BBB seminar: David O. Bates
VEGFs, fluid balance and vessel growth
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David O. Bates
Microvascular Research Laboratories, Department of Physiology, Preclinical Veterinary School, University of Bristol, UK
Vascular Endothelial Growth Factors (VEGFs) are critical regulators of angiogenesis in normal physiology, heart disease, cancer, arthritis, diabetes etc. They are also potent permeability factors that regulate fluid balance during vascular growth. Moreover, they regulate normal renal function of haematopoeisis, neuronal development and many other non-endothelial systems. The Microvascular Research Laboratories investigate the role of VEGFs in regulation of fluid balance through their effects on vascular permeability, angiogenesis, glomerular filtration and lymphatic function. This lecture will describe the recent findings in these areas.
The signal transduction pathways underlying increased vascular permeability have been elucidated using single capillary perfusion. The role of VEGF is being investigated in maintenance of glomerular filtration, and its signalling through nephrin to mediate apoptosis. Lymphangiogenesis in skin cancer and breast cancer related lymphoedema is elucidating mechanisms of metastasis. Finally, we recently discovered a novel VEGF isoform formed by differential splicing from the end of exon 7 into the 3' untranslated region of the mRNA. This mRNA encodes a 165 amino acid peptide with alternative terminal 6 amino acids - VEGF165b. The mRNA is downregulated in both renal and prostate cancer, and the protein is found in normal human serum and a variety of tissues. This isoform significantly and dose dependently inhibits VEGF165 mediated proliferation and migration of endothelial cells and vasodilatation of mesenteric arteries by binding to VEGF-receptor 2 (VEGF-R2) but not phosphorylating it. Furthermore, in vivo angiogenesis assays show that this isoform is not angiogenic, and inhibits VEGF165 mediated angiogenesis. Finally a switch in splicing can inhibit tumour growth in vivo. This novel isoform VEGF165b is therefore an endogenous renal secreted inhibitory form of VEGF that is downregulated in renal and prostate cancer and is anti-angiogenic.
Dr. Dave Bates is lecturer in Basic Biomedical Sciences, University Senior Research Fellow and Director of the Microvascular Research Laboratories, Department of Physiology, University of Bristol. He started his career at the Department of Physiology, St George's Medical School, University of London where he studied Starling forces in lymphoedema. He had postdoctoral positions at the Department of Genetics, University of Glasgow and the Department of Human Physiology, University of California, Davis. His main research interest has been capillary permeability in normal and pathological conditions. At present his research concentrates on the biology of Vascular Endothelial Growth Factors (VEGFs), and in addition to investigate regulation of vascular permeability, he carries out studies on angiogenesis and lymphangiogenesis. |