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G12-G13–LARG–mediated signaling in vascular smooth muscle is required for salt-induced hypertension

Nature Medicine volume 14, pages 64–68 (2008)Cite this article

A Corrigendum to this article was published on 01 February 2008

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Abstract

The tone of vascular smooth muscle cells is a primary determinant of the total peripheral vascular resistance and hence the arterial blood pressure. Most forms of hypertension ultimately result from an increased vascular tone that leads to an elevated total peripheral resistance1,2,3. Regulation of vascular resistance under normotensive and hypertensive conditions involves multiple mediators, many of which act through G protein–coupled receptors on vascular smooth muscle cells4. Receptors that mediate vasoconstriction couple with the G-proteins Gq-G11 and G12-G13 to stimulate phosphorylation of myosin light chain (MLC) via the Ca2+/MLC kinase– and Rho/Rho kinase–mediated signaling pathways, respectively4,5,6. Using genetically altered mouse models that allow for the acute abrogation of both signaling pathways by inducible Cre/loxP-mediated mutagenesis in smooth muscle cells, we show that Gq-G11–mediated signaling in smooth muscle cells is required for maintenance of basal blood pressure and for the development of salt-induced hypertension. In contrast, lack of G12-G13, as well as of their major effector, the leukemia-associated Rho guanine nucleotide exchange factor (LARG), did not alter normal blood pressure regulation but did block the development of salt-induced hypertension. This identifies the G12-G13–LARG–mediated signaling pathway as a new target for antihypertensive therapies that would be expected to leave normal blood pressure regulation unaffected.

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Figure 1: Generation of mice with smooth muscle–specific Gαq-Gα11 and Gα12-Gα13 deficiency and in vitro analysis.
Figure 2: Basal blood pressure and pressor responses of smooth muscle–specific Gαq-Gα11– and Gα12-Gα13–deficient mice.
Figure 3: The role of Gαq-Gα11 and Gα12-Gα13 in DOCA-salt–induced hypertension.
Figure 4: Role of LARG in DOCA-salt–induced hypertension.

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  • 09 January 2008

    In the version of this article initially published, the name of one author was incorrectly listed as Silvio Gutkind. The correct name is J. Silvio Gutkind. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

The authors are grateful to M. Ritzal and T. Németh for their expert technical assistance. Z.B. and B.H. were supported by a Marie Curie Individual Fellowship and a European Molecular Biology Organization Fellowship, respectively. This work was supported by the Deutsche Forschungsgemeinschaft (Of 19/9) and the Fonds der Chemischen Industrie.

Author information

Author notes

  1. Barbara Leutgeb & Erich Greiner

    Present address: Present addresses: Solvay Arzneimittel GmbH, Hans-Böckler-Allee 20, 30173 Hannover, Germany (B.L.); EvotecOAI AG, Schnackenburgallee 114, 22525 Hamburg, Germany (E.G.).,

  2. Zoltán Benyó and Martina Lukasova: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, Heidelberg, 69120, Germany

    Angela Wirth, Zoltán Benyó, Martina Lukasova, Barbara Leutgeb, Nina Wettschureck, Petra Örsy, Béla Horváth, Christiane Maser-Gluth & Stefan Offermanns

  2. Institute of Human Physiology and Clinical Experimental Research, Semmelweis University, Üllöi ut 78/A, Budapest, 1082, Hungary

    Zoltán Benyó

  3. Institute of Pharmacology, Medical Faculty Mannheim, University of Heidelberg, Maybachstrasse 14, Mannheim, 68169, Germany

    Stefan Gorbey & Björn Lemmer

  4. Division of Molecular Biology of the Cell 1, German Cancer Research Center, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany

    Erich Greiner & Günther Schütz

  5. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, 20892-4340, Maryland, USA

    J. Silvio Gutkind

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Contributions

A.W. planned and performed most in vivo experiments, analyzed SMMHC-CreERT2 mice and was involved in writing the manuscript, Z.B. and M.L. planned and performed most in vitro experiments, B.L. helped generate and analyze SMMHC-CreERT2 mice, N.W. and S.G. helped perform in vivo experiments, P.Ö. and B.H. helped perform in vitro experiments, C.M.-G. performed DOCA level determinations, E.G. helped generate SMMHC-CreERT2 mice, B.L. helped perform in vivo experiments, G.S. helped generate SMMHC-CreERT2 mice, S.G. generated LARG-deficient mice, and S.O. planned and supervised the project and wrote the manuscript.

Corresponding author

Correspondence to Stefan Offermanns.

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Supplementary Figs. 1–3 and Supplementary Methods (PDF 299 kb)

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Wirth, A., Benyó, Z., Lukasova, M. et al. G12-G13–LARG–mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat Med 14, 64–68 (2008). https://doi.org/10.1038/nm1666

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