Compromised microcirculation in women with Polycystic Ovary Syndrome

描述(申请人提供)：多囊卵巢综合征(PCOS)是年轻女性最常见的生殖内分泌疾病，影响6%-10%的育龄妇女。肥胖、胰岛素抵抗、高雄激素症和高雌激素症是多囊卵巢综合征的核心功能障碍，并使女性面临更高的微血管功能障碍风险。患有多囊卵巢综合征的女性循环中的内皮素-1(ET-1)浓度较高，这是微循环(包括皮肤)中的一种有效的血管收缩因子，可导致血压升高并导致内皮损伤。这一建议的中心假设是，睾酮对ET-1的影响介导了与PCOS相关的外周微血管功能障碍。这一假说将使用延长的皮肤加热模型来验证，以研究外周微血管的反应。局部皮肤加热已被广泛用于研究在许多生理条件下控制外周微循环的机制，包括肥胖、胰岛素抵抗和高血压。在患有或不患有多囊卵巢综合征的妇女中，尚未研究睾酮或ET-1对微血管局部加热反应的影响。这项提案试图通过追求两个具体目标来提供这一缺失的信息。具体目标1将应用剂量-反应曲线来研究ET-1影响外周血管扩张的机制。具体目标2将确定睾酮影响多囊卵巢综合征患者和非多囊卵巢综合征患者外周微循环反应的机制。这些研究将具有广泛的公共卫生意义，因为我们关于高雄激素对血管内皮细胞功能影响的研究结果可能会提供适用于女性和男性心血管健康的见解。公共卫生相关性：患有多囊卵巢综合征(PCOS)的女性患心血管疾病的风险更高，特别是可能导致高血压和葡萄糖代谢的外周循环功能障碍。这项研究将确定高雄激素在多囊卵巢综合征女性微血管反应性中的作用，以及睾酮可能影响内皮功能的机制。这些研究还具有广泛的公共卫生意义，因为我们关于高雄激素对血管内皮细胞功能影响的研究结果可能提供可以改善所有肥胖女性和男性心血管健康的见解。

DESCRIPTION (provided by applicant): 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.