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Reviews |
a Department of Biology, Technion, Israel Institute of Technology, Technion City, Haifa 32000, Israel
Vascular endothelial growth factor (VEGF) is a highly specific mitogen for vascular endothelial cells. Five VEGF isoforms are generated as a result of alternative splicing from a single VEGF gene. These isoforms differ in their molecular mass and in biological properties such as their ability to bind to cell-surface heparan-sulfate proteoglycans. The expression of VEGF is potentiated in response to hypoxia, by activated oncogenes, and by a variety of cytokines. VEGF induces endothelial cell proliferation, promotes cell migration, and inhibits apoptosis. In vivo VEGF induces angiogenesis as well as permeabilization of blood vessels, and plays a central role in the regulation of vasculogenesis. Deregulated VEGF expression contributes to the development of solid tumors by promoting tumor angiogenesis and to the etiology of several additional diseases that are characterized by abnormal angiogenesis. Consequently, inhibition of VEGF signaling abrogates the development of a wide variety of tumors. The various VEGF forms bind to two tyrosine-kinase receptors, VEGFR-1 (flt-1) and VEGFR-2 (KDR/flk-1), which are expressed almost exclusively in endothelial cells. Endothelial cells express in addition the neuropilin-1 and neuropilin-2 coreceptors, which bind selectively to the 165 amino acid form of VEGF (VEGF165). This review focuses on recent developments that have widened considerably our understanding of the mechanisms that control VEGF production and VEGF signal transduction and on recent studies that have shed light on the mechanisms by which VEGF regulates angiogenesis.—Neufeld, G., Cohen, T., Gengrinovitch, S., Poltorak, Z. Vascular endothelial growth factor (VEGF) and its receptors. FASEB J. 13, 9–22 (1999)
Key Words: hypoxia • angiogenesis • oncogene • heparan-sulfate proteoglycan • cytokine
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W. Zhang, R. Swanson, Y. Xiong, B. Richard, and S. T. Olson Antiangiogenic Antithrombin Blocks the Heparan Sulfate-dependent Binding of Proangiogenic Growth Factors to Their Endothelial Cell Receptors: EVIDENCE FOR DIFFERENTIAL BINDING OF ANTIANGIOGENIC AND ANTICOAGULANT FORMS OF ANTITHROMBIN TO PROANGIOGENIC HEPARAN SULFATE DOMAINS J. Biol. Chem., December 8, 2006; 281(49): 37302 - 37310. [Abstract] [Full Text] [PDF]
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 A. de Paulis, N. Prevete, I. Fiorentino, F. W. Rossi, S. Staibano, N. Montuori, P. Ragno, A. Longobardi, B. Liccardo, A. Genovese, et al. Expression and Functions of the Vascular Endothelial Growth Factors and Their Receptors in Human Basophils J. Immunol., November 15, 2006; 177(10): 7322 - 7331. [Abstract] [Full Text] [PDF]
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N. Singh, P. D. Jani, T. Suthar, S. Amin, and B. K. Ambati Flt-1 Intraceptor Induces the Unfolded Protein Response, Apoptotic Factors, and Regression of Murine Injury-Induced Corneal Neovascularization Invest. Ophthalmol. Vis. Sci., November 1, 2006; 47(11): 4787 - 4793. [Abstract] [Full Text] [PDF]
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M. J. Bizzarro, N. Hussain, B. Jonsson, R. Feng, L. R. Ment, J. R. Gruen, H. Zhang, and V. Bhandari Genetic Susceptibility to Retinopathy of Prematurity Pediatrics, November 1, 2006; 118(5): 1858 - 1863. [Abstract] [Full Text] [PDF]
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 Q. Ke and M. Costa Hypoxia-Inducible Factor-1 (HIF-1) Mol. Pharmacol., November 1, 2006; 70(5): 1469 - 1480. [Abstract] [Full Text] [PDF]
