Human cerebral blood flow regulation: sex, mechanism, and stress differences

项目总结/摘要 脑血管疾病是美国的第三大杀手，并降低了 生活和长期护理支出增加。患脑血管疾病的风险与 与静息脑血流量（CBF）相关。男性表现出较低的静息CBF， 与绝经前妇女相比，脑血管疾病的风险。大脑的能力 血管应对挑战的能力也与疾病风险呈负相关， 在临床前识别高危患者。然而，这些研究经常受到老化和/或 合并症，并且该协会几乎没有提供对负责的生理机制的深入了解。 性二态性脑血管病风险。相反，动物研究使用超生理学方法， 主要是年轻动物的激素治疗水平，这限制了 动物CBF机制虽然人们普遍认为雌激素对健康的人有保护作用， 成年人，性别的基本影响，性激素的生理波动，CBF的机制 控制仍然不清楚。这项研究计划的总体目标是调查机制 积极控制人类的脑血流量（CBF），特别是男性和女性在 在整个脑循环的区域基础上的控制机制。我们建议研究CBF 健康年轻（18-40岁）成年男性和女性的控制机制。总的假设是 女性性和性激素有助于更大的压力诱导的CBF增加，由于 前列腺素（考克斯）和一氧化氮（NOS）扩张更大。这一关键技术创新 建议来自多模式，高分辨率，流动敏感MRI，以量化CBF在宏观和 微血管水平，在休息，并响应环境的挑战。此外，研究 设计使我们能够量化整个大脑中两种血管控制机制的性别差异 地区我们的初步数据表明：缺氧性脑血管舒张比对照组高60-100%。 女性与男性相比，考克斯抑制减少女性的扩张，但男性没有，NOS抑制 减少女性血管舒张更多，在早期缺氧性血管舒张增加 黄体周期，部分是因为COX介导的血管舒张作用更强。我们还将使用性激素 抑制，然后添加单一激素，以系统地研究对CBF控制的影响 在两性中。我们有大量的初步发现支持我们的假设， 综合生理学、药理学和MRI方法来测试我们的假设。这种... 艺术方法将产生以前无法实现的洞察力，不仅保持CBF， 在生理需求期间控制它以增加流量。这些新颖的，高分辨率的，区域性的- 具体的、性别具体的和机制具体的研究结果将作为一个知识平台， 设计高风险疾病人群（例如糖尿病，高血压， 阿尔茨海默氏症），表现出强烈的性别特异性病因和重要的血管贡献。

Project Summary/Abstract Cerebrovascular disease is the third leading killer in the U.S., and contributes to decreased quality of life and increased long-term care spending. The risk of cerebrovascular disease is inversely associated with resting cerebral blood flow (CBF). Men exhibit a lower resting CBF and have twice the risk of cerebrovascular disease when compared to premenopausal women. The ability of cerebral vessels to respond to challenges is also inversely related to disease risk, and may be useful in identifying at-risk patients pre-clinically. However, these studies are often confounded by aging and/or comorbidities, and the associations provide little insight into physiologic mechanisms responsible for sexually dimorphic cerebrovascular disease risk. Conversely, animal studies use supraphysiologic levels of hormone treatment in primarily young animals, which limits the translational relevance of animal CBF mechanisms. While there is general agreement that estrogen is protective in healthy adults, the basic impact of sex, and physiologic fluctuations in sex hormones, on mechanisms of CBF control remains unclear. The overall goal of this research program is to investigate the mechanisms which actively control cerebral blood flow (CBF) in humans, particularly how men and women differ in control mechanisms on a regional basis throughout the brain circulation. We propose to study CBF control mechanisms in healthy younger (18-40 yrs) adult men and women. The overall hypothesis is that female sex and sex hormones contribute to larger stress-induced increases in CBF, due to greater prostanoid (COX) and nitric oxide (NOS) dilation. A key technological innovation of this proposal derives from multi-mode, high-resolution, flow sensitive MRI to quantify CBF at macro- and microvascular levels, at rest, and in response to environmental challenges. Additionally, the research design allows us to quantify sex differences in two vascular control mechanisms across all brain regions. Our preliminary data demonstrate: hypoxic cerebral vasodilation is 60-100% higher in women compared to men, COX inhibition reduces dilation in women but not men, NOS inhibition reduces vasodilation more in women, and hypoxic vasodilation is increased in women during early luteal cycle, in part to greater COX-mediated vasodilation. We also will use sex hormone suppression, followed by single hormone addition, to systematically study the impacts on CBF control in both sexes. We have substantial preliminary findings that support our hypotheses, and have integrated physiologic, pharmacologic, and MRI approaches to test our hypotheses. This state-of-the- art approach will yield previously unattainable insight into not only maintaining CBF, but actively controlling it during physiologic demands for increased flow. These novel, high resolution, regionally- specific, sex-specific, and mechanism-specific findings will serve as a knowledge platform, for designing sex-specific CBF studies in high risk disease populations (e.g. diabetes, hypertension, Alzheimer’s) which exhibit strong sex-specific etiology and important vascular contributions.