Estrogens may provide a """"""""protective action"""""""" against cardiovascular disease for premenopausal women. Additionally, the outcome for postmenopausal women following interventional coronary artery procedures is worse than the outcome for men. The reasons for this are unclear. The unifying hypothesis of this proposal is that sex hormonal status affects expression of hormone receptors (estrogen, progesterone and androgen) which in turn regulates structural and functional characteristics of coronary arteries. The experiments of this proposal represent a collaboration among established investigators in the areas of endocrine, endothelia and muscle physiology. Receptor binding assays will be used to quantify the number of affinity of receptors for estrogen, progesterone and androgen in coronary arteries of sexually mature male, female and ovariectomized female pigs (Specific Aim 1). Structural characteristics of the arterial wall will be studied using molecular techniques to characterize matrix proteins in the arterial wall and their regulation by sex hormones. These proteins dictate the viscoelastic properties of the arterial wall which will be defined in isolated strips of coronary arterial smooth muscle (Specific Aim 2). The effects of sex hormonal status on the functional characteristics of the arteries will be evaluated using a combination of molecular, cell culture and isolated tissue techniques. These functional characteristics include the relationship of sex hormones and expression of hormone receptors on cell proliferation, the production of endothelium-derived nitric oxide and endothelins, the number and affinity of endothelin-receptors on the smooth muscle, and the effects of sex steroids on sensitivity (Specific Aim 3). All results will be assessed relative to the hormonal status of the animal as defined by circulating sex steroid hormones and the number of estrogen receptors. Results form these studies will provide new information about the regulation of sex steroid receptors and how they may affect the structure and function of coronary arteries. By understanding these basic regulatory mechanisms, potentially selective therapies can be developed for prevention and treatment of coronary artery disease in humans.
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