# Project 3: Crippled Cerebral Blood Flow Regulation in Chronic Hypertension

> **NIH NIH P20** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $251,228

## Abstract

PROJECT SUMMARY
Hypertension is the leading risk factor for cardiovascular and cerebrovascular diseases. Epidemiological
studies have demonstrated the deleterious influence of midlife hypertension, especially long-standing
hypertension, on later-life cognitive impairment. Exquisite regulation of cerebral blood flow (CBF), delivering
adequate amounts of oxygen and nutrients that is spatially and temporally matched to ever-changing neuronal
activity, is crucial to maintain proper brain function such as cognition. This moment-to-moment adjustment of
local blood flow in the brain is known as functional hyperemia. Our recent work has demonstrated a novel
signaling pathway, capillary-to-arteriole electrical signaling, is a major contributor to functional hyperemia.
The overall goal of this proposal is to elucidate the impact of chronic hypertension on functional hyperemia,
specifically on capillary-to-arteriole electrical signaling, at the molecular, cellular, tissue and whole body level,
using a murine model of poly-genic hypertension (BPH/2J mice). Our preliminary studies demonstrate that life-
time hypertension causes significant impairment of functional hyperemia and disrupted capillary-to-arteriole
signaling in 8-month-old male BPH/2J mice, an age that is approximated to equal humans in their fifth decade.
Studies in Aim 1 will mechanistically examine sex differences in the progression of hypertension-induced
impairment of functional hyperemia and capillary-to-arteriole electrical signaling in hypertensive BPH/2J mice
and a normotensive control strain (BPN/3J) of mice. In Aim 2, we will elucidate whether different classes of
first-line, anti-hypertensive drugs provide a differential level of benefit with respect to restoring functional
hyperemia deficiencies. Employing three clinically-used anti-hypertensive drugs, which act via distinct
pharmacological mechanisms (i.e., a Ca2+ channel blocker, an angiotensin receptor antagonist, and an
adrenergic β receptor blocker), we will measure systemic blood pressure, in vivo functional hyperemia and ex
vivo and in vivo capillary-to-arteriole signaling in male and female BPH/2J mice. The continual anti-
hypertensive treatment of mice will start after the development of hypertension to mimic the scenario often
occurring in humans. Further, we will examine plasma aldosterone concentrations to test the hypothesis that
plasma aldosterone contributes to the class-dependent efficacy of anti-hypertensive drugs.
In summary, through application of an innovative combination of sophisticated approaches and therapeutic
interventions, this proposal should provide conceptually new translational insights including a wealth of
information on potential novel therapeutic approaches such as sex-specific treatments for hypertension and
“tailor-made” anti-hypertensive drug regimens.

## Key facts

- **NIH application ID:** 10230995
- **Project number:** 5P20GM135007-02
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Masayo Koide
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $251,228
- **Award type:** 5
- **Project period:** 2020-08-06 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10230995

## Citation

> US National Institutes of Health, RePORTER application 10230995, Project 3: Crippled Cerebral Blood Flow Regulation in Chronic Hypertension (5P20GM135007-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10230995. Licensed CC0.

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