Role of smooth muscle cell mineralocorticoid receptor in vascular tone

Abstract

Identification of the mineralocorticoid receptor (MR) in the vasculature (i.e., endothelial and smooth muscle cells) raised the question of its role in vascular function and blood pressure control. Using a mouse model with conditional inactivation of MR in vascular smooth muscle cell (VSMC) (MR(SMKO)), we have recently shown that the VSMC MR is crucial for aldosterone-salt-induced carotid stiffening. In the present study, we have investigated the specific contribution of the VSMC MR in the regulation of vascular tone in large vessels. In MR(SMKO) mice, contractions induced by potassium chloride and calcium (Ca(2+)) are decreased in the aorta, whereas contraction is normal in response to phenylephrine and caffeine. The difference in response to Ca(2+) suggests that the VSMC-specific deficiency of the MR modifies VSM Ca(2+) signaling but without altering the intracellular Ca(2+) store handling. The relaxation induced by acetylcholine is not affected by the absence of MR. However, the relaxation induced by Ach in the presence of indomethacin and the relaxation induced by sodium nitroprussiate are significantly reduced in MR(SMKO) mice compared to controls. Since endothelial nitric oxide synthase (eNOS) activity is increased in mutant mice, their altered relaxation reflects impairment of the nitric oxide (NO) signaling pathway. In addition to altered NO and Ca(2+) signaling, the activity of myosin light chain and its regulators, myosin light chain kinase (MLCK) and myosin phosphatase (MLCP), is reduced. In conclusion, MR expressed in VSMC is required for NO and Ca(2+) signaling pathways and contractile protein activity leading to an altered contraction/relaxation coupling.

Emerging Roles of the Mineralocorticoid Receptor in Pathology: Toward New Paradigms in Clinical Pharmacology

“…Indeed, the Cav1.2 agonist BayK8644 (1,4-Dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-3-pyridinecarboxylic acid, methyl ester) had lower vasoconstrictive effects in mesenteric arteries from aged VSMC-MR KO mice (McCurley et al, 2012). The impaired Ca 2+ signaling can affect the contractile machinery, as demonstrated by reduced phosphorylation of myosin phosphatasetargeting subunit 1, myosin light chain kinase, and myosin light chain 2 (Tarjus et al, 2015b).…”

L-DOPA sensitizes vasomotor tone by modulating the vascular alpha1-adrenergic receptor

“…To further investigate the mechanisms underlying inhibition of phenylephrine-induced vascular contraction by deletion of GPR143, we also examined phosphorylation levels of myosin light chain 2 (pMLC2) and ERK (pERK), a member of the MAPK family, in the WT and Gpr143 -/y intact vessels with or without phenylephrine ( Figure 4, A-C). Indeed, MLC2 and ERK phosphorylation is causally related to ADRA1-mediated contraction (19)(20)(21)(22). Because phenylephrine-induced pressor response was attenuated in Gpr143 -/y mice, we expected that phenylephrine-induced phosphorylation of these proteins was attenuated in Gpr143 -/y vessels.…”

Mineralocorticoid regulation of cell function: the role of rapid signalling and gene transcription pathways

“…The phosphorylation of MLC by MLCK is a necessary step in enabling actin-myosin coupling (Goulopoulou & Webb 2014) and occurs within 15 min of MR activation via PI3K signalling (Gros et al 2011a). The basal expression of genes coding for contractile elements, ion channels or signalling systems is unaffected by MR deletion in VSMC (Tarjus et al 2015a). However, MR does regulate Ca v 1.2 gene expression in mesenteric artery VSMC, an L-type calcium channel which increases vasomotor tone when active (McCurley et al 2012).…”

“…VSMC MR has a role in hypertension, with VSMC MR knockout mice having lower basal blood pressures (Galmiche et al 2014) and protection against age-related increases to systolic blood pressure (McCurley et al 2012). However, MR also is important for NO-mediated relaxation of VSMC, and increases cAMP that has a vasodilatory effect, which may be autoregulatory in the presence of functional endothelium (Christ et al 1999, Tarjus et al 2015a). …”

“…3, bottom section). If MR is deleted, cGMP-and calcium-dependent signalling is impaired with reduction in baseline activation of the contractile regulators myosin light chain kinase (MLCK) and myosin light chain (MLC) 2 (Tarjus et al 2015a). The phosphorylation of MLC by MLCK is a necessary step in enabling actin-myosin coupling (Goulopoulou & Webb 2014) and occurs within 15 min of MR activation via PI3K signalling (Gros et al 2011a).…”