This is a proposal to explore in depth the biology of the artery wall in relation to the etiology and pathogenesis of atherosclerosis. This program studies endothelium, smooth muscle, monocyte/macrophages, T cell and platelets and their interrelationships in arterial biology and atherogenesis with particular emphasis on 1) understanding the growth factors derived from platelets, macrophages, endothelium, and smooth muscle in terms of understanding the mechanism by which they induce mitogenesis and other cell functions including understanding the nature of PDGF and its receptor and development of means of inhibiting PDGF activity; 2) in vivo studies of atherogenesis in hypercholesterolemic non- human primates and rabbits and in the WHHL rabbit, including localization of PDGF in tissues and determination of causality of PDGF in lesion formation; 3) the nature of the cellular changes that occur in vein grafts when placed in the arterial circulation; 4) the controls on endothelial regeneration and maintenance of endothelial continuity in terms of endothelial cell-cell interactions and endothelial-smooth muscle interactions; 5) the relationship between monocytes and endothelial cells and the effects of hypercholesterolemia on leukocyte adherence to endothelium; 6) interactions of lipoproteins with arterial cells and their effects on intra cellular cholesterol homeostasis and atherogenesis; 7) factors that determine proteoglycan accumulation and metabolism in the artery wall in relation to atherosclerosis and 8) how the extracellular environment including extracellular matrix, influences the function of endothelium and smooth muscle. All of these relate to further testing of the response to injury hypothesis of atherosclerosis.
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