Atherosclerotic vascular disease is a major cause of morbidity and mortality in the U.S. Endothelial cell injury/dysfunction is responsible for the initiation of at least some of the disease and the endothelial cell (EC) response to injury is a major factor in determining and modulating the resultant migratory, proliferative, synthetic and contractile responses of the medial smooth muscle cells and the angiogenic response of the adventitial microvasculature. The EC response to injury, modulated by the composition and organization of the underlying extracellular matrix and endothelial cell-extracellular matrix interactions, although incompletely understood, is thought to be a dynamic, complex one involving several classes of matrix binding proteins. The long-term goal of this proposal is to elucidate the roles of integrin and non-integrin cell surface matrix binding proteins in modulating large vessel endothelial cell migration and proliferation and microvascular endothelial cell angiogenesis following injury and in response to soluble factors. Specifically, tissue culture and animal models of large vessel endothelial cell denudation injury-repair and microvascular endothelial cell angiogenesis will be used to characterize and determine the mechanism(s) of action of integrin and non- integrin matrix binding proteins during tissue culture, immunolabeling at light, confocal and electron microscopic levels, Northern, Southern and in situ hybridization and differential library screening, biosynthetic labeling, immunoprecipitation and immunoblotting. Experiments will center around the use of synthetic peptides of various binding domains of matrix molecules, antibodies raised against matrix molecules and matrix binding proteins and cRNA and cDNA probes specific for matrix molecules and matrix binding proteins in vitro large vessel endothelial cell migrations and during in vitro angiogenesis studies with microvascular endothelial cells. A better understanding of cell-matrix interactions during these processes may lead to the design, production and implementation of improved synthetic grafting materials, agents that promote optimal endothelial cell migration following therapeutic intervention and agents that can be used to modulate the angiogenic response following injury and during the metastatic spread of cancer.
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