# Obesity-induced cerebral vascular remodeling and poor brain ischemic tolerance

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $347,925

## Abstract

Obesity increases the risk for stroke. Patients with obesity have worse outcome after
stroke. It is conceivable that obesity-induced cerebral vascular remodeling contributes to
these effects. Our preliminary results showed that the high fat diet (HFD)-fed wild-type mice
are obese, hyperglycemic and hyperlipidemia, conditions that are similar to human. These
mice have an increased tortuosity and vascular density and reduced internal diameters in
their cerebral arteries. They also have decreased brain ischemic tolerance and increased
blood-brain barrier permeability after stroke. The activity of matrix metalloprotease-9 (MMP-
9), a collagenase and gelatinase, was increased in the brain tissues of HFD-fed mice. HFD
did not induce cerebral vascular remodeling and worsen neurological outcome after focal
brain ischemia in MMP-9 knockout mice. Also, it has been reported in the literature that
obesity induces inflammation and oxidative stress that can activate MMP-9. Thus, we
hypothesize that obesity induces MMP-9-dependent cerebral vascular remodeling to reduce
cerebral vascular reserve to lead to reduced ischemic tolerance and that obesity may
involve neuroinflammation and oxidative stress to activate MMP-9. In this project, we will
test this hypothesis by using HFD-fed mice. A state-of-the-art technique called
photoacoustic microscopy (PAM) will be used to monitor the dynamic changes of blood flow
and oxygen supply in the ischemic penumbral brain region and cerebral vascular reserve
under in vivo condition when mice are awake. A classical focal brain ischemia model will be
used. Various pharmacological, genetic and molecular biological approaches will be used to
determine how cerebral vascular reserve is affected and MMP-9 is activated in the brain.
These studies may not only improve our understanding of obesity-induced cerebral vascular
remodeling and poor ischemic tolerance but also identify potential targets for achieving
better neurological outcome after brain ischemia in patients with obesity.

## Key facts

- **NIH application ID:** 10133744
- **Project number:** 5R01NS099118-04
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** ZHIYI ZUO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $347,925
- **Award type:** 5
- **Project period:** 2018-05-15 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10133744

## Citation

> US National Institutes of Health, RePORTER application 10133744, Obesity-induced cerebral vascular remodeling and poor brain ischemic tolerance (5R01NS099118-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10133744. Licensed CC0.

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