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H. Xu, L. Zeng, H. Peng, S. Chen, J. Jones, T.-L. Chew, M. M. Sadeghi, Y. S. Kanwar, and F. R. Danesh HMG-CoA reductase inhibitor simvastatin mitigates VEGF-induced "inside-out" signaling to extracellular matrix by preventing RhoA activation Am J Physiol Renal Physiol, November 1, 2006; 291(5): F995 - F1004. [Abstract] [Full Text] [PDF]
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L. Poliseno, A. Tuccoli, L. Mariani, M. Evangelista, L. Citti, K. Woods, A. Mercatanti, S. Hammond, and G. Rainaldi MicroRNAs modulate the angiogenic properties of HUVECs Blood, November 1, 2006; 108(9): 3068 - 3071. [Abstract] [Full Text] [PDF]
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W.-U. Kim, S. S. Kang, S.-A. Yoo, K.-H. Hong, D.-G. Bae, M.-S. Lee, S. W. Hong, C.-B. Chae, and C.-S. Cho Interaction of Vascular Endothelial Growth Factor 165 with Neuropilin-1 Protects Rheumatoid Synoviocytes from Apoptotic Death by Regulating Bcl-2 Expression and Bax Translocation J. Immunol., October 15, 2006; 177(8): 5727 - 5735. [Abstract] [Full Text] [PDF]
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 H. R. Lijnen, V. Christiaens, I. Scroyen, G. Voros, M. Tjwa, P. Carmeliet, and D. Collen Impaired adipose tissue development in mice with inactivation of placental growth factor function. Diabetes, October 1, 2006; 55(10): 2698 - 2704. [Abstract] [Full Text] [PDF]
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 S M Hyder Sex-steroid regulation of vascular endothelial growth factor in breast cancer. Endocr. Relat. Cancer, September 1, 2006; 13(3): 667 - 687. [Abstract] [Full Text] [PDF]
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M. Iemitsu, S. Maeda, S. Jesmin, T. Otsuki, and T. Miyauchi Exercise training improves aging-induced downregulation of VEGF angiogenic signaling cascade in hearts Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1290 - H1298. [Abstract] [Full Text] [PDF]
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 A. D.-Y. Lin, A. Mannikarottu, B. A Kogan, C. Whitbeck, P. Chichester, R. E Leggett, and R. M Levin Estrogen induces angiogenesis of the female rabbit bladder. J. Endocrinol., August 1, 2006; 190(2): 241 - 246. [Abstract] [Full Text] [PDF]
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 J. Tang, Q. Xie, G. Pan, J. Wang, and M. Wang Mesenchymal stem cells participate in angiogenesis and improve heart function in rat model of myocardial ischemia with reperfusion. Eur. J. Cardiothorac. Surg., August 1, 2006; 30(2): 353 - 361. [Abstract] [Full Text] [PDF]
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 M. Atri New Technologies and Directed Agents for Applications of Cancer Imaging J. Clin. Oncol., July 10, 2006; 24(20): 3299 - 3308. [Abstract] [Full Text] [PDF]
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Y. Su, Z. Cui, Z. Li, and E. R. Block Calpain-2 regulation of VEGF-mediated angiogenesis FASEB J, July 1, 2006; 20(9): 1443 - 1451. [Abstract] [Full Text] [PDF]
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 Y.-J. Na, S.-H. Yang, D.-W. Baek, D.-H. Lee, K.-H. Kim, Y.-M. Choi, S.-T. Oh, Y.-S. Hong, J.-Y. Kwak, and K.-S. Lee Effects of peritoneal fluid from endometriosis patients on the release of vascular endothelial growth factor by neutrophils and monocytes Hum. Reprod., July 1, 2006; 21(7): 1846 - 1855. [Abstract] [Full Text] [PDF]
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 V. Balasubramaniam, A. M. Maxey, D. B. Morgan, N. E. Markham, and S. H. Abman Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia Am J Physiol Lung Cell Mol Physiol, July 1, 2006; 291(1): L119 - L127. [Abstract] [Full Text] [PDF]
