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.

项目摘要/摘要 脑血管疾病是美国的第三大杀手，并有助于提高质量 生活和增加长期护理支出。脑血管疾病的风险成反比 与静止的脑血流（CBF）有关。男人暴露了较低的休息CBF，有两次 与绝经前妇女相比，脑血管疾病的风险。脑的能力 应对挑战的船只也与疾病风险成反比，并且可能对 临时识别高危患者。但是，这些研究通常会被衰老和/或 合并症和协会对负责的生理机制几乎没有见解 性二态性脑血管疾病风险。相反，动物研究使用超生理学 基本年轻动物中马酮治疗的水平，这限制了翻译的相关性 动物CBF机制。虽然普遍同意雌激素受到健康保护 成人，性别的基本影响以及性激素对CBF机制的生理波动 控制仍然不清楚。该研究计划的总体目标是研究机制 这积极控制人类的脑血流（CBF），尤其是男人和女人的不同 整个大脑循环中的区域基础控制机制。我们建议研究CBF 健康的年轻（18 - 40年）成年男女的控制机制。总体假设是 女性性别和性激素促成CBF的压力引起的更大的增长 前列腺素（COX）和一氧化氮（NOS）词典。对此的关键技术创新 提案源自多模式，高分辨率，流动性MRI，以量化宏和 微血管水平，静止，并应对环境挑战。此外，研究 设计使我们能够在所有大脑的两个血管控制机制中量化性别差异 地区。我们的初步数据证明：低氧脑血管舒张高60-100％ 与男性相比，妇女的抑制作用减少了女性的扩张，但不能减少男性，nos抑制作用 女性的血管舒张量更多，女性早期的低氧血管舒张增加 黄体循环，部分是针对更大的Cox介导的血管舒张。我们还将使用性爱 抑制，然后是单个激素添加，以系统地研究对CBF控制的影响 在两个性别中。我们有实质性的初步发现，可以支持我们的假设，并有 综合生理，药物和MRI方法来检验我们的假设。这个最先进的 艺术方法将不仅要维护CBF，而且会积极地产生以前无法实现的见解 在生理需求增加流量时控制它。这些新颖的高分辨率，区域性 - 特定，特定性和机制的特定发现将作为知识平台 在高风险疾病人群中设计性别特异性的CBF研究（例如糖尿病，高血压， 阿尔茨海默氏症）暴露了强大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.

• DOI: 10.1113/jp281975
• 发表时间: 2021-11
• 期刊: JOURNAL OF PHYSIOLOGY-LONDON
• 影响因子: 5.5
• 作者: Carter, Katrina J.;Ward, Aaron T.;Kellawan, J. Mikhail;Eldridge, Marlowe W.;Al-Subu, Awni;Walker, Benjamin J.;Lee, Jeffrey W.;Wieben, Oliver;Schrage, William G.
• 通讯作者: Schrage, William G.