Development of a clinically-relevant test for assessment of cerebral vascular function

项目总结 本研究项目的总体目标是开发一种脑血管功能测试，并提供 对肌源性、神经源性和剪切性反应贡献程度的机械论洞察 对脑血管系统的调节。脑血管疾病也是第五大致死原因。 是中老年人认知障碍和残疾的主要原因。了解 衰老与脑血管功能的关系对治疗的发展至关重要 将提高生活质量和降低脑血管事件风险的干预措施。目前有 没有临床前工具来预测健康人未来的脑血管疾病/事件； 这项研究旨在解决这一知识差距。中心假设是我们对“脑血管”的测试 功能“将引起血管扩张刺激，而这种刺激在健康的老年人和长期吸烟者中会减少， 而这些反应的损害将与周围血管调节受损和 降低脑血管对二氧化碳的反应性。第二个假设是，对肌源性和非肌源性的阻断 对“脑血管功能”测试的神经源性反应将有助于评估血管内皮细胞的切变。 脑血流调节的应激依赖机制。我们将从两个方面来阐述这些假设 具体目标：1)评估脑血管功能测试的反应，并将反应与 脑血管对二氧化碳反应性的经典测试及健康人的外周血管反应性测试 年轻受试者和已知全身血管功能受损的受试者(年长的健康受试者和 慢性吸烟者)，以及；2)确定肌源性血管内皮细胞介导的充血的相对贡献 以及对脑血流量的神经性控制。人类受试者将被招募来实现这些目标，方法是 外周血流介导的脑缺血再灌流(FMD)途径对脑的适应 利用下体负压(LBNP)建立血管系统。下体负压(-60毫米汞柱)将用于诱导 对脑组织的“缺血”压力；这种压力的迅速释放会引起脑部剪应力 血管扩张。颅内和颅外动脉反应性充血将通过计算 每种反应的峰值和曲线下面积作为阻力血管功能的指标。独立地， 将评估臂动脉和股动脉的FMD。拟议的研究的基本原理是开发 一种用于评估脑血管功能和确定先前脑血管功能的机制的临床相关测试 观察到模拟“缺血-再灌流”应激引起的脑血流量增加。这种方法是创新的 因为它可能提供证据表明，脑反应性充血是一种新的方法学方法和有效的 刺激以评估脑血管功能。这一贡献意义重大，因为它将提供对 随着年龄的增长而发生的有害的脑血管适应，以及内皮细胞 功能障碍可能在这一过程中发挥作用。

PROJECT SUMMARY The overall goal of this research project is to develop a test of cerebral vascular function, and provide mechanistic insight into the extent to which the myogenic, neurogenic, and shear-mediated responses contribute to the regulation of the cerebral vasculature. Cerebrovascular disease is the 5th leading cause of death, as well as being a major cause of cognitive impairment and disability in middle-aged to older adults. Understanding the relationship between aging and cerebrovascular function is essential to the development of therapeutic interventions that will improve quality of life and reduce the risk of cerebrovascular events. There are currently no preclinical tools for prediction of future cerebrovascular disease/events in healthy humans; the proposed study aims to address this knowledge gap. The central hypothesis is that our test of “Cerebral-Vascular Function” will elicit a vasodilatory stimulus, which will be reduced in healthy older subjects, and chronic smokers, and that impairment in these responses will be associated with impaired peripheral vascular regulation and with reduced cerebral vascular reactivity to CO2. A secondary hypothesis is that that blockade of myogenic and neurogenic responses to the “Cerebral-Vascular Function” test will facilitate assessment of the endothelial shear- stress dependent mechanism of cerebral blood flow regulation. We will address these hypotheses in two broad Specific Aims: 1) assess the responses to the Cerebral-Vascular Function test , and compare responses with a classic test of Cerebral Vascular Reactivity to CO2, and the Peripheral-Vascular Reactivity tests in healthy young subjects, and subjects known to have impaired systemic vascular function, (older healthy subjects, and chronic smokers), and; 2) determine the relative contribution of endothelial-mediated hyperemia from myogenic and neurogenic control of cerebral blood flow. Human subjects will be recruited to address these aims, by adapting the peripheral flow-mediated dilation (FMD) approach of ischemia-reperfusion to the cerebral vasculature by use of lower body negative pressure (LBNP). LBNP (-60 mmHg) will be applied to induce an “ischemic” stress to the cerebral tissue; rapid release of this stress will elicit shear stress induced cerebral vasodilation. Reactive hyperemia in the intracranial and extracranial arteries will be assessed via calculation of the peak and area under the curve for each response as an index of resistance vessel function. Independently, FMD in the brachial and femoral arteries will be assessed. The rationale for the proposed research is to develop a clinically-relevant test for assessment of cerebral vascular function and identify a mechanism for the previously observed increase in cerebral blood flow to simulated “ischemia-reperfusion” stress. The approach is innovative as it may provide evidence that cerebral reactive hyperemia is a novel methodological approach and a valid stimulus to assess cerebrovascular function. This contribution is significant as it will provide insight into the detrimental cerebrovascular adaptations that occur with aging, and the overall contribution that endothelial dysfunction may play within this process.