Polycystic ovary syndrome (PCOS) is the most common reproductive endocrinopathy in young women, affecting 6-10 % of women of reproductive age. Obesity, insulin resistance, hyperandrogenism and hyperestrogenism are core functional disorders of PCOS and place women at increased risk for microvascular dysfunction. Women with PCOS have greater circulating concentrations of endothelin-1 (ET-1), a potent vasoconstrictor in the microcirculation (including that of the skin), which can increase blood pressure and lead to endothelial damage. The central hypothesis of this proposal is that testosterone effects on ET-1 mediate the peripheral microvascular dysfunction associated with PCOS. This hypothesis will be tested using a prolonged skin heating model to study peripheral microvascular responsiveness. Local skin heating has been used extensively to study mechanisms controlling peripheral microcirculation under a number of physiological conditions, including obesity, insulin resistance and hypertension. The impact of testosterone or ET-1 on microvascular responsiveness to local heating has not been studied in women with or without PCOS. This proposal seeks to provide this missing information via pursuit of two Specific Aims. Specific Aim 1 will apply dose-response curves to examine the mechanism by which ET-1 influences peripheral vasodilation. Specific Aim 2 will determine the mechanism by which testosterone affects peripheral microcirculatory responsiveness in women with and without PCOS. These studies will have broad public health implications because our findings on the effect of hyperandrogenism on endothelial function may provide insights applicable to cardiovascular health in women and men. PUBLIC HEALTH RELEVANCE: Women with Polycystic Ovary Syndrome (PCOS) have greater risk for cardiovascular disease, in particular dysfunction of the peripheral circulation that can lead to hypertension and comprised glucose disposal. This research will determine the role of hyperandrogenism in microvascular responsiveness in women with PCOS, and the mechanisms by which testosterone may impact endothelial function. These studies also have broad public health implications because our findings on the effect of hyperandrogenism on endothelial function may provide insights that can improve cardiovascular health of all obese women and men.