Centre for Cardiovascular Biology and Medicine, BHF Laboratories, Department of Medicine, The Rayne Institute, University College London, London , UK.
Vascular endothelial growth factor (VEGF or VEGF-A) and its receptors play essential roles in the formation of blood vessels during embryogenesis and in disease. Most biological effects of VEGF are mediated via two receptor tyrosine kinases, VEGFR1 and VEGFR2, but specific VEGF isoforms also bind neuropilins (NP) 1 and 2, non-tyrosine kinase receptors originally identifi ed as receptors for semaphorins, polypeptides with essential roles in neuronal patterning. There is abundant evidence that VEGF-A has neurotrophic and neuroprotective effects on neuronal and glial cells in culture and in vivo, and can stimulate the proliferation and survival of neural stem cells. VEGFR2 and NP1 are the major VEGF receptors expressed on neuronal cells and, while the mechanisms mediating neuroprotective effects of VEGF are not fully understood, VEGF stimulates several signaling events in neuronal cell types, including activation of phospholipase C- , Akt and ERK. Findings in diverse models of nerve damage and disease suggest that VEGF has therapeutic potential as a neuroprotective factor. VEGF is a key mediator of the angiogenic response to cerebral and peripheral ischaemia, and promotes nerve repair following traumatic spinal injury. Recent work has revealed a role for reduced VEGF expression in the pathogenesis of amyotrophic lateral sclerosis, a rare neurodegenerative disease caused by selective loss of motor neurons. In many instances, the neuroprotective effects of VEGF appear to result from a combination of the indirect consequences of increased angiogenesis, and the direct stimulation of neuronal function. However, more work is required to determine the specific functional role of direct neuronal effects of VEGF.
Since its initial discovery in 1983  and subsequent cloning of the gene in 1989 [2, 3] , vascular endothelial growth factor (VEGF-A, VEGF or vascular permeability factor) has been established to be an essential regulator of angiogenesis in both vertebrate development and in a variety of common chronic human diseases  . Alternative splicing of the human VEGF-A gene gives rise to at least six different transcripts, encoding isoforms (excluding signal peptide) of 121 (mouse equivalent, VEGFA 120 ), 145, 165 (mouse VEGF-A 164 ), 183, 189 and 206 amino acid residues  . All transcripts contain exons 1–5, encoding the signal sequence and core VEGFR-binding or VEGF/PDGF homology domain, and exon 8, with diversity generated through the alternative splicing of exons 6 and 7. Exon 6 encodes a heparin-binding domain, while exons 7 and 8 encode a domain that mediates binding to neuropilin-1 (NP1) and heparin. Human VEGFA 165 , the most abundant and biologically active form, and VEGF-A 121 are secreted as covalently linked homodimeric proteins, whereas the larger isoforms, VEGF-A 189 and VEGF-A 206 , though thought to be secreted, are not readily diffusible and may remain sequestered in the extracellular matrix. VEGF-A is also the prototypical member of a family of related growth factors, which includes placental growth factor (PLGF), VEGFs B, C, and D, and the viral VEGF-Es encoded by strains D1701, NZ2 and NZ7 of the parapoxvirus Orf [6–8] . All VEGF family members are able to regulate angiogenesis, and in addition, VEGFs C and D are implicated as biologically important mediators of lymphangiogenesis; however, in contrast to VEGFA, the precise biological roles of other VEGFs are not yet fully understood. The biological functions of VEGF-A are mediated via the protein tyrosine kinase receptors, VEGFR2 (KDR/Flk-1) and VEGFR1 (Flt-1) [4, 9, 10].