The training and research proposed in this application will be sponsored by Dr. Adams and will take place in both the Arteriosclerosis Research Center and the Comparative Medicine Clinical Research Center. Dr. Wagner is seeking SERCA support to further her development as an independent investigator with special emphasis on cardiovascular health of aging females. The studies will utilize a well characterized primate model, the female cynomolgus monkey, which like women in most Western societies, develops less severe atherosclerotic coronary heart disease (CHD) than its male counterpart. Pathogenetic mechanisms of atherogenesis are difficult to study in women, since atherosclerosis develops slowly over a period of many years. Also, while CHD is the leading cause of morbidity and mortality in American women, clinical events occur relatively infrequently. For these reasons we propose to utilize a primate model to study the effect of sex hormone deficiency, sex hormone replacement and oral contraceptive treatment on the pathogenesis of atherosclerosis. Studies of both human and nonhuman primates have found that only a portion of the beneficial effects of estrogens can be attributed to changes in plasma lipoprotein risk variables. This suggests that estrogens may retard atherogenesis by interacting by either directly at the arterial wall or by modifying plasma components in addition to lipoproteins. The studies proposed will explore molecular and cellular mechanisms by which estrogens and progestins may be acting. The effects of sex steroids on the following parameters will be investigated: 1) functional parameters of early atherogenesis eg., endothelial dysfunction as determined by arterial LDL uptake and degradation, monocyte adhesion to the endothelium, and intimal cell proliferation, 2) whole body and hepatic LSL metabolism, 3) plasma HDL composition and its function in reverse cholesterol transport, 4) expression of cytokines and growth factors by arterial cells, and 5) atherosclerosis-related impairment of vascular responses. If, as suspected, beneficial effects are found, this would provide a rational basis for the prophylactic or therapeutic use of these steroids in CHD.
