Endothelial cell activation and/or injury is thought to be an initiating event in the development of atherosclerosis. The major objective of this program project is to test the hypothesis that soluble mediators (eicosanoids, growth factors, cytokines) and thromboregulators (tPA,uPA, ecto-ADPase, PGl2, and endothelin) derived from activated or injured endothelium alter vascular cell and platelet reactivity, binding of inflammatory cells, and cholesterol metabolism. This program project grant will focus on interactions between hematologic and vascular cells in an attempt to elucidate the role of these interactions on functional and metabolic properties of arterial smooth muscle cells and macrophages. Particular emphasis will be placed on the role of: 1) transcellular metabolites derived from interactions of hematologic and vascular cells which can modulate vascular and platelet reactivity and lipid metabolism; 2) thromboregulators in mediating fibrinolysis and vascular tone; 3) cytokines in modulating the synthesis and release of thromboregulators and cell surface expression of adhesive glycoproteins which mediate cell- to-cell interactions; 4) lipoprotein (a) and modified lipoproteins in altering tissue plasminogen activator (tPA) binding to endothelial cells and subsequent fibrinolysis; 5) foam cells in the production and release of vascular cell-derived growth factors which, in turn, can influence smooth muscle cell proliferation and lipid metabolism, and 6) eicosanoids as mediators of cholesterol trafficking in smooth muscle cells and macrophages. The overall program project has been designed to promote synergistic interactions among individual investigators. Our ongoing collaborative efforts will underscore the success of the program. Furthermore, our research strategy will provide new insights into the pathogenesis of atherosclerosis at the cellular and molecular level and will identify the links between thrombosis and atherosclerosis.
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