Salt is well known to promote hypertension, but the mechanisms involved in regulating the tone of arterial smooth muscle are poorly characterized. This is particularly true with regard to our understanding of whether similar or distinct mechanisms are responsible for regulating both basal blood pressure and salt-induced hypertension. Phosphorylation of myosin light chain (MLC) is critical for the vascular constriction that is associated with hypertension. Many receptors promote the phosphorylation of MLC either by stimulating MLC kinase, through the activation of heterotrimeric GTP-binding proteins (G proteins) of the G q and G 11 families, or by inhibiting, through G 12 and G 13 G proteins, the phosphatase that returns MLC to its inactive form. Wirth et al . produced mice that could be induced by treatment with tamoxifen to lack both G q and G 11 (G q -G 11 KO) or both G 12 and G 13 (G 12 -G 13 KO) in smooth muscle cells. Treatment with tamoxifen caused an increase in blood pressure in all mice, but whereas the blood pressure of wild-type and G 12 -G 13 KO mice soon returned to basal levels, that of G q -G 11 KO mice became 10 to 15% lower than normal, implicating G q and G 11 in the regulation of basal blood pressure. Treatment of wild-type mice with a salt preparation increased their blood pressure, but G q -G 11 KO and G 12 -G 13 KO mice were unaffected, showing that both sets of G proteins mediate salt-induced hypertension. Mice deficient in LARG, an effector of G 12 and G 13 found in smooth muscle cells that mediates the inhibition of myosin phosphatase, responded to salt treatment similarly to G 12 -G 13 KO mice. As Schoner discusses in commentary, this study makes possible the development of therapies that could interfere with salt-induced hypertension while leaving basal blood pressure regulation intact.
A. Wirth, Z. Benyó, M. Lukasova, B. Leutgeb, N. Wettschureck, S. Gorbey, P. Őrsy, B. Horváth, C. Maser-Gluth, E. Greiner, B. Lemmer, G. Schütz, J. S. Gutkind, S. Offermanns, G 12 -G 13 -LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension. Nat. Med. 14 , 64-68 (2008). [PubMed]
W. Schoner, Salt abuse: The path to hypertension. Nat. Med. 14 , 16-17 (2008). [PubMed]