The purpose of this grant is to delineate the effects of sex hormones and gender on coronary vascular smooth muscle. We will determine if the sex hormones, 17beta-estradiol and dihydrotestosterone, influence reactivity of coronary arterioles and arteries, and also influence vascular smooth muscle proliferation. The experimental plan is to study five different groups of animals: intact males, intact females, neutered, neutered supplemented with 17beta-estradiol, and neutered supplemented with dihydrotestosterone. We will also determine if the effects of the sex hormones are influenced by diet, specifically comparing effects of a normal diet versus that of an atherosclerotic diet. We propose to test two major hypotheses. First, 17beta-estradiol exerts a """"""""protective"""""""" role in large coronary arteries when compared to the effects of dihydrotestosterone. This hypothesis will be tested utilizing physiological studies of coronary artery reactivity, molecular studies of gene expression in the arterial wall following an angioplasty procedure (in situ hybridization), and studies of vascular cells in culture. In culture we plan to determine if the sex hormones modulate the proliferative response of vascular smooth muscle to various mitogens, or if the hormones influence endothelial production of substances, which also then modulate the proliferative response of vascular smooth muscle. The second general hypothesis that we propose to test is that testosterone will exert a """"""""protective"""""""" role in coronary arterioles as opposed to the effects of estrogen. We propose that the protective effect of dihydrotestosterone will be exhibited by enhanced production of endothelium-derived nitric oxide and enhanced vasodilatory responses to endothelium-dependent stimuli with lessened responses to vasoconstrictors. In contrast, we also speculate that 17beta-estradiol will exert effects opposite to that of testosterone. Our experimental plan is to compare effects of the hormone-treated animals to that of the neutered group and intact males and females, which will mimic results for the dihydrotestosterone - or 17beta-estradiol-treated animals, respectively. The results of these studies would provide novel information regarding the effects of sex hormones on reactivity of coronary arteries, and effects of the hormones on the development of atherosclerotic lesions in the coronary arteries. These results should offer insight into mechanisms by which the incidence of coronary artery disease is greater in men than in pre-menopausal women, and why women more frequently suffer from Syndrome X (microvascular spasm in the heart) than men.
