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) (MRSMKO), 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 MRSMKO mice, contractions induced by potassium chloride and calcium (Ca2+) are decreased in the aorta, whereas contraction is normal in response to phenylephrine and caffeine. The difference in response to Ca2+ suggests that the VSMC-specific deficiency of the MR modifies VSM Ca2+ signaling but without altering the intracellular Ca2+ 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 MRSMKO 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 Ca2+ 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 Ca2+ signaling pathways and contractile protein activity leading to an altered contraction/relaxation coupling.
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Funding
This work was supported by the “Institut National pour la Santé et Recherche Médicale” and grants from the “Agence Nationale pour la Recherche” [ANR09-BLAN-0156-01], the “Centre de Recherche Industrielle et Technique,” and the Fondation de France. A. Tarjus was recipient of a PhD fellowship of the Université Pierre et Marie Curie. E. Belozertseva was recipient of a PhD fellowship of the “Agence Nationale pour la Recherche” [ANR-13-BSV1-0026-01].
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Frédéric Jaisser and Guillaume Galmiche equally contributed to this study.
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Tarjus, A., Belozertseva, E., Louis, H. et al. Role of smooth muscle cell mineralocorticoid receptor in vascular tone. Pflugers Arch - Eur J Physiol 467, 1643–1650 (2015). https://doi.org/10.1007/s00424-014-1616-x
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DOI: https://doi.org/10.1007/s00424-014-1616-x