Aging, Estrogen, and Coronary Endothelial Function

描述（由申请人提供）：随着年龄的增长，患心脏病的风险急剧增加。在绝经前，女性患心脏病的风险比男性低；然而，绝经后，女性的风险增加到比男性更高的水平。尽管年龄相关的冠状动脉血流能力下降可能会增加男性和女性患心脏病的风险，但对于年龄和雌激素对冠状动脉抵抗血管反应性的相互作用知之甚少，冠状动脉抵抗血管是控制冠状动脉血流的主要部位。最近的研究表明，年龄会损害雄性和雌性大鼠冠状动脉阻力小动脉内皮依赖性、一氧化氮（NO）介导的血管舒张；然而，初步数据表明，导致no介导的扩张受损的机制变化在性别之间存在差异。因此，本建议的总体目的是确定年龄和雌激素状态改变内皮依赖、no介导的冠状动脉血管舒张的机制。目的1是确定年龄和雌激素水平对调节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是确定年龄和雌激素水平对一氧化氮合酶（NOS）异构体对内皮依赖性扩张的贡献和冠状动脉（NOS）异构体活性的影响。目的3：确定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。这些研究将确定一氧化氮介导的血管舒张的年龄相关损伤机制，并确定雌激素治疗是否可以通过恢复这些信号机制来改善一氧化氮介导的血管舒张。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，并为男性和女性中与年龄相关的内皮功能丧失的机制提供见解。

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.