Angiogenesis during development, during healing, and during tumor vascularization are processes which have major impact upon both an organism's ability to develop and survive. The control/modulation of angiogenesis is thought to involve integrated dynamic interactions among endothelial cells, extracellular matrix, soluble factors and other adjacent cell types. Advances in our understanding of these interactions in angiogenesis in the last several years have occured in the areas of cell-cell, cell-matrix and cell-growth factor interactions. Cell-cell interactions between and among endothelial cells and endothelial cell-matrix interactions heve been implicated in the various stages of the angiogenic process, including tube formation, maintenance and involution. Extracellular matrix-driven, integrin-mediated modulation of endothelial behavior has been shown to be critical in the angiogenic process. In particular, integrin modulation of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) phosphorylation has been shown to be an important regulator of angiogenesis both in vio and in vitro. In particular, extracellular matrix-driven, integrin-mediated PECAM-1 tyrosine phosphorylatibn/dephosphorylation has been implicated in modulating endothelial cell migration, vasculogenesis and angiogenesis. Thus we propose to elucidate the tyrosine and serine phosphorylation states of PECAM-1 and their effects on the conformation of the PECAM-1 ITAM domain, binding sites and affinities for selected signaling and adapter molecules (c-src, SHPTP-2 and p- catenin) and putative PECAM-1 - PECAM-1 interactions. The findings accrued from these studies will be correlated with and confirmed in a series of in vitro tissue culture studies utilizing wild type and endothelial cells expressing mutated and truncated PECAM-1 constructs. Lastly, we will employ PECAM-1 transgenic and knock out mice in developmental and wounding studies to determine PECAM-1 roles in angiogenesis in living organisms. The hypothesis to be tested is that matrix-dependent modulation of vascular cell behavior is mediated via integrin-mediated signal transduction pathways which, in turn, modulate cell adhesion molecule (PECAM-1) expression, conformation, organization and functions.
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