André Gwennan, Sandoval Juan E, Retailleau Kevin, Loufrani Laurent, Toumaniantz Gilles, Offermanns Stefan, Rolli-Derkinderen Malvyne, Loirand Gervaise, Sauzeau Vincent
Inserm UMR_S1087, CNRS UMR_C6291, l'institut du thorax, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.) Université de Nantes, Nantes, F-44000, France (G.A., J.E.S., G.T., M.R.D., G.L., V.S.).
Inserm UMR_S1083, CNRS UMR_C6214, BNMI, Angers, F-49000, France (K.R., L.L.).
J Am Heart Assoc. 2014 Jun 17;3(3):e000852. doi: 10.1161/JAHA.114.000852.
Increasing evidence implicates overactivation of RhoA as a critical component of the pathogenesis of hypertension. Although a substantial body of work has established that Rac1 functions antagonize RhoA in a broad range of physiological processes, the role of Rac1 in the regulation of vascular tone and blood pressure is not fully elucidated.
To define the role of Rac1 in vivo in vascular smooth muscle cells (vSMC), we generated smooth muscle (SM)-specific Rac1 knockout mice (SM-Rac1-KO) and performed radiotelemetric blood pressure recordings, contraction measurements in arterial rings, vSMC cultures and biochemical analyses. SM-Rac1-KO mice develop high systolic blood pressure sensitive to Rho kinase inhibition by fasudil. Arteries from SM-Rac1-KO mice are characterized by a defective NO-dependent vasodilation and an overactivation of RhoA/Rho kinase signaling. We provide evidence that Rac1 deletion-induced hypertension is due to an alteration of cGMP signaling resulting from the loss of Rac1-mediated control of type 5 PDE activity. Consequently, cGMP-dependent phosphorylation and binding of RhoA with its inhibitory partner, the phosphatase-RhoA interacting protein (p116(RIP3)), are decreased.
Our data reveal that the depletion of Rac1 in SMC decreases cGMP-dependent p116(RIP3)/RhoA interaction and the subsequent inhibition of RhoA signaling. Thus, we unveil an in vivo role of Rac1 in arterial blood pressure regulation and a new pathway involving p116(RIP3) that contributes to the antagonistic relationship between Rac1 and RhoA in vascular smooth muscle cells and their opposite roles in arterial tone and blood pressure.
越来越多的证据表明，RhoA过度激活是高血压发病机制的关键组成部分。尽管大量研究已证实Rac1功能在广泛的生理过程中拮抗RhoA，但Rac1在血管张力和血压调节中的作用尚未完全阐明。
为了确定Rac1在血管平滑肌细胞（vSMC）中的体内作用，我们构建了平滑肌（SM）特异性Rac1基因敲除小鼠（SM-Rac1-KO），并进行了无线电遥测血压记录、动脉环收缩测量、vSMC培养及生化分析。SM-Rac1-KO小鼠出现对法舒地尔抑制Rho激酶敏感的高收缩压。SM-Rac1-KO小鼠的动脉具有一氧化氮（NO）依赖性血管舒张功能缺陷和RhoA/Rho激酶信号过度激活的特征。我们提供的证据表明，Rac1缺失诱导的高血压是由于Rac1介导的5型磷酸二酯酶（PDE）活性调控缺失导致cGMP信号改变所致。因此，cGMP依赖性磷酸化以及RhoA与其抑制性伴侣磷酸酶-RhoA相互作用蛋白（p116(RIP3)）的结合减少。
我们的数据表明，平滑肌细胞中Rac1的缺失会降低cGMP依赖性p116(RIP3)/RhoA相互作用以及随后对RhoA信号的抑制。因此，我们揭示了Rac1在动脉血压调节中的体内作用以及一条涉及p116(RIP3)的新途径，该途径有助于血管平滑肌细胞中Rac1与RhoA之间的拮抗关系及其在动脉张力和血压中的相反作用。
