This growth factor is the principal driver of physiological and pathological angiogenesis, acting as a potent and highly selective mitogen for vascular endothelial cells. VEGF is the predominant and most biologically active isoform of VEGF-A, arising from alternative splicing of the VEGFA transcript, and is distinguished from the shorter VEGF121 isoform by retention of the basic, exon 6/7-encoded heparin-binding domain. That domain confers binding to heparan sulfate proteoglycans in the extracellular matrix and to the neuropilin co-receptors, which is why VEGF165 combines the diffusibility needed to establish a gradient with the matrix retention needed to hold that gradient in place, and why it is substantially more potent than VEGF121 in most assays.
Beyond proliferation it induces endothelial migration and tube formation, promotes endothelial survival, and is the most potent known inducer of vascular permeability, the property for which it was originally isolated as vascular permeability factor. Expression is strongly induced by hypoxia through HIF-1a stabilisation and binding to the VEGFA hypoxia response element, and is highest in well-vascularised tissues including lung, thyroid, heart and adrenal gland.
Signalling upregulates transcriptional programmes governing (i) endothelial proliferation via PLCg/PKC/ERK, (ii) survival via PI3K/AKT and BCL-2, (iii) permeability and vasodilation via AKT/eNOS and nitric oxide, and (iv) migration and cytoskeletal remodelling via p38 MAPK and FAK/paxillin.
