Aging, Endothelial Dysfunction, and ATP-mediated Vasodilation in Humans

描述(申请人提供)：人类的外周血管内皮细胞功能随着年龄的增长而逐渐下降，增加动脉粥样硬化和缺血性血管疾病的风险。除了在维持血管健康方面发挥作用外，内皮在调节局部血管张力方面也起着重要作用。最近的证据表明，红细胞(RBC)可以作为“传感器”，在氧需求和供氧不匹配的情况下释放ATP，这种ATP可以通过与内皮上的嘌呤能(P2y)受体结合，在这种情况下引起血管扩张，改善局部血流量。我们的初步数据表明，在特定的生理应激条件下，衰老与BB损害前臂血管控制有关，而ATP介导的血管扩张已被证明参与其中。因此，该研究计划的总体目标是直接验证UU假说，即老年人内皮依赖的ATP介导的血管扩张功能受损，这与特定生理应激条件下的血管反应受损有关。为了验证我们的假设，我们将解决以下具体目标：(1)我们将确定与年轻健康成年人相比，老年人对局部动脉内给药的前臂血管扩张反应是否受损；以及(2)我们将确定在有节奏的握手运动、全身缺氧以及联合运动和全身缺氧过程中，红细胞释放的ATP是否随着年龄的增加而减少，并与老年人的前臂血管扩张受损有关。用来解决这些目标的方法是最先进的，包括在静息状态下局部(动脉内)给药，以及在生理应激条件下测量年轻和老年健康人的前臂静脉血浆ATP浓度。这些研究结果将为以下方面提供独特的见解：(A)内皮依赖的ATP介导的血管扩张剂反应性是否随着年龄的增长而降低，(B)红细胞对ATP的释放是否随着年龄的增长而减少，以及(C)在引起氧需求和输送不匹配的特定生理应激因素期间，血管对ATP的反应性和红细胞对ATP的释放的损害是否有助于降低血管扩张剂的反应。我们的发现对于了解老年健康和疾病人群在生理(例如，运动、缺氧)和病理生理(例如，冠状动脉和脑血管缺血)条件下，内皮功能障碍与局部血管控制受损之间的关系具有重要意义。衰老与心血管疾病风险增加有关。本申请中的研究旨在了解血管功能受损如何导致老年人对特定组织输送的血液不足的反应能力下降，并可能为如何最终改善老年人的心血管健康提供建议。

DESCRIPTION (provided by applicant): Peripheral vascular endothelial function declines progressively with advancing age in humans, increasing the risk for atherosclerotic and ischemic vascular disease. In addition to its role in maintaining vascular health, the endothelium plays an important role in the regulation of local vascular tone. Recent evidence indicates that the red blood cell (RBC) can act as a "sensor" and releases ATP during mismatches in oxygen demand and delivery, and this ATP can evoke vasodilation and improve local blood flow under such conditions via binding to purinergic (P2y) receptors on the endothelium. Our preliminary data indicates that aging is associated with BB impaired forearm vascular control during specific physiological stressors in which ATP-mediated vasodilation has been documented to be involved. Thus, the overall goal of this research program is to directly test the UU hypothesis that endothelium-dependent ATP-mediated vasodilation is impaired in aging humans, and that this is related to impaired vascular responses during specific physiological stressors. To test our hypothesis we will address the following specific aims: (1) we will determine whether the forearm vasodilator responses to local intra-arterial administration of ATP is impaired in older compared with young healthy adults; and (2) we will determine whether RBC release of ATP during rhythmic handgrip exercise, systemic hypoxia, and combined exercise and systemic hypoxia is reduced with age and relates to impaired forearm vasodilation in older adults. The methods employed to address these aims are state-of-the-art and involve local (intra-arterial) administration of various study drugs at rest, and measurements of forearm venous plasma ATP concentrations in young and older healthy humans during physiological stressors. The findings from the proposed studies should provide unique insight into whether (a) endothelium-dependent ATP-mediated vasodilator responsiveness is reduced with age, (b) whether RBC release of ATP is reduced with age, and (c) whether impairments in both the vascular responsiveness to, and RBC release of, ATP contribute to reduced vasodilator responses during specific physiological stressors that evoke mismatches in oxygen demand and delivery. Our findings could have significant implications for understanding how endothelial dysfunction relates to impaired local vascular control during physiological (e.g., exercise, hypoxia) and pathophysiological (e.g., coronary and cerebrovascular ischemia) conditions in older healthy and diseased humans. Aging is associated with an increased risk for cardiovascular disease. The studies in this application are designed to understand how impaired blood vessel function might contribute to a reduced ability of older adults to respond to conditions in which not enough blood is being delivered to specific tissues, and could provide ideas on how to eventually improve cardiovascular health of older adults.