Hypertension is one of the most frequent pathology in the industrialized world. Although it is recognized to be dependent on a combination of genetic and environmental factors, its molecular basis remains elusive. A possible candidate is the monomeric G protein RhoA which activates Rho kinase. However, how it is activated and whether it has a causative role in hypertension is still unknown. By in vitro experiments, we provide evidence that Arhgef1 is the RhoA guanine exchange factor specifically responsible for Angiotensin II (Ang II)-induced RhoA/Rho kinase activation in arterial smooth muscle cells. To analyze in vivo the role of Arhgef1, we generated mice lacking Arhgef1 specifically in smooth muscle cells (SM-Arhgef1-KO). We used Arhgef1lox/lox mice, which were mated to SMMHC-CreERT2 to produce SMMHC-CreERT2 ; Arhgef1lox/lox mice (SM-Arhgef1lox/lox). SM-Arhgef1-KO mice were then obtained by treating SM-Arhgef1lox/lox mice with tamoxifen. Remarkably, SM-Arhgef1-KO mice were resistant to hypertension induced by chronic Ang II infusion (sub-cutaneous osmotic pump, 1μg/kg/min). Furthermore, Arhgef1 deletion after induction of hypertension by Ang II restored normal arterial pressure level. Basal arterial pressure and responses to vasoconstrictors other than Ang II (phenylephrine, U46619, endotheline) were not modified in SM-Arhgef1-KO mice.

Our results show that Arhgef1 activation and its downstream RhoA/Rho kinase signaling are central to the development of Ang IIdependent hypertension. We identify Arhgef1 as an alternative potential target for the treatment of hypertension.