Aging, Endothelial Dysfunction, and Impaired Vascular Control During Exercise

描述（由申请人提供）：项目总结：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调查老年人在动态运动过程中肌肉血流和血管张力控制受损的机制。该提案旨在将氧化应激诱导的外周内皮功能障碍与老年人动态运动期间受损的血管控制机制联系起来。一般的概念是，与年龄相关的氧化应激增加降低内皮源性一氧化氮（NO）的生物利用度，并导致产生环氧合酶源性血管收缩剂前列腺素（PGs），从而损害老年人运动期间的局部血管舒张反应。为了验证我们的假设，我们将致力于以下具体目标：（1）我们将确定在老年人动态运动期间观察到的肌肉血流量和血管张力控制受损是否是由于内皮依赖性血管舒张的年龄相关性损伤，具体地说，我们将确定NO和PG对这种损伤的独立和交互作用;（2）我们将确定老年人氧化应激的急性减少是否改善内皮血管舒张功能，从而改善运动期间的肌肉血流量和局部血管舒张反应。用于解决这些目标的方法是最先进的，涉及运动期间局部（动脉内）给予各种研究药物，以研究NO、PG和氧化应激在年轻和老年健康人肌肉血流量控制中的作用。拟议研究的结果应该为老年人运动期间肌肉血流和血管控制的调节提供独特的见解，并且还可能对理解和治疗也表现出内皮功能障碍的患病人群的运动不耐受具有重要意义，例如，心力衰竭患者）。相关性：衰老与生活质量下降有关，部分原因是运动能力下降。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，并将提供有关如何预防或改善这种功能的想法，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 (PGs), 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 (intraarterial) 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.