Rapid Aldosterone Signaling and Vascular Reactivity: Relax or Don't Do It

Leopold, Jane A.

doi:10.1097/fjc.0b013e3181c37ddc

Cited by 6 publications

(9 citation statements)

References 34 publications

(30 reference statements)

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“…Aldosterone has been reported to mediate rapid endothelium-dependent vasodilation and consequent increased limb blood flow in vivo (25) and endothelium-dependent attenuation of vasoconstrictor responses in vitro (27). The effects on vascular reactivity mediated by the GPER agonist G1 parallel those mediated by aldosterone (17,20). In contrast, aldosterone-mediated vasoconstrictor effects have also been reported (1).…”

Section: Discussionmentioning

confidence: 81%

“…Effects of aldosterone on a diverse range of endothelial cell functions, including NOS-dependent vasodilation (22), cell swelling and stiffness (17,25), and growth-regulatory pathways (22), have been reported. The receptor mechanisms underlying these effects have not been determined or have been presumed to be due to activation of classic or membrane-associated MRs, on the basis of the inhibitory effects of presumed mineralocorticoid-specific or selective antagonists such as eplerenone and spironolactone (20). However, with the appreciation that these aldosterone antagonists can also inhibit GPER-mediated effects, the experimental basis for attributing, a priori, all the endothelium-dependent actions of aldosterone to the classic MR should be viewed as suspect (14).…”

Section: Discussionmentioning

confidence: 99%

“…In vascular tissues, the rapid effects of aldosterone have been linked to regulation of vascular contractility (vasodilator and vasoconstrictor) via regulation of endothelial nitric oxide synthase (NOS) (16,20,22,24) and vascular smooth muscle cell (VSMC) myosin light chain phosphorylation (13), regulation of MAP kinase (22), and regulation of apoptosis (14). These effects occurred over a time course (Ͻ15 min) not consistent with transcriptional mechanisms (8).…”

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confidence: 99%

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Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation

Gros

Ding

Liu

et al. 2013

American Journal of Physiology-Cell Physiology

149

144

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The importance of the rapid vascular effects of aldosterone is increasingly appreciated. Through these rapid pathways, aldosterone has been shown to regulate vascular contractility, cell growth, and apoptosis. In our most recent studies, we demonstrated the effects of aldosterone on cell growth and contractility in vascular smooth muscle cells. We showed that these effects could occur via activation of the classic mineralocorticoid receptor, as well the recently characterized G protein-coupled estrogen receptor (GPER), initially characterized as an estrogen-specific receptor. However, the mechanisms underlying aldosterone's endothelium-dependent actions are unknown. Furthermore, the ERK regulatory and proapoptotic effects of aldosterone mediated by GPER activation in cultured vascular smooth muscle cells were only apparent when GPER was reintroduced into these cells by gene transfer. Whether GPER activation via aldosterone might be an important regulator in native vascular cells has been questioned. Therefore, to determine the role of GPER in mediating aldosterone's effects on cell growth and vascular reactivity in native cells, we examined rat aortic vascular endothelial cells, a model characterized by persistent robust expression of GPER, but without detectable mineralocorticoid receptor expression. In these endothelial cells, the GPER agonist G1 mediates a rapid increase in ERK phosphorylation that is wholly GPER-dependent, paralleling the actions of aldosterone. The effects of G1 and aldosterone to stimulate ERK phosphorylation paralleled their proapoptotic and antiproliferative effects. In previous studies, we reported that aldosterone mediates a rapid endothelium-dependent vasodilatory effect, antagonistic to its direct vasoconstrictor effect in endothelium-denuded preparations. Using a rat aortic ring/organ bath preparation to determine the GPER dependence of aldosterone's endothelium-dependent vasodilator effects, we demonstrate that aldosterone inhibits phenylephrine-mediated contraction. This vasodilator effect parallels the actions of the GPER agonist G1. Furthermore, the effects of aldosterone were completely ablated by the GPER antagonist G15. These data support an important role of GPER activation in aldosterone-mediated regulation of endothelial cell growth, as well as in aldosterone's endothelium-mediated regulation of vasoreactivity.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation

Gros

Ding

Liu

et al. 2013

American Journal of Physiology-Cell Physiology

149

144

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“…In EC, Aldo also reduces expression of glucose-6-phosphate dehydrogenase (G6PD), a critical regulator of the intracellular redox state, thereby increasing oxidative stress (Leopold et al, 2007). Although there is some conflicting data in this area, most studies support that MR activation in EC decreases eNOS activity and NO production, further contributing to oxidative stress ((Liu et al, 2003) (Mutoh et al, 2008; Nagata et al, 2006a)and reviewed in (Leopold, 2009)). MR-enhanced vascular oxidative stress has important consequences for vascular cell function.…”

Section: Mr Aldosterone and Vascular Oxidative Stressmentioning

confidence: 99%

“…As summarized in Table 1, MR activation in vascular SMC and EC increases ROS and decreases bioavailable NO and thus would be expected to promote VSMC contraction by decreasing GC activity. In addition, MR activation in cultured VSMC may directly promote SMC contraction by post-translational modification of soluble GC making it unresponsive to NO or by directly promoting calcium mobilization ((Maron et al, 2009; Leopold, 2009; Michea et al, 2005), see Table 2). …”

Section: The Role Of Mr In Vascular Constriction and Relaxationmentioning

confidence: 99%

Mineralocorticoid receptors in vascular function and disease

McCurley

Jaffe

2012

Molecular and Cellular Endocrinology

153

163

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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.

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Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease

McCurley

McGraw

Pruthi

et al. 2013

Pflugers Arch - Eur J Physiol

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The mineralocorticoid receptor (MR), a member of the steroid receptor family, regulates blood pressure by mediating the effects of the hormone aldosterone on renal sodium handling. In recent years, it has become clear that MR is expressed in vascular smooth muscle cells (SMC) and interest has grown in understanding the direct role of SMC MR in regulating vascular function. This interest stems from multiple clinical studies where MR inhibitor treatment reduced the incidence of cardiovascular events and mortality. This review summarizes the most recent advances in our understanding of SMC MR in regulating normal vascular function and in promoting vascular disease. Many new studies suggest a role for SMC MR-activation in stimulating vascular contraction, 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, SMC MR activation may promote hypertension, atherosclerosis, and vascular aging. Further exploration of the molecular mechanisms for the effects of SMC MR activation has the potential to identify novel therapeutic targets to prevent or treat common cardiovascular disorders.

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Rapid Aldosterone Signaling and Vascular Reactivity: Relax or Don't Do It

Cited by 6 publications

References 34 publications

Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation

Aldosterone mediates its rapid effects in vascular endothelial cells through GPER activation

Mineralocorticoid receptors in vascular function and disease

Smooth muscle cell mineralocorticoid receptors: role in vascular function and contribution to cardiovascular disease

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