Regulation of microvascular permeability by vascular endothelial growth factors

Abstract

Generation of new blood vessels from pre‐existing vasculature (angiogenesis) is accompanied in almost all states by increases in vascular permeability. This is true in physiological as well as pathological angiogenesis but is more marked during disease states. Physiological angiogenesis occurs during growth states, fat deposition, hair growth and wound repair, as well as during the female reproductive cycle in the endometrium. Pathological angiogenesis is seen in a wide variety of diseases, which include all the major causes of mortality in the west; heart disease, cancer, stroke, vascular disease and diabetes. Angiogenesis is regulated by vascular growth factors, particularly vascular endothelial growth factor (VEGF). These peptides act on 2 specific receptors in the vascular system (VEGF‐R1 and 2) to stimulate new vessel growth. VEGFs also directly stimulate increased vascular permeability to water and large molecular weight proteins. This increased vascular permeability appears to have a minor effect in physiological angiogenesis, but causes considerable damage in pathologies. VEGFs result in cerebral oedema in glioblastoma multiformae, ascites and pleural effusions in liver metastasis and lung cancer, respectively, may contribute to increased lipid deposition in atherosclerosis, substrate formation in neointimal hyperplasia, and neuropathy and nephropathy in diabetes. We have shown in MS222 anaesthetised frogs that VEGFs increase vascular permeability in mesenteric microvessels by stimulation of tyrosine autophosphorylation of VEGF‐R2 on endothelial cells, and subsequent activation of phospholipase C (PLC). This in turn results in increased production of diacylglycerol (DAG) and inositol tris phosphate (IP3). This PLC activation results in increased intracellular calcium through influx of calcium through store independent calcium channels, possibly the TrpC family of calcium channels). It is not known how this results in increased vascular permeability in endothelial cells in vivo. We have shown however, that VEGF can stimulate formation of a variety of pathways through the endothelial cell wall, including transcellular gaps, vesicoluvacuolar organelle formation, fenestrations and intercellular gaps. It is not clear whether these are all part of the same process.