Neuroprotective role of vascular endothelial growth factor: signalling mechanisms, biological function, and...

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 identified 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 signalling events in neuronal cell types, including activation of phospholipase C-gamma, 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.