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

人类脑血流调节：性别、机制和应激差异

• 批准号: 10650368
• 负责人: WILLIAM G SCHRAGE
• 金额: $ 61.02万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10650368
• 关键词: 4D MRI; Acute; Address; Adult; Age; Aging; Agreement; Alzheimer' s Disease; Animals; Anterior; Automobile Driving; Blood Vessels; Blood flow; Brain; Brain region; Cerebral Hypoxia; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular Physiology; Cerebrovascular system; Cerebrum; Clinical; Data; Dementia; Diabetes Mellitus; Disease; Disease Progression; Endothelium; Estradiol; Estrogens; Etiology; Exhibits; Female; Functional disorder; Goals; Gonadal Steroid Hormones; Health; Hormones; Human; Hypercapnia; Hypertension; Hypoxia; Knowledge; Link; Long-Term Care; Magnetic Resonance Imaging; Mediating; Methods; Nitric Oxide; Nitric Oxide Synthase; Obesity; Outcome; Patients; Pattern; Perfusion; Physiological; Population; Premenopause; Prostaglandin-Endoperoxide Synthase; Prostaglandins; Quality of life; Rattus; Regulation; Research; Research Design; Resolution; Rest; Risk; Sex Differences; Sexual Reassignment; Signal Transduction; Stimulus; Stress; Supplementation; Techniques; Testing; Testosterone; Therapeutic; Vasodilation; Vasodilator Agents; Woman; active control; animal data; arterial spin labeling; brain circulation; cerebral artery; cerebrovascular; clinically relevant; comorbidity; design; disorder risk; functional improvement; functional restoration; gain of function; high risk; high risk population; in vivo; insight; juvenile animal; loss of function; male; men; multimodal data; novel; pharmacologic; physiologic stressor; pre-clinical; programs; regional difference; response; sex; sexual dimorphism; stroke risk; technological innovation; vascular contributions; vasoconstriction; young adult

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.

项目概要/摘要 脑血管疾病是美国第三大杀手，导致医疗质量下降 寿命延长与长期护理支出增加成反比。 与静息脑血流量 (CBF) 相关，男性表现出较低的静息 CBF，并且有两次。 与绝经前女性相比，患脑血管疾病的风险更高。 血管应对挑战的能力也与疾病风险成反比，并且可能有助于 临床前识别高危患者然而，这些研究常常因年龄和/或年龄而受到干扰。 合并症，并且这些关联几乎没有提供对导致这些疾病的生理机制的深入了解 性二态性脑血管疾病风险离线，动物研究使用超生理学。 主要针对幼龄动物的激素治疗水平，这限制了转化相关性 虽然人们普遍认为雌激素对健康有保护作用。 成人、性别和性激素生理波动对 CBF 机制的基本影响 该研究计划的总体目标是调查其机制。 它主动控制人类的脑血流量（CBF），特别是男性和女性在 我们建议研究 CBF 在整个大脑循环中的区域控制机制。 健康年轻（18-40 岁）成年男性和女性的控制机制总体假设是。 女性和性激素会导致压力引起的 CBF 增加更大，这是由于 更大的前列腺素（COX）和一氧化氮（NOS）扩张是这一技术的关键创新。 该提案源自多模式、高分辨率、血流敏感 MRI，以在宏观和宏观层面量化 CBF 此外，该研究还研究了休息时和应对环境挑战的微血管水平。 设计使我们能够量化全脑两种血管控制机制的性别差异 我们的初步数据表明：缺氧时脑血管舒张程度要高出 60-100%。 女性与男性相比，COX 抑制可减少女性扩张，但不会减少男性扩张，NOS 抑制 更能减少女性的血管舒张，并且女性在早期缺氧的血管舒张会增加 黄体周期，部分是为了更大的 COX 介导的血管舒张，我们还将使用性激素。 抑制，然后添加单一激素，系统研究对 CBF 控制的影响 我们有大量的初步研究结果支持我们的假设，并且有 综合生理学、药理学和 MRI 方法来检验我们的假设。 艺术方法将产生以前无法实现的洞察力，不仅可以维持 CBF，而且可以积极地 在增加流量的生理需求期间控制它。这些新颖的、高分辨率的、区域性的。 特定的、特定性别的和特定机制的研究结果将作为一个知识平台， 在高危疾病人群（例如糖尿病、高血压、 阿尔茨海默病）表现出强烈的性别特异性病因和重要的血管贡献。

项目成果

Nitric oxide synthase inhibition in healthy adults reduces regional and total cerebral macrovascular blood flow and microvascular perfusion.

健康成人中一氧化氮合酶的抑制会减少局部和总的脑大血管血流量和微血管灌注。

• 发表时间: 2021
• 作者: Carter, Katrina J;Ward, Aaron T;Kellawan, J Mikhail;Eldridge, Marlowe W;Al;Walker, Benjamin J;Lee, Jeffrey W;Wieben, Oliver;Schrage, William G
• 通讯作者: Schrage, William G