# Mechanisms of Vascular Dysfunction with Advancing Reproductive Age

> **NIH NIH R01** · UNIVERSITY OF DELAWARE · 2021 · $451,479

## Abstract

PROJECT SUMMARY/ABSTRACT
With advancing reproductive age, there is a loss of ovarian function and fluctuations in sex steroids that
contribute to a greater susceptibility of vascular dysfunction. Importantly, impairments in endothelial function
have been demonstrated before menopause, and specifically in the early peri-menopause transition. However,
the mechanisms underlying this decline in endothelial function are not known. The purpose of this R01 is to
examine key mechanisms contributing to impaired endothelial function in women advancing across
reproductive ages, and in particular, the interactions between endothelin-1 (ET-1) and estradiol (E2). The
overall hypothesis is that activation of ET-1 and a loss of ETB mediated dilation play a primary role in
contributing to impaired endothelial function with advancing reproductive age, and that E2 administration
during peri-menopause will attenuate these responses. Accordingly, the first aim of this project will test the
hypothesis that ET-1 contributes to impaired endothelial function with advancing reproductive age. The second
aim of this project will test the hypothesis that alterations in ETB receptors contribute to impaired endothelial
function with advancing reproductive age. The third aim will test the hypothesis that E2 modulates ET-1
receptor control of endothelial function. We will use a cross-sectional design to measure macro- and micro-
vascular endothelial-dependent dilation in premenopausal, early peri-menopausal, late peri-menopausal, and
postmenopausal women (classified based on reproductive age) under control conditions and in response to
ETB receptor and ETA receptor blockade. In addition, we will perform venous endothelial cell biopsies to
assess intracellular ET-1 protein expression and ETB receptor expression in endothelial cells. Aim 3 will
expand on these cross-sectional comparisons by using a controlled hormone intervention to better isolate the
effects of E2 on endothelial function and ET-1 receptor responses in early and late peri-menopausal women.
This comprehensive assessment of the ET-1 system will provide novel information on the mechanisms
contributing to vascular dysfunction in women, and the impact of E2 therapy on these pathways at specific time
points across the menopausal transition. Given the recent controversy surrounding hormone therapy in
women, understanding the mechanisms contributing to impaired endothelial function with advancing
reproductive age is of both physiological and clinical importance to identify an appropriate time frame for
intervention and to optimize the benefits of hormone therapy.

## Key facts

- **NIH application ID:** 10131850
- **Project number:** 5R01HL146558-03
- **Recipient organization:** UNIVERSITY OF DELAWARE
- **Principal Investigator:** Megan M Wenner
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $451,479
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131850

## Citation

> US National Institutes of Health, RePORTER application 10131850, Mechanisms of Vascular Dysfunction with Advancing Reproductive Age (5R01HL146558-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10131850. Licensed CC0.

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