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This study tests basic differences in how men and women control brain (cerebral) blood flow (CBF), at rest and under stress. The stress is low oxygen or high carbon dioxide. The investigators hypothesize that sex differences per se, plus sex hormone differences, drive different signals in blood vessels that change the way CBF is regulated. The investigators will test these mechanisms with medicine infusions during stress, and measure CBF using state-of-the-art MRI approaches. Research confounding variables like aging and disease will be mitigated by comparing younger adults (18-40 years old).
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. The investigators 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 the quantification of sex differences in two vascular control mechanisms across all brain regions. 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. Sex hormone suppression, followed by single hormone addition, will be used to systematically study the impacts on CBF control in both sexes.
Substantial preliminary findings support these hypotheses, and integrated physiologic, pharmacologic, and MRI approaches are available to test them. 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.
Three Specific Aims will be addressed in this study:
Aim 1: Test the hypothesis that healthy males exhibit reduced cerebral vasodilation compared to healthy females despite exhibiting similar vasodilation to hypercapnia.
- Aim 1A: Vasodilation to hypoxia will be markedly lower in males, more so in anterior brain regions.
- Aim 1B: Vasodilation to hypercapnia will be similar between sexes.
Aim 2: Test the hypothesis that acute inhibition of COX or NOS will reduce sex differences in hypoxia-mediated cerebral vasodilation.
- Aim 2A: COX-mediates vasodilation primarily in females.
- Aim 2B: NOS mediates vasodilation more in females than males.
Aim 3: Test the hypothesis that manipulating sex steroids can abolish or magnify sex differences in vasodilation.
- Aim 3A: Short-term suppression of sex steroids will abolish sex differences in resting and hypoxic CBF via greater losses of COX- and NOS-mediated vasodilation in females than males.
- Aim 3B: Short-term supplementation of unopposed testosterone in males will magnify sex differences by driving COX vasoconstriction (TXA2) and uncoupled NOS vasoconstriction.
- Aim 3C: Short-term supplementation of unopposed estradiol in females will magnify sex differences via increased NOS and COX vasodilation.
Cerebral Arterial Diseases
L-NMMA, Ketorolac Tromethamine, Ganirelix Acetate, Testosterone Transdermal Product, Estradiol Topical
University of Wisconsin, Madison
Not yet recruiting
University of Wisconsin, Madison
Published on BioPortfolio: 2020-02-16T17:40:57-0500
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