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Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors

Nature Medicine volume 18, pages 1429–1433 (2012)Cite this article

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Abstract

Hypertension is a cardiovascular risk factor present in over two-thirds of people over age 60 in North America; elevated blood pressure correlates with increased risk of heart attack, stroke and progression to heart and kidney failure. Current therapies are insufficient to control blood pressure in almost half of these patients1,2. The mineralocorticoid receptor (MR), acting in the kidney, is known to regulate blood pressure through aldosterone binding and stimulation of sodium retention3. However, recent studies support the concept that the MR also has extrarenal actions4,5,6,7 and that defects in sodium handling alone do not fully explain the development of hypertension and associated cardiovascular mortality8,9. We and others have identified functional MR in human vascular smooth muscle cells (SMCs)10,11, suggesting that vascular MR might directly regulate blood pressure. Here we show that mice with SMC-specific deficiency of the MR have decreased blood pressure as they age without defects in renal sodium handling or vascular structure. Aged mice lacking MR in SMCs (SMC-MR) have reduced vascular myogenic tone, agonist-dependent contraction and expression and activity of L-type calcium channels. Moreover, SMC-MR contributes to angiotensin II–induced vascular oxidative stress, vascular contraction and hypertension. This study identifies a new role for vascular MR in blood pressure control and in vascular aging and supports the emerging hypothesis that vascular tone contributes directly to systemic blood pressure.

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Figure 1: Lower blood pressure in aged mice with SMC-specific MR deficiency.
Figure 2: Intact renal MR function in SMC-MR–deficient mice.
Figure 3: Normal vascular structure with decreased tone in mice with SMC-specific MR deficiency.
Figure 4: SMC-MR contributes to the hypertensive, contractile and oxidative stress responses to AngII.

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Acknowledgements

We thank the Mouse Clinical Institute (Illkirch) for help in generating MRf/f mice, Y. Yang, A. Stupica and Z. Nourian for technical assistance, and J.D. Jaffe for assistance with figures. This work was supported by grants from the US National Institutes of Health (HL095590 to I.Z.J., HL092241 to M.A.H. and T32 HL069770) and the American Heart Association (11GRNT7240000 to I.Z.J. and 11POST7590096 to A.M.).

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Authors and Affiliations

  1. Molecular Cardiology Research Institute, Tufts Medical Center, Boston, Massachusetts, USA

    Amy McCurley, Mark Aronovitz, Michael E Mendelsohn & Iris Z Jaffe

  2. Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA

    Paulo W Pires & Anne M Dorrance

  3. Department of Internal Medicine, University of Missouri School of Medicine, Columbia, Missouri, USA

    Shawn B Bender

  4. College of Medical Sciences, Nova Southeastern University, Fort Lauderdale, Florida, USA

    Michelle J Zhao

  5. Institut de Génétique et de Biologie Moléculaire et Cellulaire, (Centre National de la Recherche Scientifique/Institut National de la Santé et de la Recherche Medicale/Université de Strasbourg/Collège de France), Illkirch, France

    Daniel Metzger & Pierre Chambon

  6. Dalton Cardiovascular Research Center and Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, Missouri, USA

    Michael A Hill

  7. Merck Research Laboratories, Rahway, New Jersey, USA

    Michael E Mendelsohn

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  1. Amy McCurley
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Contributions

A.M., M.A.H., M.E.M. and I.Z.J. designed the experiments. A.M., P.W.P., S.B.B., M.A., M.J.Z. and A.M.D. obtained the data and analyzed it with advice from I.Z.J. D.M. and P.C. created the MRf/f and SMA-Cre-ERT2 mice. A.M. and I.Z.J. wrote the manuscript. All authors participated in discussion, contributed ideas and edited the manuscript.

Corresponding author

Correspondence to Iris Z Jaffe.

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Competing interests

M.E.M. is employed by Merck and retains an academic appointment at Tufts University School of Medicine.

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McCurley, A., Pires, P., Bender, S. et al. Direct regulation of blood pressure by smooth muscle cell mineralocorticoid receptors. Nat Med 18, 1429–1433 (2012). https://doi.org/10.1038/nm.2891

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