The incidence of hypertension (HTN) increases dramatically with age, is poorly treated in the elderly, and contributes significantly to morbidity and mortality in our aging society. Vascular aging is characterized by enhanced angiotensin II (AngII) signaling, increased vascular oxidative stress, and increased vascular tone and contraction. The stimuli driving this aging vascular phenotype are not well understood and no strategy is known to retard arterial aging in humans. Mineralocorticoid receptors (MR) regulate blood pressure (BP) by binding the hormone aldosterone (Aldo) in the kidney to promote sodium retention. We previously identified functional MR in human vascular smooth muscle cells (SMC), discovered that SMC-MR can be directly activated by AngII, and developed a novel mouse model with inducible, SMC-specific deletion of MR (SMC- MR-KO). SMC-MR deletion prevented AngII-induced HTN, vascular oxidative stress and mesenteric vessel contraction and the aging-induced rise in BP. Preliminary data show that AngII activates MR in human SMC in a PKC -dependent manner suggesting a novel ligand-independent mechanism of SMC-MR activation. New data reveals decreased L-type calcium channel (LTCC) expression and current density, a loss of the rise in expression of the Ca-activated Cl channel TMEM16A with aging, and decreased calcium and contractile responses to LTCC activation in mesenteric cells and vessels from aged SMC-MR-KO mice. Furthermore vessels from aged SMC-MR-KO mice have decreased expression of the NADPH-oxidase subunit Nox2 and lower basal and AngII-induced oxidative stress. Based on these data, we propose to test the novel hypothesis that in the aging vasculature, SMC-MR is directly activated by AngII via PKC -mediated phosphorylation and regulates LTCC, TMEM16A and Nox2 expression and activity, promoting the age-associated increase in vascular oxidative stress and contraction, thereby contributing to hypertension. We propose to test this hypothesis with three specific aims investigating: SA1). The mechanism of AngII activation of SMC-MR;SA2) SMC-MR regulation of vascular ion channels and the impact on vascular tone and contraction with aging;and SA3) SMC-MR contribution to vascular oxidative stress with aging and the role in modulating vascular tone and BP. We propose to use molecular approaches in freshly isolated cells and whole vessels in each aim and in vivo telemetry studies in SA3 to explore the impact on blood pressure. Since SMC-MR deletion was more effective in blocking AngII-induced HTN than pharmacologic MR antagonist and widespread use of MR antagonists is limited by hyperkalemia from renal MR blockade, understanding the mechanisms by which SMC-MR is activated and directly contributes to systemic BP could identify novel HTN therapies that are more effective and safer than current drugs, particularly in the elderly.

Public Health Relevance

As people age, high blood pressure (BP) becomes extremely common and contributes substantially to promoting heart attacks and strokes in the elderly. We genetically engineered mice that lack a specific hormone- responding factor from the muscle cells lining the blood vessels. Remarkably, these mice are protected from many aspects of blood vessel aging, including the rise in BP with age. We now propose to study exactly how these mice are protected from blood vessel aging. Since current medicines are insufficient to achieve normal BP in half of elderly people with high blood pressure, these studies have tremendous potential to identify better drugs to treat high BP and its complications, specifically in the growing elderly population.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Maric-Bilkan, Christine
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