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J. R. Basile, R. M. Castilho, V. P. Williams, and J. S. Gutkind Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis PNAS, June 13, 2006; 103(24): 9017 - 9022. [Abstract] [Full Text] [PDF]
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S. Jesmin, S. Zaedi, N. Yamaguchi, S. Maeda, N. Shimojo, K. Masuzawa, I. Yamaguchi, K. Goto, and T. Miyauchi Differential effects of selective endothelin type a receptor antagonist on the gene expression of vascular endothelial growth factor and its receptors in streptozotocin-induced diabetic heart. Experimental Biology and Medicine, June 1, 2006; 231(6): 902 - 906. [Abstract] [Full Text] [PDF]
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K. A Vonnahme, D. A Redmer, E. Borowczyk, J. J Bilski, J. S Luther, M. L. Johnson, L. P Reynolds, and A. T Grazul-Bilska Vascular composition, apoptosis, and expression of angiogenic factors in the corpus luteum during prostaglandin F2{alpha}-induced regression in sheep. Reproduction, June 1, 2006; 131(6): 1115 - 1126. [Abstract] [Full Text] [PDF]
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E. Pau, I. Alonso-Muriel, R. Gomez, E. Novella, A. Ruiz, J. A. Garcia-Velasco, C. Simon, and A. Pellicer Plasma levels of soluble vascular endothelial growth factor receptor-1 may determine the onset of early and late ovarian hyperstimulation syndrome Hum. Reprod., June 1, 2006; 21(6): 1453 - 1460. [Abstract] [Full Text] [PDF]
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 R. Schindler and R. Mentlein Flavonoids and Vitamin E Reduce the Release of the Angiogenic Peptide Vascular Endothelial Growth Factor from Human Tumor Cells J. Nutr., June 1, 2006; 136(6): 1477 - 1482. [Abstract] [Full Text] [PDF]
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V. Balasubramaniam, A. M. Maxey, B. W. Fouty, and S. H. Abman Nitric oxide augments fetal pulmonary artery endothelial cell angiogenesis in vitro Am J Physiol Lung Cell Mol Physiol, June 1, 2006; 290(6): L1111 - L1116. [Abstract] [Full Text] [PDF]
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 W. Li, W. Shen, R. Gill, A. Corbly, B. Jones, R. Belagaje, Y. Zhang, S. Tang, Y. Chen, Y. Zhai, et al. High-Resolution Quantitative Computed Tomography Demonstrating Selective Enhancement of Medium-Size Collaterals by Placental Growth Factor-1 in the Mouse Ischemic Hindlimb Circulation, May 23, 2006; 113(20): 2445 - 2453. [Abstract] [Full Text] [PDF]
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K. Y. Kim and H. G. Cheon Antiangiogenic Effect of Rosiglitazone Is Mediated via Peroxisome Proliferator-activated Receptor {gamma}-activated Maxi-K Channel Opening in Human Umbilical Vein Endothelial Cells J. Biol. Chem., May 12, 2006; 281(19): 13503 - 13512. [Abstract] [Full Text] [PDF]
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T. Shibuya, K. Watanabe, H. Yamashita, K. Shimizu, H. Miyashita, M. Abe, T. Moriya, H. Ohta, H. Sonoda, T. Shimosegawa, et al. Isolation and Characterization of Vasohibin-2 as a Homologue of VEGF-Inducible Endothelium-Derived Angiogenesis Inhibitor Vasohibin Arterioscler. Thromb. Vasc. Biol., May 1, 2006; 26(5): 1051 - 1057. [Abstract] [Full Text] [PDF]
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J. A. Marwick, C. S. Stevenson, J. Giddings, W. MacNee, K. Butler, I. Rahman, and P. A. Kirkham Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition Am J Physiol Lung Cell Mol Physiol, May 1, 2006; 290(5): L897 - L908. [Abstract] [Full Text] [PDF]
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