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

项目摘要/摘要 脑血管疾病是美国的第三大杀手，也是导致脑血管疾病质量下降的原因之一 生活和增加长期护理支出。患脑血管疾病的风险则相反。 与静息脑血流量(CBF)相关。男性表现出较低的静息脑血流，并有两次 与绝经前妇女相比，患脑血管疾病的风险。大脑的能力 血管应对挑战也与疾病风险成反比，可能在 临床前识别高危患者。然而，这些研究经常被老化和/或 合并症，而这些联系几乎没有提供对导致 性二型脑血管疾病的风险。相反，动物研究使用超生理学。 主要是幼年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有保护作用 成人、性别的基本影响和性激素的生理性波动对CBF机制的影响 控制权仍不明朗。这项研究计划的总体目标是研究这种机制。 它们主动控制人类的脑血流量，特别是男性和女性在 在整个大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。总体假设是 女性性激素和性激素对压力引起的脑血流量增加有更大的作用，这是由于 大前列腺素(COX)和一氧化氮(NOS)扩张。其中的一项关键技术创新 建议源自多模式、高分辨率、对血流敏感的磁共振成像，以量化宏观和 微血管水平、静息状态和对环境挑战的反应。此外，这项研究 设计使我们能够量化所有大脑中两种血管控制机制的性别差异 地区。我们的初步数据显示：缺氧性脑血管扩张在 与男性相比，COX抑制减少了女性的扩张，而不是男性，一氧化氮合酶的抑制 在早期，女性会更多地减少血管扩张，而缺氧性血管扩张会增加 黄体周期，部分是由于COX介导的更大的血管扩张。我们还将使用性激素 抑制，然后添加单一激素，系统地研究对CBF控制的影响 男性和女性都有。我们有大量的初步发现支持我们的假设，并有 综合生理学、药理学和核磁共振方法来检验我们的假说。这一现状-- ART方法将产生以前无法获得的洞察力，不仅是维持CBF，而且是积极 在生理需要时控制它以增加流量。这些新颖、高分辨率、地区性的- 具体的、性别具体的和机制具体的调查结果将作为一个知识平台， 在高危疾病人群(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.