ROLE OF THE ARTERIAL WALL IN ATHEROSCLEROSIS

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The object of the program project is to enhance the understanding of the pathogenesis of hypertensive and atherosclerotic vascular disease particularly of the coronary and cerebral vessels. In achieving the objective, studies are being conducted in nonhuman primate models (cynomolgus monkey) with experimental atherosclerosis and/or hypertension and in tissue culture models using smooth muscle cells and macrophages. Atherosclerosis in the monkey is produced by surgically coarcting the thoracic aorta. The specific aims of the program are to determine (1) the effects of hypercholesterolemic atherogenic diet and/or hypertension on the levels of circulating immune complexes in the cynomolgus monkey; (2) the participation of immunological factors in atherosclerosis and its aggravation by hypertension by correlating the immunological findings in the blood vessels and circulation with the extent and severity of the experimentally induced vascular disease; (3) whether the lipid-protein complexes contained in human atherosclerotic plaques are autoimmune complexes consisting of apolipoproteins and anti-apolipoprotein antibodies; (4) effects of atherosclerosis and hypertension on collagen gene expression in the cynomolgus monkey aortic tissue; (5) the production of Type I and II collagen protein and the processing elastin synthesis, secretion and accumulation in vascular smooth muscle cells; (6) the nature of the mechanisms of control of the biosynthetic pathway in which lysyl oxidase is synthesized in cultured aortic smooth muscle cells (SMC); (7) the steroid specificity of the control levels of lysyl oxidase activity in cultured SMC; (8) the biosynthesis of the connective tissue components during the course of matrix development in response to matrix injury; (9) the effect of proteolytic or mechanical injury to SMC culture with respect to the regulation of Type I and Type III collagen genes and cell proliferation; (10) secretory and phagocytic function of the smooth muscle cell derived foam cell. The use of non-human primate models as well as tissue culture models is believed to represent an important and effective approach to the study of vascular disease at the tissue, cellular and molecular level.