hearts obtained from a previous study were used for this purpose. Animals received 1 mg/kg of Epi or water (vehicle) via oral gavage (twice daily). Epi and/or Ex (by treadmill) was provided for 15 days. Results indicate that Ex or Epi significantly stimulate myocardial angiogenesis by ~30% above control levels. The use of Epi-Ex lead to further significant increases (to ~50%). Effects were associated with increases in protein levels and/or activation of canonical angiogenesis pathway associated events (HIF1a, VEGF, VEGFR2, PI3K, PDK, AKT, eNOS, NO, cGMP, MMP-2/-9, Src-1, and CD31). Thus, the use of Epi may represent a safe and novel means to stimulate myocardial angiogenesis.

  6. 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.

  7. Is apolipoprotein E4 an important risk factor for vascular dementia?

    Science.gov (United States)

    Rohn, Troy T

    2014-01-01

    Despite the fact that vascular dementia (VaD) represents the seconding leading cause of dementia in the USA, behind only Alzheimer's disease (AD), there remains a lack of consensus on the pathological criteria required for diagnosis of this disease. A number of clinical diagnostic criteria exist but are poorly validated and inconsistently applied. It is clear that vascular risk factors play an important role in the etiology of VaD, including hypertension, stroke, diabetes, and atherosclerosis. Vascular risk factors may increase the risk for VaD by promoting inflammation, cerebral vascular disease, white matter lesions, and hippocampal sclerosis. Because vascular risk factors seem to impart a high degree of risk for conferring VaD, it seems logical that the apolipoprotein E (APOE) status of individuals may be important. APOE plays a critical role in transporting cholesterol in and out of the CNS and in AD it is known that harboring the APOE allele increases the risk of AD perhaps due to the improper functioning of this protein. The purpose of this review is to examine the important pathological features and risk factors for VaD and to provide a critical assessment of the current literature regarding whether or not apoE4 also confers disease risk in VaD. The preponderance of data suggests that harboring one or both APOE4 alleles elevates the risk for VaD, but not to the same extent as found in AD.

  8. The impact of vascular endothelial growth factor and basic fibroblast growth factor on cardiac fibroblasts grown under altered gravity conditions

    DEFF Research Database (Denmark)

    Ulbrich, Claudia; Leder, Annekatrin; Pietsch, Jessica

    2010-01-01

    Myocardium is very sensitive to gravitational changes. During a spaceflight cardiovascular atrophy paired with rhythm problems and orthostatic intolerance can occur. The aim of this study was to investigate the impact of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor...... (VEGF) on cardiac fibroblasts (CF) grown under altered gravity conditions....

  9. Vascular endothelial growth factor -634G/C and vascular endothelial growth factor -