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

人类衰老、内皮功能障碍和 ATP 介导的血管舒张

基本信息

批准号：
7409649
负责人：
FRANK A DINENNO
金额：
$ 18.38万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-05-01 至 2010-03-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：随着人类年龄的增长，外周血管内皮功能逐渐下降，增加动脉粥样硬化和缺血性血管疾病的风险。内皮细胞除了在维持血管健康方面发挥作用外，在调节局部血管张力方面也发挥着重要作用。最近的证据表明，红细胞 (RBC) 可以充当“传感器”，在需氧量和输送量不匹配时释放 ATP，这种 ATP 可以通过与内皮上的嘌呤能 (P2y) 受体结合，在这种情况下引起血管舒张并改善局部血流。我们的初步数据表明，衰老与特定生理应激条件下 BB 受损的前臂血管控制有关，其中 ATP 介导的血管舒张已被证明参与其中。因此，该研究项目的总体目标是直接检验 UU 假设，即内皮依赖性 ATP 介导的血管舒张在老年人中受损，并且这与特定生理应激源期间血管反应受损有关。为了检验我们的假设，我们将实现以下具体目标：（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注射 ATP 的前臂血管舒张反应是否受损； (2)我们将确定在有节奏的握力运动、全身性缺氧以及运动和全身性缺氧相结合的过程中，红细胞释放的ATP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。用于实现这些目标的方法是最先进的，包括在休息时局部（动脉内）施用各种研究药物，以及在生理应激源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 介导的血管舒张反应是否随着年龄的增长而降低，（b）红细胞 ATP 的释放是否随着年龄的增长而减少，以及（c）在引起需氧量不匹配的特定生理应激源期间，血管对 ATP 的反应性和红细胞释放的 ATP 的损害是否会导致血管舒张反应的减少。和交货。我们的研究结果对于理解老年健康和患病人类的生理（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如何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情况的反应能力降低，并可以为如何最终改善老年人的心血管健康提供思路。