The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure.
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.
Guilluy
Christophe
C
Inserm, U915, Nantes, France.
Brégeon
Jérémy
J
Toumaniantz
Gilles
G
Rolli-Derkinderen
Malvyne
M
Retailleau
Kevin
K
Loufrani
Laurent
L
Henrion
Daniel
D
Scalbert
Elizabeth
E
Bril
Antoine
A
Torres
Raul M
RM
Offermanns
Stephan
S
Pacaud
Pierre
P
Loirand
Gervaise
G
D000804:Angiotensin II / Q000502:physiology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D006973:Hypertension / Q000209:etiology / Q000503:physiopathology; D053614:Janus Kinase 2 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000502:physiology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
C577231:Arhgef1 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D011518:Proto-Oncogene Proteins; D064067:Rho Guanine Nucleotide Exchange Factors; D000804:Angiotensin II; D014443:Tyrosine; D053614:Janus Kinase 2