This is a proposal to explore in depth the biology of the artery wall in relation to the etiology and pathogenesis of the lesions of atherosclerosis. This program project will involve studies of six principal areas. They are: 1) studies of non-human primate arterial smooth muscle cells in culture, with particular emphasis on serum and plasma factors responsible for smooth muscle proliferation; 2) studies of the genesis of the lesions of atherosclerosis in non-human primates resulting from mechanical and various forms of chemical injury including homocystinemia and hyperlipoproteinemia, and characterization of the platelet factors responsible for smooth muscle proliferation in vitro, and studies of the role of platelets and platelet factors in the genesis of in vivo lesions, 3) development and characterization of a nonhuman primate model to study lipoprotein metabolism in relation to dietary hypercholesteremia and hormonal regulation; 4) studies of human arterial smooth muscle in cell culture with emphasis upon the ability of these cells to take up and degrade lipoproteins and other plasma constituents in comparison with non-human primate smooth muscle; 5) studies of connective tissue metabolism in the artery wall with analysis of the connective tissue matrix components made by both smooth muscle and endothelial cells, and further studies of the interactions between lipoproteins and connective tissue glycosaminoglycans; 6) studies of the arterial endothelium in cell culture with analysis of factors that will """"""""injure"""""""" endothelium in relation to endothelial cell turnover in vitro and in vivo. The hypothesis that endothelial injury leads to a sequence of events in the artery wall resulting in intimal smooth muscle proliferation and lesion formation will be persued, utilizing the above approaches to better understand the factors that are important in controlling the ability of smooth muscle cells to proliferate, form connective tissues and metabolize lipids.
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