Aging, Estrogen, and Coronary Endothelial Function

描述（由申请人提供）：心脏病的风险随着年龄的增长而急剧增加。在绝经年龄之前，妇女患心脏病的风险比男子低;然而，绝经之后，妇女患心脏病的风险比男子高。 尽管年龄相关的冠状动脉血流能力下降可能导致男性和女性心脏病风险增加，但年龄和雌激素对冠状动脉阻力血管系统（控制冠状动脉血流的主要部位）血管反应性的交互作用知之甚少。最近的研究表明，年龄损害内皮依赖性，一氧化氮（NO）介导的血管舒张的冠状动脉阻力小动脉从男性和女性大鼠;然而，初步数据表明，机制的变化，导致受损的NO介导的扩张不同性别之间。因此，本研究的总体目标是确定年龄和雌激素状态改变冠状动脉内皮依赖性、NO介导的血管舒张的机制。目的1是确定年龄和雌激素状态对调节NO介导的冠状动脉扩张的细胞信号传导机制的影响。 目的2：探讨年龄和雌激素水平对冠状动脉内皮依赖性舒张功能和一氧化氮合酶（NOS）活性的影响。 目的3探讨年龄和雌激素水平对冠状动脉NOS亚型mRNA和蛋白表达的影响。这些研究将确定与年龄相关的NO介导的血管舒张损伤的机制，并确定雌激素治疗是否可以通过恢复这些信号传导机制来改善NO介导的血管舒张。 从这项工作中获得的信息将增加我们对年龄和雌激素在冠状动脉阻力血管系统中的作用的理解，并提供对男性和女性中与年龄相关的内皮功能丧失机制的深入了解。

DESCRIPTION (provided by applicant): The risk for heart disease increases dramatically with advancing age. Before the age of menopause, the risk for heart disease in women is reduced compared to that of men; however, after menopause the risk in women increases to a level greater than that of men. Although an age related decrease in coronary blood flow capacity may contribute to the increased risk of heart disease in both males and females, little is known of the interactive effects of age and estrogen on vasoreactivity of the coronary resistance vasculature, the major site for control of coronary blood flow. Recent work indicates that age impairs endothelium-dependent, nitric oxide (NO)-mediated vasodilation of coronary resistance arterioles from both male and female rats; however, preliminary data suggest that the mechanistic changes that result in impaired NO-mediated dilation differ between genders. Therefore, the overall aim of this proposal is to determine the mechanisms by which age and estrogen status alter endothelium dependent, NO-mediated vasodilation in coronary arterioles. Aim 1 is to determine the effect of age and estrogen status on cellular signaling mechanisms that regulate NO-mediated dilation in coronary arterioles. Aim 2 is to determine the effects of age and estrogen status on the contribution of nitric oxide synthase (NOS) isoforms to endothelium-dependent dilation and the activity of (NOS) isoforms in coronary arterioles. Aim 3 is to determine the effects of age and estrogen status on mRNA and protein expression of NOS isoforms in coronary arterioles. These studies will identify mechanisms that contribute to the age-related impairment of NO-mediated vasodilation and determine whether estrogen treatment can improve NO-mediated vasodilation thru restoration of these signaling mechanisms. The information gained from this work will increase our understanding of the effects of age and estrogen in the coronary resistance vasculature and provide insight into the mechanisms that contribute to the age-related loss of endothelial function in both males and females.