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Letter
Nature Medicine 14, 64 - 68 (2008)
Published online: 16 December 2007 | Corrected online: 9 January 2008 | doi:10.1038/nm1666
There is a Corrigendum (February 2008) associated with this Letter.
G12-G13–LARG–mediated signaling in vascular smooth muscle is required for salt-induced hypertension
Angela Wirth1, Zoltán Benyó1,2,7, Martina Lukasova1,7, Barbara Leutgeb1,6, Nina Wettschureck1, Stefan Gorbey3, Petra Örsy1, Béla Horváth1, Christiane Maser-Gluth1, Erich Greiner4,6, Björn Lemmer3, Günther Schütz4, J. Silvio Gutkind5 & Stefan Offermanns1
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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