Human Cerebral Blood Flow Regulation

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Abstract

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).

Description

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.

Dates

Last Verified:	05/31/2020
First Submitted:	02/06/2020
Estimated Enrollment Submitted:	02/06/2020
First Posted:	02/10/2020
Last Update Submitted:	06/03/2020
Last Update Posted:	06/08/2020
Actual Study Start Date:	07/31/2020
Estimated Primary Completion Date:	05/31/2025
Estimated Study Completion Date:	04/30/2026

Condition or disease

Cerebral Arterial Diseases

Intervention/treatment

Drug: L-NMMA

Drug: Ketorolac Tromethamine

Drug: Ganirelix Acetate

Drug: Testosterone Transdermal Product

Drug: Estradiol Topical

Phase

Arm Groups

Arm	Intervention/treatment
Experimental: Male NOS Males visit MRI twice. Once for hypercapnia visit (no drugs), and once for hypoxia visit (IV and drug infusion to inhibit NOS). CBF measured via MRI sequences, and hemodynamics monitored for safety/research.
Experimental: Male COX Males visit MRI twice. Once for hypercapnia visit (no drugs), and once for hypoxia visit (IV and drug infusion to inhibit COX). CBF measured via MRI sequences, and hemodynamics monitored for safety/research.
Experimental: Female NOS Females visit MRI twice. Once for hypercapnia visit (no drugs), and once for hypoxia visit (IV and drug infusion to inhibit NOS). CBF measured via MRI sequences, and hemodynamics monitored for safety/research.
Experimental: Female COX Females visit MRI twice. Once for hypercapnia visit (no drugs), and once for hypoxia visit (IV and drug infusion to inhibit COX). CBF measured via MRI sequences, and hemodynamics monitored for safety/research.

Eligibility Criteria

Ages Eligible for Study	18 Years To 18 Years
Sexes Eligible for Study	All
Accepts Healthy Volunteers	Yes
Criteria	Inclusion Criteria: - All participants will be healthy adults between 18-40 years old, matched for age and aerobic fitness - Participants will be non-hypertensive (<125/80mm Hg) - Participants will be non-obese (BMI 19-25 kg/m2) - Participants will have normal blood glucose (<100 g/dl) - Participants will have normal lipids (LDL cholesterol <130 mg/dl, triglycerides <150 mg/dl) - Women must have a natural regular menstrual cycle Exclusion Criteria: - Participants with a history of: - peripheral vascular disease - hepatic disease - renal disease - hematologic disease - stroke - obesity - prediabetes - diabetes - sleep apnea - Participants with current BP>130/85 mmHg - Regular smokers - Taking cardiovascular medications - Women who take hormonal birth control - Women who are pregnant or have polycystic ovarian syndrome [Hormonal birth control will not be allowed in women]

Outcome

Primary Outcome Measures

1. Cerebrovascular Conductance (CVC) in response to Hypoxia [up to 75 minutes for entire visit, but hypoxia lasts about 20 minutes]

CVC is the ratio between Cerebral Blood Flow (CBF) and blood pressure (BP). Change in CVC in response to hypoxia between male and female groups, where baseline CVC is subtracted from hypoxia CVC. Hypoxia typically lasts about 20 minutes. The hypothesis is that women will exhibit 50-60% more vasodilation in response to hypoxia [Aim 1].

2. CVC in response to Hypercapnia [up to 75 minutes for entire visit, but hypercapnia lasts about 10-15 minutes]

CVC is the ratio between Cerebral Blood Flow (CBF) and blood pressure (BP). Change in CVC in response to hypercapnia between male and female groups, where CBF is normalized for BP. Baseline CVC will be subtracted from hypercapnia CVC. Hypercapnia typically lasts about 10-15 minutes.The hypothesis is that hypercapnic vasodilation will be similar between groups [Aim 1B].

3. CVC change in response to Drug Infusion [approximately 10 minutes in the middle of 75 minute study visit]

CVC is the ratio between Cerebral Blood Flow (CBF) and blood pressure (BP). Change in CVC in response to drug infusion between male [NOS or COX] and female [NOS or COX] groups. The hypothesis is that acute inhibition of COX or NOS will reduce sex differences in hypoxia-mediated cerebral vasodilation [Aim 2].

4. Change in hypoxia CVC in response to Ganirelix compared to no ganirelix Baseline (Aim 3a) [baseline and up to 7 days during ganirelix treatment]

Change in hypoxia CVC response to ganirelix compared to baseline within male and female groups, where CVC is CBF is normalized for BP. The hypothesis is that GnRH suppression will abolish hypoxic CBF differences, indicating sex steroids play a vital role in CBF control [Aim 3].

5. Change in hypoxia CVC response to sex hormone suppression with single sex hormone add-back [baseline and up to 14 days]

Change in hypoxia CVC response to ganirelix+testosterone (in males Aim 3B) or ganirelix+estradiol (in females, Aim 3C) compared to baseline within male and female groups, where CVC is CBF is normalized for BP. The hypothesis is that adding a sex steroid will magnify hypoxic CVC differences, indicating sex steroids play a vital role in CBF control [Aim 3].

6. Change in hypoxia CVC response to NOS or COX inhibition during ganirelix+single sex hormone add-back [baseline and up to 14 days]

Change in hypoxia CVC drug response to NOS or COX inhibition during ganirelix+testosterone (in males Aim 3B) or ganirelix+estradiol (in females, Aim 3C) compared to baseline hypoxia studies from Aim 2. The hypothesis is that adding a sex steroid will magnify hypoxic CVC differences in drug effects, indicating sex steroids play a vital role in CBF control [Aim 3].