ReviewMineralocorticoid receptors in vascular function and disease
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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