title: The Rho exchange factor Arhgef1 mediates the effects of angiotensin II on vascular tone and blood pressure.
abstract: 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.
authors.affiliation: Inserm, U915, Nantes, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guilluy
authors.forename: Jérémy
authors.initials: J
authors.lastname: Brégeon
authors.forename: Gilles
authors.initials: G
authors.lastname: Toumaniantz
authors.forename: Malvyne
authors.initials: M
authors.lastname: Rolli-Derkinderen
authors.forename: Kevin
authors.initials: K
authors.lastname: Retailleau
authors.forename: Laurent
authors.initials: L
authors.lastname: Loufrani
authors.forename: Daniel
authors.initials: D
authors.lastname: Henrion
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Scalbert
authors.forename: Antoine
authors.initials: A
authors.lastname: Bril
authors.forename: Raul M
authors.initials: RM
authors.lastname: Torres
authors.forename: Stephan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Pierre
authors.initials: P
authors.lastname: Pacaud
authors.forename: Gervaise
authors.initials: G
authors.lastname: Loirand
mesh_terms: 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
chemical_list: 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