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The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure

Nature Medicine volume 16, pages 183–190 (2010)Cite this article

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Abstract

Hypertension is one of the most frequent pathologies in the industrialized world. Although recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. Increased activity of the monomeric G protein RhoA in arteries is a common feature of hypertension. However, how RhoA is activated and whether it has a causative role in hypertension remains unclear. Here we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for angiotensin II–induced activation of RhoA signaling in arterial smooth muscle cells. We found that angiotensin II activates Arhgef1 through a previously undescribed mechanism in which Jak2 phosphorylates Tyr738 of Arhgef1. Arhgef1 inactivation in smooth muscle induced resistance to angiotensin II–dependent hypertension in mice, but did not affect normal blood pressure regulation. Our results show that control of RhoA signaling through Arhgef1 is central to the development of angiotensin II–dependent hypertension and identify Arhgef1 as a potential target for the treatment of hypertension.

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Figure 1: The RhoA exchange factor Arhgef1 is activated by Ang II in rat aortic smooth muscle cells and mediates Ang II–induced RhoA activation.
Figure 2: Ang II–induced Arhgef1 activation is mediated by Tyr738 phosphorylation of Arhgef1.
Figure 3: Ang II–induced Tyr738 phosphorylation of Arhgef1 is mediated by Jak2.
Figure 4: Smooth muscle cell–specific Arhgef1 inactivation prevents Ang II induced RhoA signaling activation and contraction in arteries.
Figure 5: Smooth muscle cell–specific Arhgef1 deficiency prevents Ang II–induced acute rise in blood pressure and Ang II–dependent hypertension.
Figure 6: Arhgef1 deletion in smooth muscle or Jak2 inhibition reverses Ang II–induced hypertension.

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References

  1. Staessen, J.A., Wang, J., Bianchi, G. & Birkenhager, W.H. Essential hypertension. Lancet 361, 1629–1641 (2003).

    Article  Google Scholar 

  2. de Gasparo, M., Catt, K.J., Inagami, T., Wright, J.W. & Unger, T. International union of pharmacology. XXIII. The angiotensin II receptors. Pharmacol. Rev. 52, 415–472 (2000).

    CAS  PubMed  Google Scholar 

  3. Touyz, R.M. & Berry, C. Recent advances in angiotensin II signaling. Braz. J. Med. Biol. Res. 35, 1001–1015 (2002).

    Article  CAS  Google Scholar 

  4. Chrissobolis, S. & Sobey, C.G. Evidence that Rho-kinase activity contributes to cerebral vascular tone in vivo and is enhanced during chronic hypertension: comparison with protein kinase C. Circ. Res. 88, 774–779 (2001).

    Article  CAS  Google Scholar 

  5. Mukai, Y. et al. Involvement of Rho-kinase in hypertensive vascular disease: a novel therapeutic target in hypertension. FASEB J. 15, 1062–1064 (2001).

    Article  CAS  Google Scholar 

  6. 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 

  7. 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 

  8. Masumoto, A. et al. Possible involvement of Rho-kinase in the pathogenesis of hypertension in humans. Hypertension 38, 1307–1310 (2001).

    Article  CAS  Google Scholar 

  9. Jaffe, A.B. & Hall, A. Rho GTPases: biochemistry and biology. Annu. Rev. Cell Dev. Biol. 21, 247–269 (2005).

    Article  CAS  Google Scholar 

  10. 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 

  11. Loirand, G., Guerin, P. & Pacaud, P. Rho kinases in cardiovascular physiology and pathophysiology. Circ. Res. 98, 322–334 (2006).

    Article  CAS  Google Scholar 

  12. Kataoka, C. et al. Important role of Rho-kinase in the pathogenesis of cardiovascular inflammation and remodeling induced by long-term blockade of nitric oxide synthesis in rats. Hypertension 39, 245–250 (2002).

    Article  CAS  Google Scholar 

  13. 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 

  14. Higashi, M. et al. Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system. Circ. Res. 93, 767–775 (2003).

    Article  CAS  Google Scholar 

  15. Rossman, K.L., Der, C.J. & Sondek, J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat. Rev. Mol. Cell Biol. 6, 167–180 (2005).

    Article  CAS  Google Scholar 

  16. Bos, J.L., Rehmann, H. & Wittinghofer, A. GEFs and GAPs: critical elements in the control of small G proteins. Cell 129, 865–877 (2007).

    Article  CAS  Google Scholar 

  17. Garcia-Mata, R. et al. Analysis of activated GAPs and GEFs in cell lysates. Methods Enzymol. 406, 425–437 (2006).

    Article  CAS  Google Scholar 

  18. Mehta, P.K. & Griendling, K.K. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am. J. Physiol. Cell Physiol. 292, C82–C97 (2007).

