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

描述（由申请人提供）：人类外周血管内皮功能随着年龄的增长而逐渐下降，增加了动脉粥样硬化和缺血性血管疾病的风险。除了维持血管健康的作用外，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”，在氧气需求和输送不匹配时释放ATP，这种ATP可以通过与内皮上的嘌呤能（P2y）受体结合而引起血管舒张并改善局部血流量。我们的初步数据表明，在特定的生理应激源下，衰老与BB损伤的前臂血管控制有关，其中atp介导的血管舒张已被证实参与其中。因此，本研究计划的总体目标是直接测试UU假设，即内皮依赖性atp介导的血管舒张在衰老的人类中受损，这与特定生理应激源下血管反应受损有关。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人相比，老年人前臂血管舒张剂对局部动脉内给药ATP的反应是否受损；(2)我们将确定在有节奏的握力锻炼、全身缺氧以及运动与全身缺氧联合时，红细胞ATP释放是否会随着年龄的增长而减少，并与老年人前臂血管舒张受损有关。为了实现这些目标所采用的方法是最先进的，包括在休息时局部（动脉内）给药各种研究药物，以及在生理应激条件下测量年轻人和老年人前臂静脉血浆ATP浓度。这些研究的结果将为以下问题提供独特的见解：(a)内皮依赖性ATP介导的血管扩张剂反应是否随着年龄的增长而降低，(b)红细胞ATP释放是否随着年龄的增长而降低，以及(c)在引起氧气需求和输送不匹配的特定生理应激源中，血管对ATP的反应和红细胞ATP释放的损伤是否有助于血管扩张剂反应的降低。我们的研究结果可能对理解内皮功能障碍与老年健康和患病人群在生理（如运动、缺氧）和病理生理（如冠状动脉和脑血管缺血）条件下局部血管控制受损的关系具有重要意义。衰老与患心血管疾病的风险增加有关。本应用程序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供血不足的情况的反应能力下降，并为如何最终改善老年人的心血管健康提供思路。

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.