Vascular Endothelial Growth Factor (VEGF) and Peripheral Nerve Regeneration

Abstract: This thesis concerns vascular endothelial growth factor (VEGF) and its possible role as a neurotrophic factor. I have investigated the effect of VEGF on neurons in culture but also in vivo, following a crush lesion of the sciatic nerve, and following nerve repair. Attempts were also made to unravel the mechanism by which VEGF affects neurons and Schwann cells, using a pharmacological approach in combination with techniques like tissue culture, BrdU-labelling, in situ hybridization, immunocytochemistry, image analysis, SDS-PAGE and Western blotting. I found that VEGF stimulates axonal outgrowth from dorsal root (DRG)- and superior cervical ganglia (SCG) through activation of the flk-1 receptor and the MAPK pathway, and that activation of the same receptor on Schwann cells results in a proliferative response. VEGF also promotes survival of neurons and satellite cells. We suggest that VEGF acts both by auto- and paracrine mechanisms in the peripheral nervous system, considering the expression of VEGF and flk-1 in cells of DRG, SCG and the sciatic nerve. My second approach was to develop a cell-free nerve graft which could be used for nerve repair. The idea was that by removing the cells from the graft but maintaining the basal lamina the rejection process could be suppressed while regeneration was enhanced. I could show that nerve grafts made acellular by chemical extraction supported regeneration of nerve fibers when transplanted into a defect in the sciatic nerve of recipient rats of a different rat strain. In this system VEGF treatment promoted both vascularization and migration of Schwann cells in the graft, suggesting that for nerve repair VEGF treatment could be beneficial since it stimulates two important aspects of the regeneration process i.e. Schwann cell invasion and neovascularization. Taken together my work lend strong support to our hypothesis that VEGF is a neurotrophic factor, a finding which can have implications for our understanding of nerve injuries.