    Article  CAS  Google Scholar 

  19. Rubtsov, A. et al. Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response. Immunity 23, 527–538 (2005).

    Article  CAS  Google Scholar 

  20. Wirth, A. et al. G12–G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat. Med. 14, 64–68 (2008).

    Article  CAS  Google Scholar 

  21. Fukuhara, S., Murga, C., Zohar, M., Igishi, T. & Gutkind, J.S. A novel PDZ domain containing guanine nucleotide exchange factor links heterotrimeric G proteins to Rho. J. Biol. Chem. 274, 5868–5879 (1999).

    Article  CAS  Google Scholar 

  22. Kozasa, T. et al. p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13. Science 280, 2109–2111 (1998).

    Article  CAS  Google Scholar 

  23. Suzuki, N., Nakamura, S., Mano, H. & Kozasa, T. Galpha 12 activates Rho GTPase through tyrosine-phosphorylated leukemia-associated RhoGEF. Proc. Natl. Acad. Sci. USA 100, 733–738 (2003).

    Article  CAS  Google Scholar 

  24. Fukuhara, S., Chikumi, H. & Gutkind, J.S. Leukemia-associated Rho guanine nucleotide exchange factor (LARG) links heterotrimeric G proteins of the G(12) family to Rho. FEBS Lett. 485, 183–188 (2000).

    Article  CAS  Google Scholar 

  25. Wells, C.D. et al. Mechanisms for reversible regulation between G13 and Rho exchange factors. J. Biol. Chem. 277, 1174–1181 (2002).

    Article  CAS  Google Scholar 

  26. Frank, G.D. et al. Requirement of Ca(2+) and PKCdelta for Janus kinase 2 activation by angiotensin II: involvement of PYK2. Mol. Endocrinol. 16, 367–377 (2002).

    CAS  PubMed  Google Scholar 

  27. Marrero, M.B. et al. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature 375, 247–250 (1995).

    Article  CAS  Google Scholar 

  28. Ohtsu, H. et al. Central role of Gq in the hypertrophic signal transduction of angiotensin II in vascular smooth muscle cells. Endocrinology 149, 3569–3575 (2008).

    Article  CAS  Google Scholar 

  29. Keys, J.R., Greene, E.A., Koch, W.J. & Eckhart, A.D. Gq-coupled receptor agonists mediate cardiac hypertrophy via the vasculature. Hypertension 40, 660–666 (2002).

    Article  CAS  Google Scholar 

  30. Marrero, M.B. et al. Role of Janus kinase/signal transducer and activator of transcription and mitogen-activated protein kinase cascades in angiotensin II- and platelet-derived growth factor-induced vascular smooth muscle cell proliferation. J. Biol. Chem. 272, 24684–24690 (1997).

    Article  CAS  Google Scholar 

  31. Shaw, S. et al. High glucose augments the angiotensin II-induced activation of JAK2 in vascular smooth muscle cells via the polyol pathway. J. Biol. Chem. 278, 30634–30641 (2003).

    Article  CAS  Google Scholar 

  32. Banes-Berceli, A.K. et al. Angiotensin II and endothelin-1 augment the vascular complications of diabetes via JAK2 activation. Am. J. Physiol. Heart Circ. Physiol. 293, H1291–H1299 (2007).

    Article  CAS  Google Scholar 

  33. Garcia-Mata, R. & Burridge, K. Catching a GEF by its tail. Trends Cell Biol. 17, 36–43 (2007).

    Article  CAS  Google Scholar 

  34. Fujii, A.M. & Vatner, S.F. Direct versus indirect pressor and vasoconstrictor actions of angiotensin in conscious dogs. Hypertension 7, 253–261 (1985).

    Article  CAS  Google Scholar 

  35. Rowe, B.P., Noble, A.R. & Munday, K.A. Blockade of pressor responses to angiotensins I and II and noradrenaline using phentolamine, propranolol and hexamethonium in conscious rabbits. Pflugers Arch. 382, 269–274 (1979).

    Article  CAS  Google Scholar 

  36. Cline, W.H. Jr. Role of released catecholamines in the vascular response to injected angiotensin II in the dog. J. Pharmacol. Exp. Ther. 216, 104–110 (1981).

    CAS  PubMed  Google Scholar 

  37. Ferrario, C.M., Barnes, K.L., Szilagyi, J.E. & Brosnihan, K.B. Physiological and pharmacological characterization of the area postrema pressor pathways in the normal dog. Hypertension 1, 235–245 (1979).

    Article  CAS  Google Scholar 

  38. Falcon, J.C. II, Phillips, M.I., Hoffman, W.E. & Brody, M.J. Effects of intraventricular angiotensin II mediated by the sympathetic nervous system. Am. J. Physiol. 235, H392–H399 (1978).

    CAS  PubMed  Google Scholar 

  39. Crowley, S.D. et al. Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney. Proc. Natl. Acad. Sci. USA 103, 17985–17990 (2006).

    Article  CAS  Google Scholar 

  40. Ruilope, L.M., Lahera, V., Rodicio, J.L. & Carlos Romero, J. Are renal hemodynamics a key factor in the development and maintenance of arterial hypertension in humans? Hypertension 23, 3–9 (1994).

