Endothelial Dependence of Microcirculatory Regulation

建议的工作是基于首席调查员以前与该方案有关的研究 项目和最近获得的与血管功能障碍进展相关的初步数据 老化过程。我们的结果使我们得出结论，随着年龄的增长，观察到的血管功能障碍是 特征是一氧化氮(NO)的合成和/或生物利用度逐渐减少，导致 内皮细胞氧化应激增加引起的或由其引起的。在监管方面存在显著差异 在内皮型一氧化氮中也发现了骨骼肌和冠脉功能的内皮介质 一氧化氮合酶基因敲除(eNOS-KO)小鼠以及2型糖尿病(db/db)小鼠。我们工作的目的是 建议评估血管老化的影响在多大程度上加速 心血管疾病和血管老化是否可能提供额外的危险因素 不良心血管事件。这些问题将在两种代谢综合征模型中进行研究 不同病因，即2型糖尿病小鼠和eNOS.KO小鼠。在这个项目中，我们计划测试 假设NADPH氧化酶衍生的氧化剂、超氧化物和过氧化氢的影响，以及 它们与一氧化氮的相互作用对冠脉和骨骼肌阻力血管功能的影响 衰老的过程，是血管功能障碍发展的首要原因。具体目标1是 研究对扩张剂和缩窄剂的反应、压力和阻力流量的改变中介作用 血管老化。具体目标2是研究代谢综合征随年龄增长的进展。这些 研究将包括新陈代谢和荷尔蒙参数的测量，以及在 衰老过程中的血管。最后，在特定目标3中，我们旨在阐明活性氧化剂物种的作用 关于血管随年龄变化的调节，以及氧化剂的最新定位 成像方法。这些研究将有助于更好地了解年龄相关血管的原因 功能障碍与代谢综合征的发病机制，为代谢综合征提供了新的治疗靶点 这些疾病的预防或治疗。

The work proposed is based on the principal investigator's previous studies in connection with this Program Project and recent preliminary data obtained related to the progression of vascular dysfunction during the aging process. Our results allowed us to conclude that the vascular dysfunction observed with aging, is characterized by a progressive reduction in the synthesis and/or bioavailability of nitric oxide (NO), resulting in or caused by an increased oxidant stress in endothelial cells. Significant differences in the regulation by endothelial mediators of skeletal muscle and coronary vessel function were also found in endothelial nitric oxide synthase knockout (eNOS-KO) mice as well as type 2 diabetic (db/db) mice. The aim of our work proposed is to evaluate to what extent the effects of aging of blood vessels is accelerated with cardiovascular disorders and whether aging of blood vessels may provide an additional risk factor for adverse cardiovascular events. These issues will be studied in two models of metabolic syndrome of different etiology, namely type 2 diabetic mice and eNOS.KO mice. In this project we plan to test the hypothesis that the effects of NADPH oxidase-derived oxidants, superoxide and hydrogen peroxide, and their interactions with nitric oxide, on the function of coronary and skeletal muscle resistance vessels during the process of aging, is the primary cause of the development of vascular dysfunction. Specific Aim 1 is to investigate altered mediation of responses to dilator and constrictor agents, pressure and flow of resistance vessels with aging. Specific Aim 2 is to study the progression of metabolic syndrome with aging. These studies will involve measurements of metabolic and hormonal parameters, as well as gene expression in blood vessels during aging. Finally in Specific Aim 3 we aim to elucidate the role of reactive oxidant species on altered regulation of blood vessels with aging, as well as localization of oxidants by state-of-the-art imaging methods. These studies will lead to a better understanding of the causes of age related vascular dysfunction and the pathogenesis of metabolic syndrome, suggesting novel therapeutic targets for the prevention or treatment of these conditions.