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.

Public Health Relevance

Poor cerebral blood flow is associated with high risks of stroke, dementia, and Alzheimer?s Disease, all of which are linked to poor brain blood vessel function. These brain conditions can be more prominent in men versus women, suggesting function of brain blood vessels may differ between the sexes. The goal of this application is to examine sex differences and similarities in how brain vessels function in healthy men and women, particularly when the brain demands more blood flow. These findings can be used as a platform to determine how vascular function declines with age or disease in unique ways in men versus women. Only then can we understand the most promising ways to restore function of brain blood vessels with optimal sex-specific treatments. The findings of how sex influences brain blood vessel function will provide ideas on how to limit disease progression, or improve function, in an effort to restore the quality of life of both sexes as they age successfully.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Charette, Marc F
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University of Wisconsin Madison
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United States
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