Smooth muscle proliferation and extracellular matrix production are two very important causes of human atherosclerotic plaque growth. Based on in vitro studies, common growth regulatory factors can govern both of these processes, particularly the synthesis of collagen types which comprise a major component of the arterial extracellular matrix. Although much progress has been made in identifying several smooth muscle growth factors in the artery wall and in human atherosclerosis, the significance of these growth factors with respect to actual cell proliferation and collagen gene expression remains undetermined. Our hypothesis is that specific growth regulatory factors control the cell proliferation and collagen type synthesis seen in these lesions. We therefore propose detailed histopathologic studies of human arteries (normal and with various degrees of atherosclerosis) to determine which topographical features, cell types, and putative growth regulatory factors are best associated with these two aspects of plaque growth. The specific human tissues to be used in these studies include: normal internal mammary arteries, normal and atherosclerotic coronary arteries, and carotid atherosclerotic plaques. Finally, to better understand how epidemiologic risk factors affect smooth muscle proliferation and collagen gene expression during atherogenesis, we will also collaborate with the ongoing Pathologic Determinants of Atherosclerosis in Youth (PDAY) multicenter study. Here we will measure levels of cell proliferation and collagen gene expression in human aortas, and correlate our findings with atherosclerosis risk factors such as race, sex, lipoprotein status, cigarette smoking exposure, and diabetic state.
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