    Article  CAS  Google Scholar 

  41. Schiffrin, E.L. Effects of aldosterone on the vasculature. Hypertension 47, 312–318 (2006).

    Article  CAS  Google Scholar 

  42. Lemarie, C.A., Paradis, P. & Schiffrin, E.L. New insights on signaling cascades induced by cross-talk between angiotensin II and aldosterone. J. Mol. Med. 86, 673–678 (2008).

    Article  CAS  Google Scholar 

  43. Montezano, A.C. et al. Aldosterone and angiotensin II synergistically stimulate migration in vascular smooth muscle cells through c-Src-regulated redox-sensitive RhoA pathways. Arterioscler. Thromb. Vasc. Biol. 28, 1511–1518 (2008).

    Article  CAS  Google Scholar 

  44. Hein, L. et al. Overexpression of angiotensin AT1 receptor transgene in the mouse myocardium produces a lethal phenotype associated with myocyte hyperplasia and heart block. Proc. Natl. Acad. Sci. USA 94, 6391–6396 (1997).

    Article  CAS  Google Scholar 

  45. Paradis, P., Dali-Youcef, N., Paradis, F.W., Thibault, G. & Nemer, M. Overexpression of angiotensin II type I receptor in cardiomyocytes induces cardiac hypertrophy and remodeling. Proc. Natl. Acad. Sci. USA 97, 931–936 (2000).

    Article  CAS  Google Scholar 

  46. Struthers, A.D. & MacDonald, T.M. Review of aldosterone- and angiotensin II-induced target organ damage and prevention. Cardiovasc. Res. 61, 663–670 (2004).

    Article  CAS  Google Scholar 

  47. Feng, J. et al. Inhibitory phosphorylation site for Rho-associated kinase on smooth muscle myosin phosphatase. J. Biol. Chem. 274, 37385–37390 (1999).

    Article  CAS  Google Scholar 

  48. Ren, X.D., Kiosses, W.B. & Schwartz, M.A. Regulation of the small GTP-binding protein Rho by cell adhesion and the cytoskeleton. EMBO J. 18, 578–585 (1999).

    Article  CAS  Google Scholar 

  49. 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 

  50. Krege, J.H., Hodgin, J.B., Hagaman, J.R. & Smithies, O. A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension 25, 1111–1115 (1995).

    Article  CAS  Google Scholar 

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Acknowledgements

The authors are grateful to K. Burridge (University of North Carolina, Chapel Hill), V. Perrot (University of Rouen) and J. Ihle (St. Jude Children's Research Hospital, Memphis) for providing us with GST-RhoA constructs, Arhgef1 and Jak2 plasmids, respectively. We thank C. Schleder, N. Vaillant and M. Rio for excellent technical assistance and the IBISA platform Cardiex for functional explorations. This work was supported by the Institut National de la Santé et de la Recherche Médicale, the Agence Nationale de la Recherche (ANR-05-PCOD-015-01 and ANR-08-GENO-040-01), the Fondation pour la Recherche Médicale (Dequation (20051205767)), the Programme National de Recherche Maladies Cardiovasculaires and the Société Française d'hypertension artérielle (PNRC 2007), the Centre National de la Recherche Scientifique (Groupement de Recherche 2823) and the Institut de Recherches Servier.

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Author notes

  1. Christophe Guilluy and Jérémy Brégeon: These authors contributed equally to this work.

Authors and Affiliations

  1. Inserm, U915, Nantes, France.,

    Christophe Guilluy, Jérémy Brégeon, Gilles Toumaniantz, Malvyne Rolli-Derkinderen, Pierre Pacaud & Gervaise Loirand

  2. University of Nantes, l'institut du thorax, Nantes, France

    Christophe Guilluy, Jérémy Brégeon, Gilles Toumaniantz, Malvyne Rolli-Derkinderen, Pierre Pacaud & Gervaise Loirand

  3. Inserm, U771 and CNRS UMR6214, Faculté de Médecine Angers, France

    Kevin Retailleau, Laurent Loufrani & Daniel Henrion

  4. Institut de Recherches Servier, Suresnes, France

    Elizabeth Scalbert & Antoine Bril

  5. Integrated Department of Immunology, University of Colorado, Denver, Colorado, USA

    Raul M Torres

  6. Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

    Stephan Offermanns

  7. CHU Nantes, l'institut du thorax, Nantes, France

    Gervaise Loirand

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Contributions

C.G. contributed to study design and performed all experiments with J.B. G.T. and M.R.-D. collaborated on in vitro experiments, proteomics and pulldown analyses. K.R., L.L. and D.H. collaborated on ex vivo contraction measurements. E.S. and A.B. helped with the organization of the study. R.M.T. and S.O. generated Arhgef1lox/lox mice and SMMHC-CreERT2 mice, respectively. P.P. and G.L. planned and directed the study and wrote the manuscript.

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Correspondence to Pierre Pacaud or Gervaise Loirand.

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Guilluy, C., Brégeon, J., Toumaniantz, G. et al. The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure. Nat Med 16, 183–190 (2010). https://doi.org/10.1038/nm.2079

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