Review
Mineralocorticoid receptors in vascular function and disease

https://doi.org/10.1016/j.mce.2011.06.014Get rights and content

Abstract

The mineralocorticoid receptor (MR), a member of the steroid receptor family, regulates blood pressure by mediating the effects of the hormone aldosterone (Aldo) on renal sodium handling. Over the past decade, it has become clear that MR is expressed in the cardiovascular system and interest has grown in understanding the direct role of the MR in regulating vascular function and contributing to cardiovascular disease. This interest stems from multiple clinical studies in which drugs that decrease MR activation also reduce the incidence of heart attacks, strokes, and mortality out of proportion to modest changes in systemic blood pressure. The presence of functional mineralocorticoid receptors in vascular smooth muscle and endothelial cells is now well established and, while still controversial, data supports the vasculature as an Aldo-responsive tissue. This review summarizes recent advances in our understanding of the role of vascular MR in regulating normal vascular function and in promoting vascular disease. In vitro data, in vivo animal studies, and human data are reviewed suggesting a role for MR-activation in promoting vascular oxidative stress, inhibiting vascular relaxation, and contributing to vessel inflammation, fibrosis, and remodeling. These detrimental vascular effects of MR activation appear to be independent of changes in blood pressure and are synergistic with the presence of endothelial dysfunction or damage. Thus, in humans with underlying cardiovascular disease or cardiovascular risk factors, vascular MR activation may promote vascular aging and atherosclerosis thereby contributing to the pathophysiology of heart attack, stroke, and possibly even hypertension. Further exploration of the molecular mechanisms for the detrimental vascular effects of MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders.

Highlights

► Mineralocorticoid receptors are expressed in vascular smooth muscle and endothelial cells. ► MR-activation promotes vascular oxidative stress and vascular contraction. ► MR-activation contributes to vessel inflammation, fibrosis, and remodeling. ► In humans with cardiovascular risk factors, vascular MR-activation may promote vascular aging and atherosclerosis.

Section snippets

Introduction: A role for mineralocorticoid receptors in clinical vascular outcomes

The mineralocorticoid receptor (MR), a member of the steroid receptor family, was identified 25 years ago as a critical regulator of blood pressure (BP) by mediating the effects of the hormone aldosterone (Aldo) on renal sodium handling (Rogerson and Fuller, 2000, Arriza et al., 1987). It has since become clear that MR is expressed in non-epithelial cells and interest has grown in understanding the direct role of MR in regulating vascular function and in contributing to cardiovascular diseases.

MR expression and function in the vasculature

The blood vessel is a layered structure with an inner intima, composed of a single layer of endothelial cells (EC) that line the lumen and contact circulating blood, a medial layer, composed of vascular smooth muscle cells (VSMC), and an outer adventitial layer, containing fibroblasts and extracellular matrix (ECM, see model in Fig. 2, top). In the late 1980s and early 1990s, studies demonstrated Aldo binding and MR expression in vascular cells and in whole vessels from animals and humans

MR, aldosterone, and vascular oxidative stress

The production of reactive oxygen species (ROS) by the vasculature, termed vascular oxidative stress, is a critical determinant of vascular function and a significant contributor to vascular pathology. Vascular oxidative stress is determined by the balance between vascular damaging ROS and vascular protective nitric oxide (NO). ROS are produced by vascular oxidases including NADPH oxidase, xanthine oxidase, mitochondrial oxidases, and by uncoupling of nitric oxide synthases (NOS) to produce ROS

The role of MR in vascular constriction and relaxation

While still controversial, it has recently been postulated that hypertension could arise from changes in vascular tone, independent of alterations in renal function (Mendelsohn, 2005). The presence of functional MR in blood vessels supports the possibility that MR activation could directly modulate vascular reactivity, and potentially BP, via vascular mechanisms in addition to regulation of renal sodium homeostasis. Vascular relaxation is mediated by dephosphorylation of myosin light-chain in

MR and vascular inflammation

Vascular inflammation plays a critical role in the pathogenesis of cardiovascular diseases including atherosclerosis and hypertensive vasculopathy. Direct activation of MR in human SMC and EC in vitro has been shown to promote inflammatory gene expression. Specifically, MR activation in human EC promotes expression of intracellular and vascular cell adhesion molecules (ICAM1 and VCAM1) resulting in enhanced leukocyte adhesion to human coronary EC (Caprio et al., 2008, Deuchar et al., 2011).

MR and vascular remodeling

Vascular remodeling is the pathologic response of the vessel to vascular damage and contributes to human ischemic vascular disease. Remodeling occurs when the endothelium is damaged by insults from cardiac risk factors such as cigarette smoke, diabetes, and hypertension or by mechanical injury such as balloon angioplasty and stent implantation during percutaneous revascularization. This damage initiates a cascade of events that constitute the vascular injury response, resulting in the

Summary and conclusions

The presence of functional mineralocorticoid receptors in the vasculature is now well established and, while still controversial, data supports the vasculature as an Aldo-responsive tissue. In vitro, animal, and human data support a role for MR-activation in promoting vascular cell oxidative stress, inflammation, proliferation, migration and ECM production thereby promoting vasoconstriction, atherosclerosis, vascular remodeling and fibrosis (see model in Fig. 2). The detrimental vascular

Conflict of interest

The authors have no conflict of interest to declare.

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