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The role of Rho protein signaling in hypertension

Abstract

Arterial hypertension is a common health problem that affects 25% of the adult population in industrialized societies, and is a major risk factor for myocardial infarction and stroke. However, the pathogenesis of hypertension, as well as the basic mechanisms of blood-pressure control, are insufficiently understood. Although the development of hypertension is complex, involving many different mechanisms, including dysregulation of the autonomic nervous system, renal function, and the balance between water and electrolytes, and increased vascular tone and the resulting rise in peripheral vascular resistance are major determinants of the elevated arterial pressure in hypertension. Since the discovery of the essential role of RhoA and its downstream target, Rho kinase, in the regulation of vascular tone, as well as the antihypertensive effect of a Rho kinase inhibitor, much evidence has accumulated to implicate activation of Rho family proteins in the pathogenesis of hypertension. RhoA remains the most-analyzed member of the Rho proteins in the context of vascular physiology and hypertension, but evidence is accumulating that also points to a role of Rac1 in arterial pathophysiology. In this Review, we discuss progress in our understanding of the role of Rho proteins and their regulators in the pathogenesis of high blood pressure.

Key Points

  • Arterial hypertension affects 25% of the adult population in industrialized societies

  • The Rho proteins RhoA and Rac1 participate to the control of blood pressure through multiple mechanisms both in the arterial wall and the central nervous system

  • RhoA activation is involved in the pathogenesis of hypertension in multiple animal models and in humans

  • Inhibition of the RhoA target Rho kinase reduces blood pressure in animal models of hypertension and decreases forearm vascular resistance in patients with essential hypertension

  • Genetic models of disruption of Rho protein signaling display abnormal blood pressure or resistance to hypertensive conditions

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Figure 1: Regulation of Rho protein signaling.
Figure 2: Role of RhoA and Rac1 signaling in crosstalk between endothelial cells and SMCs.
Figure 3: Effects involved in the hypertensive action of RhoA and its target Rho kinase.
Figure 4: Effects involved in the hypertensive action of Rac1.
Figure 5: Roles of Arhgef1 and Arhgef12 in Ang-II-dependent and salt-dependent hypertension.
Figure 6: Mechanisms involved in the inhibitory effects of Vav2 and Vav3 on blood pressure, identified from studies in knock-out mice, which have hypertension.

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Acknowledgements

The authors are 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.

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G. Loirand and P. Pacaud contributed to discussion of content for the article, researched data to include in the manuscript, wrote, reviewed and edited the manuscript before submission, and revised the manuscript in response to the peer-reviewers' comments.

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Correspondence to Gervaise Loirand.

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Loirand, G., Pacaud, P. The role of Rho protein signaling in hypertension. Nat Rev Cardiol 7, 637–647 (2010). https://doi.org/10.1038/nrcardio.2010.136

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