Endothelial Dependence of Microcirculatory Regulation

所提出的工作是基于主要研究者以前与本项目有关的研究 项目和最近获得的与研究期间血管功能障碍进展相关的初步数据 老化过程我们的研究结果使我们得出结论，随着年龄的增长， 其特征在于一氧化氮（NO）的合成和/或生物利用度的逐渐降低， 内皮细胞中氧化应激增加或由氧化应激增加引起。监管方面的重大差异 在内皮型一氧化氮合酶中也发现了骨骼肌和冠状血管功能的内皮介质。 氧化物合酶敲除（eNOS-KO）小鼠以及2型糖尿病（db/db）小鼠。我们工作的目的 提出的是评估血管老化的影响在多大程度上被加速， 心血管疾病和血管老化是否可能提供额外的风险因素， 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， 不同的病因，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， 它们与一氧化氮的相互作用，对冠状动脉和骨骼肌阻力血管功能的影响， 衰老过程是血管功能障碍发展的主要原因。具体目标1是 研究对扩张剂和收缩剂、压力和阻力流量反应的改变的介导 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 研究将涉及代谢和激素参数的测量，以及基因表达， 血管在衰老过程中最后，在具体目标3中，我们旨在阐明反应性氧化剂的作用 关于血管随着年龄的增长而改变的调节，以及最先进的氧化剂的定位 成像方法这些研究将有助于更好地了解年龄相关血管病变的原因。 功能障碍和代谢综合征的发病机制，提出了新的治疗目标， 预防或治疗这些疾病。

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.