Expanding the repertoire of vascular endothelial growth factor : novel roles in cytoprotection and nociception

Abstract

It is now well established that vascular endothelial growth factor-A (VEGF-A or VEGF), originally described as a key angiogenic factor, plays a crucial cytoprotective role for non- endothelial cell types, including the retinal pigmented epithelium and neuronal cell types. Anti-VEGF therapy has been approved to treat a number of angiogenic-dependent diseases, for example neovascular age-related macular degeneration and renal cell carcinoma, but neutralizing VEGF can cause detrimental effects such as retinal damage, sensory neuropathy and/or pain. Alternative splicing of VEGF mRNA produces two functionally distinct families of proteins, the conventional pro-angiogenic family, VEGFxxxa, and an anti-angiogenic family, VEGFxxxb. Using in vitro cytotoxicity assays, I investigated the cytoprotective effect of the predominant VEGFxxxb isoform, VEGF 165b, on retinal pigment epithelial (RPE) cells, hippocampal and dorsal root ganglion (DRG) neurons. Like its sister isoform VEGF 165a, VEGF 165b was cytoprotective for RPE cells and, hippocampal and DRG neurons against various insults and the underlying mechanism was explored. I investigated the effect of VEGF 165a, VEGF 165b and a VEGF neutralizing antibody on mechanical withdrawal nociceptive behaviour in normal and nerve-injured mice. Key findings were that VEGF isoforms affected nociceptive behaviour in an opposing and isoform-specific manner and the pro-nociceptive effect of VEGF 165a was dependent the ion channel, transient receptor potential- vanilloid-l (TRPVl). The VEGF isoforms also affected TRPVI channel activity in an opposing and isoform-specific manner in vitro. VEGFxxxb proteins make up a significant proportion of total VEGF in adult physiology and the adverse events that arise from anti- VEGF therapy may arise from the disruption of VEGFxxxb-mediated cytoprotection and anti- nociception. The novel effects of VEGF 165b, identified in this thesis, also indicate a potential use for the protein in degenerative conditions and painful neuropathies.EThOS - Electronic Theses Online ServiceGBUnited Kingdo