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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

基本信息

批准号：
10407466
负责人：
WILLIAM G SCHRAGE
金额：
$ 60.71万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
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/10407466
关键词：
4D MRI Acute Address Adult Age Aging Agreement Alzheimer&apos 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 Pharmacology 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 base brain circulation cerebral artery cerebrovascular clinically relevant comorbidity design disorder risk female sex hormone functional restoration gain of function high risk high risk population improved functioning in vivo insight juvenile animal male men multimodal data novel physiologic stressor pre-clinical programs regional difference response sex sexual dimorphism stroke risk technological innovation vascular contributions vasoconstriction young adult

项目摘要

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.

项目总结/文摘