G12-G13-LARG-mediated signaling in vascular smooth muscle is required for salt-induced hypertension.
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 resistance. 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 cells. Receptors that mediate vasoconstriction couple with the G-proteins G(q)-G11 and G12-G13 to stimulate phosphorylation of myosin light chain (MLC) via the Ca2+/MLC kinase- and Rho/Rho kinase-mediated signaling pathways, respectively. 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 G(q)-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.
Wirth
Angela
A
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany.
Benyó
Zoltán
Z
Lukasova
Martina
M
Leutgeb
Barbara
B
Wettschureck
Nina
N
Gorbey
Stefan
S
Orsy
Petra
P
Horváth
Béla
B
Maser-Gluth
Christiane
C
Greiner
Erich
E
Lemmer
Björn
B
Schütz
Günther
G
Gutkind
J Silvio
JS
Offermanns
Stefan
S
D000818:Animals; D001794:Blood Pressure; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006973:Hypertension / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D016296:Mutagenesis; D010766:Phosphorylation; D064067:Rho Guanine Nucleotide Exchange Factors; D012492:Salts / Q000494:pharmacology*; D015398:Signal Transduction; D019076:Transgenes; D014661:Vasoconstriction
C577223:Arhgef12 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D064067:Rho Guanine Nucleotide Exchange Factors; D012492:Salts; D044365:GTP-Binding Protein alpha Subunits, G12-G13