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

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.

Change history

  • 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.

References

  1. Brown, R., Mullins, J. & Webb, D.J. Mechanisms and molecular pathways in hypertension. in Molecular Basis of Cardiovascular Disease (ed. Chien, K.R.) 566–647 (Saunders, Philadelphia, 2004).

    Google Scholar 

  2. Cowley, A.W., Jr. Long-term control of arterial blood pressure. Physiol. Rev. 72, 231–300 (1992).

    Article  Google Scholar 

  3. Lifton, R.P., Gharavi, A.G. & Geller, D.S. Molecular mechanisms of human hypertension. Cell 104, 545–556 (2001).

    Article  CAS  Google Scholar 

  4. Maguire, J.J. & Davenport, A.P. Regulation of vascular reactivity by established and emerging GPCRs. Trends Pharmacol. Sci. 26, 448–454 (2005).

    CAS  PubMed  Google Scholar 

  5. Gohla, A., Schultz, G. & Offermanns, S. Role for G12/G13 in agonist-induced vascular smooth muscle cell contraction. Circ. Res. 87, 221–227 (2000).

    Article  CAS  Google Scholar 

  6. Somlyo, A.P. & Somlyo, A.V. Ca2+ sensitivity of smooth muscle and nonmuscle myosin II: modulated by G proteins, kinases, and myosin phosphatase. Physiol. Rev. 83, 1325–1358 (2003).

    Article  CAS  Google Scholar 

  7. Chobanian, A.V. et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 42, 1206–1252 (2003).

    Article  CAS  Google Scholar 

  8. Ezzati, M. et al. Rethinking the “diseases of affluence” paradigm: global patterns of nutritional risks in relation to economic development. PLoS Med. 2, e133 (2005).

    Article  Google Scholar 

  9. O'Shaughnessy, K.M. & Karet, F.E. Salt handling and hypertension. J. Clin. Invest. 113, 1075–1081 (2004).

    Article  CAS  Google Scholar 

  10. Meneton, P., Jeunemaitre, X., de Wardener, H.E. & MacGregor, G.A. Links between dietary salt intake, renal salt handling, blood pressure and cardiovascular diseases. Physiol. Rev. 85, 679–715 (2005).

    Article  CAS  Google Scholar 

  11. Iwamoto, T. et al. Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle. Nat. Med. 10, 1193–1199 (2004).

    Article  CAS  Google Scholar 

  12. Dostanic, I. et al. The alpha2-isoform of Na-K-ATPase mediates ouabain-induced hypertension in mice and increased vascular contractility in vitro. Am. J. Physiol. Heart Circ. Physiol. 288, H477–H485 (2005).

    Article  CAS  Google Scholar 

  13. Blaustein, M.P., Zhang, J., Chen, L. & Hamilton, B.P. How does salt retention raise blood pressure? Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R514–R523 (2006).

    Article  CAS  Google Scholar 

  14. Narumiya, S., Ishizaki, T. & Watanabe, N. Rho effectors and reorganization of actin cytoskeleton. FEBS Lett. 410, 68–72 (1997).

    Article  CAS  Google Scholar 

  15. Fukata, Y., Amano, M. & Kaibuchi, K. Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells. Trends Pharmacol. Sci. 22, 32–39 (2001).

    Article  CAS  Google Scholar 

  16. Fukuhara, S., Chikumi, H. & Gutkind, J.S. RGS-containing RhoGEFs: the missing link between transforming G proteins and Rho? Oncogene 20, 1661–1668 (2001).

    Article  CAS  Google Scholar 

  17. Wettschureck, N. et al. Absence of pressure overload induced myocardial hypertrophy after conditional inactivation of Gαq/Gα11 in cardiomyocytes. Nat. Med. 7, 1236–1240 (2001).

    Article  CAS  Google Scholar 

  18. Moers, A. et al. G13 is an essential mediator of platelet activation in hemostasis and thrombosis. Nat. Med. 9, 1418–1422 (2003).

    Article  CAS  Google Scholar 

  19. Indra, A.K. et al. Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ERT and Cre-ERT2 recombinases. Nucleic Acids Res. 27, 4324–4327 (1999).

    Article  CAS  Google Scholar 

  20. Becknell, B. et al. Characterization of leukemia-associated Rho guanine nucleotide exchange factor (LARG) expression during murine development. Cell Tissue Res. 314, 361–366 (2003).

    Article  CAS  Google Scholar 

  21. Moriki, N. et al. RhoA activation in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. Hypertens. Res. 27, 263–270 (2004).

    Article  CAS  Google Scholar 

  22. Heximer, S.P. et al. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J. Clin. Invest. 111, 445–452 (2003).

    Article  CAS  Google Scholar 

  23. Tang, K.M. et al. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat. Med. 9, 1506–1512 (2003).

    Article  CAS  Google Scholar 

  24. Seasholtz, T.M. & Brown, J.H. Rho signaling in vascular diseases. Mol. Interv. 4, 348–357 (2004).

    Article  CAS  Google Scholar 

  25. Seko, T. et al. Activation of RhoA and inhibition of myosin phosphatase as important components in hypertension in vascular smooth muscle. Circ. Res. 92, 411–418 (2003).

    Article  CAS  Google Scholar 

  26. Uehata, M. et al. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature 389, 990–994 (1997).

    Article  CAS  Google Scholar 

  27. Amano, M., Fukata, Y. & Kaibuchi, K. Regulation and functions of Rho-associated kinase. Exp. Cell Res. 261, 44–51 (2000).

    Article  CAS  Google Scholar 

  28. Noma, K., Oyama, N. & Liao, J.K. Physiological role of ROCKs in the cardiovascular system. Am. J. Physiol. Cell Physiol. 290, C661–C668 (2006).

    Article  CAS  Google Scholar 

  29. Khalil, R.A. Dietary salt and hypertension: new molecular targets add more spice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R509–R513 (2006).

    Article  CAS  Google Scholar 

  30. Mills, P.A. et al. A new method for measurement of blood pressure, heart rate, and activity in the mouse by radiotelemetry. J. Appl. Physiol. 88, 1537–1544 (2000).

    Article  CAS  Google Scholar 

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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.

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Authors and Affiliations

Authors

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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