Role of endothelial mineralocorticoid receptor on the endothelial dysfunction and oxidative stress in cardiovascular diseases

• Grant number: 14/26192-6
• Support Opportunities: Scholarships abroad - Research
• Start date: August 17, 2015
• End date: August 16, 2016
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Ana Paula Couto Davel
• Grantee: Ana Paula Couto Davel
• Host Investigator: Iris Zamir Jaffe
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Institution abroad: Tufts University, United States

Abstract

The mineralocorticoid receptor (MR) is a member of the steroid receptor family and a critical regulator of blood pressure (BP). For years the mechanism was thought to be exclusively mediated by the renal effects of the hormone aldosterone on sodium and water homeostasis. However, studies put forward the pathological role of vascular MR in cardiovascular diseases (CVD). Mice with specific deletion of MR in smooth muscle cells (SMC-MR-KO) exhibit decreased BP with aging, reduced myogenic tone and agonist-dependent contraction on resistance arteries, despite unchanged renal MR function; these data clearly supports a physiological role for SMC-MR in control of vascular tone and BP. Moreover, deletion of SMC-MR prevented the increase in SMC proliferation and fibrosis induced by aldosterone after wire-induced carotid injury suggesting that SMC-MR is also involved in vascular response to injury. However, the deletion of SMC-MR does not modulate the progression of plaque size and vascular inflammation induced by subpressor dosis of aldosterone in atherosclerosis-prone apolipoprotein E-knockout mice (ApoE-KO). These data support the hypothesis that there are BP-independent and SMC-MR-independent mechanisms contributing to aldosterone-induced atherosclerosis. NADPH oxidase activation and eNOS uncoupling induced by MR activation in endothelial cells (EC) are potential mechanisms mediating vascular oxidative stress and endothelial dysfunction (ED) in CVD. However, controversial effects of aldosterone on NO production have been reported; and if EC-MR affects vascular contractility, endothelial function and BP is not clear yet. In the present study we propose to use the first mouse model with specific deletion of MR in EC to address the role of EC-MR in mediating ED and oxidative stress in resistance arteries from CVD mouse models of hypertension and atherosclerosis.

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

DAVEL, ANA P.; LU, QING; MOSS, M. ELIZABETH; RAO, SITARA; ANWAR, IMRAN J.; DUPONT, JENNIFER J.; JAFFE, IRIS Z.. Sex-Specific Mechanisms of Resistance Vessel Endothelial Dysfunction Induced by Cardiometabolic Risk Factors. JOURNAL OF THE AMERICAN HEART ASSOCIATION, v. 7, n. 4, FEB 20 2018. (14/26192-6)

DAVEL, ANA PAULA; MOSS, MARIA ELIZABETH; ANWAR, IMRAN; LU, QING; JAFFE, IRIS ZAMIR. SEX DIFFERENCES IN MECHANISMS OF RESISTANCE VESSEL ENDOTHELIAL DYSFUNCTION DUE TO CARDIOMETABOLIC RISK FACTORS AND THE ROLE OF ENDOTHELIAL MINERALOCORTICOID RECEPTORS. FASEB JOURNAL, v. 31, p. 1-pg., 2017-04-01. (14/26192-6)

LU, QING; DAVEL, ANA P.; MCGRAW, ADAM P.; RAO, SITARA P.; NEWFELL, BRENNA G.; JAFFE, IRIS Z.. PKC delta Mediates Mineralocorticoid Receptor Activation by Angiotensin II to Modulate Smooth Muscle Cell Function. Endocrinology, v. 160, n. 9, p. 2101-2114, SEP 2019. (14/26192-6)

DAVEL, ANA P.; ANWAR, IMRAN J.; JAFFE, IRIS Z.. The endothelial mineralocorticoid receptor: mediator of the switch from vascular health to disease. CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION, v. 26, n. 2, p. 97-104, MAR 2017. (14/26192-6)

DAVEL, ANA PAULA; JAFFE, IRIS Z.; TOSTES, RITA C.; JAISSER, FREDERIC; DE CHANTEMELE, ERIC J. BELIN. New roles of aldosterone and mineralocorticoid receptors in cardiovascular disease: translational and sex-specific effects. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 315, n. 4, p. H989-H999, OCT 2018. (14/26192-6, 17/10771-5)