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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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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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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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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DOI: https://doi.org/10.1038/nm.2079
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