Aging, Endothelial Dysfunction, and Impaired Vascular Control During Exercise

描述(由申请人提供)：项目摘要：有氧运动能力随着年龄的增长而逐渐下降，最终导致老年人残疾增加、丧失独立性和生活质量下降。本研究计划的总体目标是探讨老年人动态运动中肌肉血流量和血管张力控制受损的机制(S)。这项建议试图从机制上将氧化应激导致的外周血管内皮功能障碍与老年人动态运动期间血管控制受损联系起来。一般的概念是，与年龄相关的氧化应激增加会降低内皮衍生的一氧化氮(NO)的生物利用度，并导致环氧合酶衍生的血管收缩因子前列腺素(PC)的产生，从而削弱老年人在运动时的局部血管扩张反应。为了检验我们的假设，我们将针对以下具体目标：(1)我们将确定老年人在动态运动中观察到的肌肉血流量和血管张力的控制受损是否是由于增龄相关的内皮依赖性血管扩张障碍所致，具体而言，我们将确定NO和PGs对这种损害是否独立且相互作用；(2)我们将确定老年人急性氧化应激是否改善内皮血管扩张功能，从而改善运动中的肌肉血流量和局部血管扩张反应。用来解决这些目的的方法是最先进的，包括在运动期间局部(动脉内)给药，以研究一氧化氮、前列腺素和氧化应激在控制年轻和老年健康人的肌肉血流中的作用。这项拟议研究的结果将为老年人运动过程中肌肉血流量的调节和血管控制提供独特的见解，并可能对理解和治疗也表现出内皮功能障碍的疾病人群(如心力衰竭患者)的运动耐量具有重要意义。相关性：衰老与生活质量下降有关，这在一定程度上是由于运动能力的减少。本申请中的研究旨在了解血管功能受损对老年人运动不耐受的潜在贡献，并将提供如何预防或改善这一功能的想法，从而提高老年人的生活质量。

DESCRIPTION (provided by applicant): PROJECT SUMMARY: Aerobic exercise capacity declines progressively with advancing age eventually leading to increased disability, loss of independence, and reduced quality of life in older adults. The overall goal of this research program is to investigate the mechanism(s) involved in the impaired control of muscle blood flow and vascular tone during dynamic exercise in aging humans. This proposal seeks to mechanistically-link oxidative stress-induced peripheral endothelial dysfunction with impaired vascular control during dynamic exercise in aging humans. The general concept is that age-associated increases in oxidative stress reduce endothelium-derived nitric oxide (NO) bioavailability and cause the production of cyclooxygenase-derived vasoconstrictor prostaglandins (PCs), thus impairing local vasodilator responses during exercise in older adults. To test our hypotheses we will address the following specific aims: (1) we will determine whether the impaired control of muscle blood flow and vascular tone observed during dynamic exercise in older adults is due to age-related impairments in endothelium-dependent vasodilation, and specifically, we will determine the independent and interactive contribution of NO and PGs to this impairment; (2) we will determine whether acute reductions in oxidative stress in older adults improves endothelial vasodilator function and therefore, improves muscle blood flow and local vasodilator responses during exercise. The methods employed to address these aims are state-of-the-art and involve local (intra- arterial) administration of various study drugs during exercise to investigate the roles of NO, PGs, and oxidative stress in the control of muscle blood flow in young and older healthy humans. The findings from the proposed studies should provide unique insight into the regulation of muscle blood flow and vascular control during exercise in aging humans, and also could have significant implications for the understanding and treatment of exercise intolerance in diseased populations that also demonstrate endothelial dysfunction (e.g., heart failure patients). RELEVANCE: Aging is associated with a reduced quality of life which is due, in part, to reductions in exercise capacity. The studies in this application are designed to understand the potential contribution of impaired blood vessel function to exercise intolerance in older adults, and will provide ideas on how to prevent or improve this function, thereby enhancing the quality of life of older adults.