VITRONECTIN RECEPTOR ON SKIN ENDOTHELIAL CELLS

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Injury, inflammation and vascular leakage results in extravascular deposition of serum matrix proteins. Microvascular endothelial cells utilize integrin receptors, particularly the vitronectin receptor (VnR), to bind to deposited matrix and use it as a scaffold to form new vessels. The VnR is a crucial element in the regulation of endothelial cell function in wound healing since it can bind to multiple proteins such as fibrinogen, vitronectin, thrombin, thrombospondin, and von Willebrand's factor (vWF) which are characteristically deposited in injured tissues. Preliminary studies of healing skin wounds suggest that the expression of the VnR is rapidly increased on infiltrating cells after wounding, prior to increases in the expression of other integrin receptors. However, the regulation of expression and function of the VnR on microvascular endothelial cells within the context of wound healing, inflammation, or injury has not been examined. Therefore, the specific aims of this proposal are: 1) To characterize the expression of the alpha(v)/beta(3) complex (vitronectin receptor, VnR) on human dermal microvascular endothelial cells (HDMEC) using immunofluorescence microscopy, flow cytometry, western immunoblot, and immunoprecipitation. 2) To examine the effects of the soluble factors basic fibroblast growth factor (FGF), transforming growth factor beta (TGF- beta), and protein kinase C agonists on the expression of the VnR. 3) To define the interaction of HDMEC with purified defined matrix proteins and examine whether these are modulated by agents which change the expression of the VnR. 4) To determine the molecular levels at which subunit gene expression and complex assembly and surface expression are constitutively regulated and to characterize the effects of basic FGF, PKC agonists, and TGF beta upon regulatory mechanisms. These studies will produce novel insights into endothelial cell function in wound healing and neovascularization.