The VEGF splice variants: properties, receptors, and usage for the treatment of ischemic diseases.
Vascular endothelial growth factor (VEGF) was discovered 10 years ago as a growth factor that can regulate angiogenesis and in addition the permeability of blood vessels. Numerous studies have revealed that it is essential for normal embryonic development and that it plays a major role in physiological and pathological events of angiogenesis in adults. It is unique in that its expression is regulated directly by hypoxia. These properties are now being exploited in attempts aimed at the induction of new blood vessels in pathological situations such as ischemic heart disease. Five VEGF forms of 121 to 206 aminoacids are produced from a single gene by alternative splicing. Cells expressing VEGF usually express several forms simultaneously. VEGF121 does not contain exons 6 and 7 of the gene and consequently lacks a heparin binding ability. However, this form is fully active as an inducer of angiogenesis, and as a blood vessel permeabilizing agent. Exon 6 and 7 contain 2 independent heparin binding domains. The VEGF form containing exon 7 (VEGF165) and the vascular endothelial growth factor form containing exon 6 (VEGF145) display similar biological potencies raising the question of why so many VEGF forms are required. It was found that VEGF121 diffuses better because it does not bind to heparan-sulfate proteoglycans. In contrast, VEGF145 binds to extracellular matrix and is released from it slowly. When the receptor binding properties of VEGF121 and VEGF165 were compared it was found that VEGF165 binds to a class of VEGF receptors that is not recognized by VEGF121. These receptors are encoded by the neuropilin-1 gene, and we have recently found that the related neuropilin-2 gene also encodes a VEGF165 receptor. We have recently found evidence indicating the neuropilins form complexes with another VEGF receptor, VEGFR-1. However, the biological function of this complex remains to be elucidated.
Poltorak
Z
Z
Department of Biology, Technion, Israel Institute of Technology, Haifa, Israel.
Cohen
T
T
Neufeld
G
G
D000328:Adult; D017398:Alternative Splicing; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics; D003097:Collateral Circulation; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000627:therapeutic use*; D005121:Extremities / Q000098:blood supply*; D006801:Humans; D007511:Ischemia / Q000188:drug therapy*; D008222:Lymphokines / Q000235:genetics* / Q000627:therapeutic use*; D008562:Membrane Glycoproteins / Q000235:genetics; D051379:Mice; D017202:Myocardial Ischemia / Q000188:drug therapy*; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000235:genetics; D039942:Neuropilin-1; D020033:Protein Isoforms / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000954:Antigens, Surface; D016228:Endothelial Growth Factors; D008222:Lymphokines; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D011956:Receptors, Cell Surface; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1