# Cerebral parenchymal arteriole dysfunction and cognitive decline in a life-long high fat feeding model

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $519,252

## Abstract

Abstract
Obese/overweight patients have an increased risk of developing cognitive impairments that can lead to
dementia. This is a major public health concern because the majority of the adult population is overweight or
obese. Overweight individuals have reduced cerebral perfusion and this can cause impaired cognition; the
cause of this cerebral hypoperfusion is unknown. This is an important knowledge gap; understanding the
cause of the hypoperfusion is key to identifying therapeutic targets to slow or prevent cognitive decline in a
society plagued by obesity. The parenchymal arterioles (PAs) connect the pial and capillary networks and
regulate the perfusion of the brain parenchyma. Our preliminary data show that endothelium dependent dilation
is markedly impaired in PAs from overweight rats and these rats develop cognitive dysfunction. Despite their
importance in regulating brain perfusion, little is known about PA function in health and disease. Dilation in PAs
relies heavily on intracellular calcium (Ca2+) signaling, and Ca2+ influx through transient receptor potential
(TRP) channels is an important mediator of cerebral artery endothelium dependent dilation. We showed that
activation of the vanilloid 4 TRP channel (TRPV4) causes PA dilation. Preliminary studies show that TRPV4
expression is reduced in overweight rats and this is linked to mineralocorticoid receptor activation. Circulating
levels of the mineralocorticoid aldosterone are increased in overweight patients and in our rat and mouse
models. Our hypothesis is that MR activation in PA endothelial cells leads to reduced TRPV4 expression,
impaired endothelium-dependent dilation, cerebral hypoperfusion and cognitive impairment in overweight rats.
We will utilize a combination of in vivo and in vitro techniques including MRI, confocal microscopy,
electrophysiology and pressure myography to test our hypothesis. We will determine how excess adiposity
impairs PA function, cerebral perfusion, and cognition. Our working hypothesis is that TRPV4 expression is
reduced in overweight rats and that this leads to impaired Ca2+-mediated endothelium-dependent dilation in
PAs and is associated with reduced cerebral perfusion and impaired cognition. We further propose that directly
inhibiting TRPV4 will cause cerebral hypoperfusion and cognitive decline. We will also determine the effects of
MR activation on PA function, cerebral perfusion, and cognition. Our working hypothesis is that MR activation
in PA endothelial cells causes reduced TRPV4 expression, impaired Ca2+ mediated dilation, cerebral
hypoperfusion and cognitive decline. We further propose that MR antagonism in overweight rats will improve
PA function in a TRPV4 dependent manner and that this will lead to improved cerebral perfusion and cognitive
function. The MR is a highly drugable target, MR antagonists are safe, effective FDA approved drugs. Their
use in the overweight/obese population could dramatically reduce the burden on families and...

## Key facts

- **NIH application ID:** 9967830
- **Project number:** 5R01HL137694-04
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** ANNE M. DORRANCE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $519,252
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967830

## Citation

> US National Institutes of Health, RePORTER application 9967830, Cerebral parenchymal arteriole dysfunction and cognitive decline in a life-long high fat feeding model (5R01HL137694-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9967830. Licensed CC0.

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