# Estrogen receptor alpha signaling in endothelial cells exacerbates arterial stiffening via upregulation of ENaC in insulin resistant females

> **NIH NIH R01** · UNIVERSITY OF MISSOURI-COLUMBIA · 2020 · $687,369

## Abstract

Project Summary/Abstract
Arterial stiffening is a hallmark of the aging process. However, premature stiffening is often seen in
hypertension, obesity, insulin resistance, and type 2 diabetes (T2D). Both men and women are affected, but
women with T2D are at greater risk. As augmented arterial stiffness is an independent predictor of
cardiovascular disease (CVD), the increased susceptibility of insulin-resistant (IR) and obese women to arterial
stiffening may explain their higher risk for CVD. In healthy women, estrogen signaling via estrogen receptor
alpha (ERα) prevents stiffening, but these effects are blunted in over-nutrition and obesity when the presence
of the ER may be deleterious. Endothelial cell (EC) epithelial sodium channel (ENaC) expression increases in
obese and IR female mice. Increased EC ENaC contributes to arterial stiffening and EC dysfunction, in part by
lowering nitric oxide (NO) bioavailability. Aldosterone is a major ENaC stimulus, but other steroid hormones,
specifically estrogen, also promote ENaC expression/function in various tissues. ENaC activity is regulated by
the serum glucocorticoid inducible-kinase 1 (SGK-1) pathway. Elevated aldosterone and decreased NO
bioavailability are characteristics of obese, IR and T2D women. Based on our prior work and most recent
preliminary data, our hypothesis is that estrogen action through the EC ERα upregulates EC ENaC expression
and activity, via SGK-1, exacerbating endothelial and arterial stiffening in obese, IR premenopausal females.
The corollary to this hypothesis is that ENaC inhibition will have a greater impact on arterial stiffness in obese,
premenopausal IR women than in obese IR postmenopausal women or age-matched obese, IR men.
Consequently, ENaC inhibition will have a greater impact on arterial stiffness in premenopausal obese, IR
women than in obese, IR men. We will measure arterial/EC stiffness in IR and obese EC-specific ERα and
ENaC KO mice; in isolated ECs; and in a cohort of obese, IR women (pre and post-menopausal) and age-
matched men, to accomplish the following Aims: 1) To determine whether EC ERα regulation of EC ENaC, via
SGK-1, plays an important role in the genesis of accelerated endothelial and arterial stiffening in IR female
mice and 2) to determine whether treatment with the ENaC inhibitor, amiloride, improves endothelial function
and arterial stiffness in obese IR subjects in a randomized placebo-controlled trial. To date, the specific role of
EC ERα regulation of ENaC expression/activation, in ensuing sex-related differences in arterial stiffness in
obesity and insulin resistance, remains unexplored. This proposal aims to fill that gap and show that targeting
ENaC activation holds extraordinary promise in reversing endothelial dysfunction and arterial stiffness in
obesity and insulin resistance, and ultimately preventing cardiovascular disease, especially in women.

## Key facts

- **NIH application ID:** 9928096
- **Project number:** 5R01HL142770-02
- **Recipient organization:** UNIVERSITY OF MISSOURI-COLUMBIA
- **Principal Investigator:** Camila Margarita Manrique Acevedo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $687,369
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928096

## Citation

> US National Institutes of Health, RePORTER application 9928096, Estrogen receptor alpha signaling in endothelial cells exacerbates arterial stiffening via upregulation of ENaC in insulin resistant females (5R01HL142770-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9928096. Licensed CC0.

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