# Therapeutic use of extracellular vesicles for dystrophic cardiomyopathy

> **NIH NIH P20** · UNIVERSITY OF DELAWARE · 2020 · $215,332

## Abstract

Cardiovascular disease (CVD) is the leading cause of death in women, and mortality from CVD is higher in
postmenopausal women (PMW) compared to age-matched men. PMW are at a greater risk for developing
hypertension (HTN), a major risk factor for CVD. Furthermore, PMW are more likely to have uncontrolled or
resistant HTN despite medication. Functional changes in the microcirculation can be used as an index of future
CVD risk; the mechanisms contributing to microvascular dysfunction can be easily assessed using the
cutaneous circulation. Endothelin-1 (ET-1) is a potent vasoconstrictor that has been implicated in the
development of HTN, and data in animal models indicates ET-1 receptors are modulated by hormones like
estradiol and angiotensin II (ANG II). The first aim of this project is to test the hypothesis that ET-1 contributes to
vasoconstriction in hypertensive PMW and that ANG II exacerbates the effects of ET-1. The second aim of this
project is to test the hypothesis that ET-1 expression along with ET-A and ET-B receptor expression are altered
in hypertensive PMW. Our central hypothesis is that hypertensive PMW have greater ET-1 mediated
vasoconstrictor tone due to increased ET-1 expression, down-regulation of ET-B receptors on endothelial cells
and up-regulation of both ETA and ETB receptors on vascular smooth muscle. We further hypothesize that ANG
II exacerbate the increase in ET-1, and the cellular changes ET-A and ET-B receptor expression contribute to
the exaggerated constriction with HTN in PMW. We will test our central hypothesis by measuring changes in
cutaneous blood flow during intradermal microdialysis infusions of ET-A and ET-B receptor antagonists in
normotensive PMW and hypertensive PMW before and after losartan. Endothelial cells and skin punch biopsies
will also be obtained directly from normotensive and hypertensive PMW (pre/post losartan) to examine cellular
expression of ET-1 and ET-A and ET-B receptors. This comprehensive assessment of ET-1 receptor responses
will provide novel information on the mechanisms contributing to vascular dysfunction in hypertensive PMW.
Because CVD is the leading cause of death in women and PMW have a higher prevalence of HTN and mortality
from CVD, understanding the mechanisms contributing to this higher prevalence in women is of both
physiological and clinical importance to develop future preventative and therapeutic strategies for women.

## Key facts

- **NIH application ID:** 10148353
- **Project number:** 5P20GM113125-05
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Matthew Bryant Hudson
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $215,332
- **Award type:** 5
- **Project period:** — → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10148353

## Citation

> US National Institutes of Health, RePORTER application 10148353, Therapeutic use of extracellular vesicles for dystrophic cardiomyopathy (5P20GM113125-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10148353. Licensed CC0.

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