Repair and maintenance of vascular integrity requires that endothelial cells display an integrated, coordinated regulation of cell-cell and cell- matrix attachment to minimize extravasation of blood during wound healing, tumor growth and in the dynamic expansion and contraction of microvascular beds during postnatal angiogenesis. Possible roles of tyrosine phosphatases in modulating endothelial responses to proliferative stimuli have been suggested by effects of the protein tyrosine phosphatase inhibitor, orthovanadate, to promote proliferation of cultured endothelial cells. A receptor tyrosine phosphatase they have cloned from human renal microvascular endothelial cells, DEP-1, regulates endothelial responses to stimuli for proliferation, migration, and capillary morphogenesis. They will explore molecularly specific roles for DEP-1 by assessing effects that loss of DEP-1 function and gain of function have on behavior of microvascular and large vessel endothelial cells; those responses will be compared with responses in non-endothelial cell types. Emphasis will be placed on defining effects DEP-1 mediates on the density- and matrix-dependent growth and differentiation of cultured endothelial cells. Mechanisms mediating DEP-1 accumulation will be explored, and substrates with which it interacts will be identified. Roles for intracellular targeting of the catalytically active cytoplasmic tyrosine phosphatase domain in biological function will be determined. These studies promise to define mechanisms that modulate endothelial responses to proliferative stimuli in vascularized tumors, diabetes and atherosclerosis and to assign function to tyrosine phosphatases that have not been previously defined in endothelial systems.
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