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. VEGF(121) 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 (VEGF(165)) and the vascular endothelial growth factor form containing exon 6 (VEGF(145)) display similar biological potencies raising the question of why so many VEGF forms an required. It was found that VEGF(121) diffuses better because it does not bind to heparan-sulfate proteoglycans. In contrast, VEGF(145) binds to extracellular matrix and is released from it slowly. When the receptor binding properties of VEGF(121) and VEGF165 were compared it was found that VEGF(165) binds to a class of VEGF receptors that is not recognized by VEGF(121). These receptors ore 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.