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 mechanisms as sex-specific precision medicine strategies to mitigate aging-induced vascular stiffness and the myriad of adverse consequences in our rapidly aging population.

Public Health Relevance

Aging is universal and the most potent risk factor for heart disease. Blood vessels get stiffer with age in both sexes and this predicts future heart disease risk. Women's arteries stiffen later in life, faster, and with significantly worse outcomes than men. We discovered that the salt retaining mineralocorticoid receptor (MR) contributes to artery stiffness with aging by processes that differ between males and females. This proposal will determine how arteries stiffen with aging and could lead to sex-specific treatments to prevent heart disease in aging men and women.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Varagic, Jasmina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Tufts University
United States
Zip Code
Kim, Seung Kyum; McCurley, Amy T; DuPont, Jennifer J et al. (2018) Smooth Muscle Cell-Mineralocorticoid Receptor as a Mediator of Cardiovascular Stiffness With Aging. Hypertension 71:609-621
Moss, M Elizabeth; DuPont, Jennifer J; Iyer, Surabhi L et al. (2018) No Significant Role for Smooth Muscle Cell Mineralocorticoid Receptors in Atherosclerosis in the Apolipoprotein-E Knockout Mouse Model. Front Cardiovasc Med 5:81
Good, Miranda E; Chiu, Yu-Hsin; Poon, Ivan K H et al. (2018) Pannexin 1 Channels as an Unexpected New Target of the Anti-Hypertensive Drug Spironolactone. Circ Res 122:606-615
DuPont, Jennifer J; Jaffe, Iris Z (2017) 30 YEARS OF THE MINERALOCORTICOID RECEPTOR: The role of the mineralocorticoid receptor in the vasculature. J Endocrinol 234:T67-T82
Davel, Ana P; Anwar, Imran J; Jaffe, Iris Z (2017) The endothelial mineralocorticoid receptor: mediator of the switch from vascular health to disease. Curr Opin Nephrol Hypertens 26:97-104
Morine, Kevin J; Paruchuri, Vikram; Qiao, Xiaoying et al. (2016) Circulating multimarker profile of patients with symptomatic heart failure supports enhanced fibrotic degradation and decreased angiogenesis. Biomarkers 21:91-7
Amador, Cristian A; Bertocchio, Jean-Philippe; Andre-Gregoire, Gwennan et al. (2016) Deletion of mineralocorticoid receptors in smooth muscle cells blunts renal vascular resistance following acute cyclosporine administration. Kidney Int 89:354-62
Hwang, Moon-Hyon; Yoo, Jeung-Ki; Luttrell, Meredith et al. (2016) Acute effect of mineralocorticoid receptor antagonism on vascular function in healthy older adults. Exp Gerontol 73:86-94
DuPont, Jennifer J; McCurley, Amy; Davel, Ana P et al. (2016) Vascular mineralocorticoid receptor regulates microRNA-155 to promote vasoconstriction and rising blood pressure with aging. JCI Insight 1:e88942
Burke, Suzanne D; Zsengellér, Zsuzsanna K; Khankin, Eliyahu V et al. (2016) Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia. J Clin Invest 126:2561-74

Showing the most recent 10 out of 17 publications