Review article
The neuroprotective function of vascular endothelial growth factor (VEGF)

The vascular endothelial growth factor (VEGF) is known mainly as the potent angiogenic and vascular permeability-enhancing factor. Both processes are very effective in hypoxia. The latest studies show that VEGF has neurotrophic and neuroprotective as well as angiogenic properties. It exerts neuroprotective actions directly through the inhibition of programmed cell death (PCD), or apoptosis and the stimulation of neurogenesis. VEGF is also a mediator of multiple processes including angiogenesis, enhancing blood brain barrier permeability for glucose, antioxidants activation, which indirectly result in neuroprotection. VEGF prevents neurons from death under critical conditions such as hypoxia, glucose deprivation through binding to the specific receptors, which are also expressed on the surface of neuronal cells. The increased expression of VEGFR-2/flk-1/KDR receptors on neurons subjected to hypoxia, glucose deprivation provides evidence that these receptors are mainly involved in neuroprotective effects of VEGF. Furthermore, binding to these receptors triggers the phosphatidyloinositol 3-kinase (PI3K) /Akt signal transduction system and, in consequence, leads to the inhibition of PCD by activating antiapoptotic proteins through the transcription factor NFκB and inhibiting proapoptotic signaling by Bad, caspase-9, caspase-3, and other effectors. Promotion of neuronal cells proliferation by VEGF is also associated with the increased expression of VEGFR-2 receptors and up-regulation of E2F family transcription factors, cyclin D1, cyclin E, and cdc25. It is known that the amount and types of VEGF isoforms influence its action. At least six isoforms of VEGF proteins are formed as a result of alternative mRNA splicing and it is unknown which of them and in what proportion occur in the nervous system in physiology and pathophysiology. It seems to be very essential to find out the mechanisms responsible for specific patterns of VEGF isoforms and their receptors expression in different pathologies of the nervous system. Maybe such knowledge will provide new perspectives in VEGF therapy.