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

项目摘要 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、神经源性和剪切介导的反应在多大程度上起作用的机制性见解 大脑血管系统的调节。脑血管疾病也是第五大死亡原因 这是导致中老年人认知障碍和残疾的主要原因。了解 衰老与脑血管功能之间的关系对于开发治疗脑血管疾病的药物至关重要。 改善生活质量和降低脑血管事件风险的干预措施。目前有 没有用于预测健康人未来脑血管疾病/事件的临床前工具; 研究旨在解决这一知识差距。中心假设是，我们的“脑血管”测试 功能”将引起血管舒张刺激，这将在健康的老年受试者和慢性吸烟者中减少， 并且这些反应的损伤将与外周血管调节受损以及 降低脑血管对二氧化碳的反应性第二个假设是，肌原性和 对“脑血管功能”测试的神经源性反应将有助于评估内皮剪切力- 脑血流调节的应激依赖机制。我们将在两个广泛的解决这些假设 具体目的：1）评估对脑血管功能测试的反应，并将反应与 脑血管对CO2反应性的经典测试，以及健康人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（老年健康受试者，以及 慢性吸烟者），和; 2）确定内皮介导的充血的相对贡献，从肌源性 和脑血流量的神经原性控制。将招募人类受试者来实现这些目标， 采用外周血流介导的血管扩张（FMD）方法治疗脑缺血再灌注损伤 通过使用下体负压（LBNP）对血管系统进行治疗。将应用LBNP（-60 mmHg）诱导 “缺血性”应力的脑组织;这种应力的快速释放将引起剪切应力诱导的脑 血管舒张颅内和颅外动脉的反应性充血将通过计算 每个响应的峰值和曲线下面积作为阻力血管功能的指标。独立地， 将评估肱动脉和股动脉中的FMD。拟议研究的基本原理是开发 一种临床相关的测试，用于评估脑血管功能，并确定以前的机制， 观察到模拟“缺血-再灌注”应激的脑血流量增加。方法是创新的 因为它可以提供证据表明，脑反应性充血是一种新的方法学途径和有效的 刺激以评估脑血管功能。这一贡献是重要的，因为它将提供深入了解 随着年龄的增长，有害的脑血管适应，以及内皮细胞 功能障碍可能在这个过程中发挥作用。

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.