# Smooth Muscle Mineralocorticoid Receptor in Vascular Aging and Hypertension

> **NIH NIH R01** · TUFTS MEDICAL CENTER · 2020 · $762,573

## Abstract

Aging is universal and the most potent risk factor for cardiovascular disease (CVD). Aortic stiffness increases
with age in both sexes and predicts CVD risk. Stiffening of the aorta raises central pulse pressure to contribute
to hypertension, heart attack and stroke and promotes small vessel remodeling that damages end organs
inducing heart failure, renal dysfunction, and cognitive decline. Thus, understanding aging vascular stiffness
mechanisms is a pressing unmet medical need. We recently discovered that inhibition of the aldosterone-
binding mineralocorticoid receptor (MR) or smooth muscle cell (SMC)-specific deletion of MR (SMC-MR-KO)
protects male mice from vascular stiffness with aging and now propose to explore mechanism(s). Women
develop vascular stiffness later in life, faster, and with significantly worse CVD outcomes than men. New data
reveals a similar pattern of later onset vascular stiffness in aging female mice that correlates with the timing of
increased aortic SMC-MR expression. SMC-MR deletion protects from vascular stiffening in both sexes by
sexually dimorphic mechanisms; SMC-MR contributes to vessel fibrosis in aging males and to intrinsic SMC
stiffness (by atomic force microscopy (AFM)) in both sexes. We show for the first time that MR protein
increases with age in primary human aortic SMCs (HASMC) from males and females which may be driven by
induction of the HIF1a transcription factor. Additional data from male mouse aortas reveals: (1) Decreased
expression with age of fibrosis genes and integrin receptors specifically in SMC-MR-KO mice; (2) Decreased
histone H3K27 methylation (H3K27me) with aging that is attenuated in SMC-MR-KO mice; (3) Decreased
expression of the H3K27 methyltransferase EZH2 with age with enrichment of H3K27ac, a transcriptional
activation mark, at promoters of fibrosis genes only in MR-intact mice. Analogous to the mice, aged male
HASMC had decreased EZH2 and H3K27me and increased stiffness genes, and these changes are reversed
by MR antagonism. Based on these data, we propose to test the hypothesis that: rising MR in aging SMC
promotes stiffness by suppression of EZH2 leading to decreased H3K27me and recruitment of MR and it's co-
activator CBP to increase H3K27ac and transcription of stiffness genes. SA1 determines mechanisms for
increased MR expression in aging SMCs. SA2 investigates MR as an epigenetic regulator of stiffness genes in
HASMCs in vitro. SA3 explores MR as an epigenetic regulator of vascular stiffness in aging mice. All studies
directly compare male and female HASMCs or mice with gain- and loss-of-function genetic and pharmacologic
approaches to target MR, EZH2, and CBP. The proposal uses innovative animal models and state-of-the-art
approaches to explore a novel epigenetic mechanism driving aging vascular stiffness and tests sex-specific
mechanisms by which SMC-MR contributes. The long-term goal is to determine the therapeutic potential for
antagonism of MR or its downstream mechanism...

## Key facts

- **NIH application ID:** 9948718
- **Project number:** 5R01HL119290-06
- **Recipient organization:** TUFTS MEDICAL CENTER
- **Principal Investigator:** Michael A HILL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $762,573
- **Award type:** 5
- **Project period:** 2014-08-05 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948718

## Citation

> US National Institutes of Health, RePORTER application 9948718, Smooth Muscle Mineralocorticoid Receptor in Vascular Aging and Hypertension (5R01HL119290-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9948718. Licensed CC0.

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