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

描述（由申请方提供）：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。除了在维持血管健康方面的作用外，内皮在局部血管张力的调节中起重要作用。最近的证据表明，红细胞（RBC）可以作为一个“传感器”，并释放ATP期间的氧需求和输送的不匹配，这种ATP可以引起血管舒张和改善局部血流在这种条件下通过结合到内皮上的嘌呤能（P2 γ）受体。我们的初步数据表明，老化与BB受损前臂血管控制在特定的生理应激，其中ATP介导的血管舒张已被证明参与。因此，本研究计划的总体目标是直接测试UU假设，即在老年人中内皮依赖性ATP介导的血管舒张受损，并且这与特定生理应激期间受损的血管反应有关。为了验证我们的假设，我们将致力于以下具体目标：（1）我们将确定与年轻健康成人相比，老年人前臂血管扩张对局部动脉内ATP给药的反应是否受损;以及（2）我们将确定在有节奏的握力运动、全身缺氧运动和全身性缺氧的组合随着年龄的增长而减少，并且与老年人前臂血管舒张受损有关。用于解决这些目标的方法是最先进的，包括静息时局部（动脉内）给予各种研究药物，以及在生理应激期间测量年轻和老年健康人的前臂静脉血浆ATP浓度。拟议研究的结果应提供独特的见解，以了解（a）内皮依赖性ATP介导的血管扩张反应是否随年龄的增长而降低，（B）ATP的RBC释放是否随年龄的增长而减少，以及（c）在引起氧需求和输送不匹配的特定生理应激期间，ATP的血管反应性和RBC释放的损伤是否有助于降低血管扩张反应。我们的研究结果可能对理解内皮功能障碍如何与生理过程中受损的局部血管控制（例如，运动，缺氧）和病理生理学（例如，冠状动脉和脑血管局部缺血）状况。衰老与心血管疾病的风险增加有关。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没有足够血液输送到特定组织的情况做出反应的能力降低，并可以提供有关如何最终改善老年人心血管健康的想法。

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.