Physiological angiogenesis occurs during growth states, fat deposition, hair growth and wound repair, as well as during the female reproductive cycle in the endometrium and follicular development. Angiogenesis is regulated by vascular growth factors, particularly vascular endothelial growth factors, VEGFs (Bates et al. 1999). VEGFs stimulate a variety of signalling pathways in endothelial cells, and result in a number of alterations in cell behaviour. VEGFs can stimulate endothelial-dependent vasodilatation, increased vascular permeability, breakdown of extracellular matrix components, migration of endothelial cells, and new blood vessel formation. These homodimeric peptides act on three receptors in the vascular system (VEGF-R1, -2 and -3) to stimulate new vessel growth. The growth factors are upregulated in response to increased metabolic demand, particularly hypoxia, and are overexpressed in many of the above pathologies. VEGFs also directly stimulate increased vascular permeability to water (Bates & Curry, 1996) and large molecular weight proteins. The three VEGF tyrosine kinase receptors, VEGF-R1, VEGF-R2, and VEGF-R3 are stimulated by different members of the VEGF family of polypeptides, VEGF-A acting on VEGF-R1 and VEGF-R2, PlGF and VEGF-B on VEGF-R1 only, and VEGF-C on VEGF-R2 and VEGF-R3. We have used these isoforms to show that increased permeability is brought about through activation of VEGF-R2. Using receptor-specific tyrosine kinase inhibitors, we have further shown that VEGF-A increases vascular permeability by stimulation of tyrosine autophosphorylation of VEGF-R2 on endothelial cells (Hillman et al. 2001), and subsequent activation of phospholipase C (PLC). This in turn results in increased production of diacylglycerol (DAG) and inositol trisphosphate (IP3). This DAG production results in increased intracellular calcium by influx of calcium through store-independent calcium channels, possibly the TrpC family of calcium channels (Pocock et al. 2000). It does not result in increased permeability through activation of PKC, MEK, ERK1 or -2, or DAG breakdown to arachidonic acid metabolites (Pocock & Bates, 2001). VEGF does result in chronically increased compliance of the vascular wall through activation of MEK and not through calcium influx (Bates et al. 2001). Increased [Ca2+]i stimulates nitric oxide synthase to produce nitric oxide that stimulates guanylate cyclase to liberate cyclic GMP. It is not known how this results in increased vascular permeability in endothelial cells in vivo.This work was supported by the British Heart Foundation (FS200057).
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Pocock, T.M. & Bates, D.O. (2001). J. Physiol. 534, 479-488. abstract
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