Pulmonary arterial hypertension (PAH) is a multifactorial and chronic disease characterized by an increase in pulmonary artery (PA) resistance that leads to right ventricle (RV) failure. Endothelial dysfunction and alteration NO/cGMP signaling in PA is known to play a major role in PAH. We recently described the involvement of the small G protein of the Rho family Rac1 in the control of systemic blood pressure through its involvement in NO-mediated relaxation of arterial smooth muscle cell (SMC).

The aim of this study was thus to analyze the role of SMC Rac1 in PAH.

PAH is induced by exposure of wild-type (WT) and SMC Rac1-deficient mice (SM-Rac1-KO mice) to chronic hypoxia (10% O2, 4 wk). PAH is then assessed by the measurement of RV systolic pressure and hypertrophy (Fulton index). Isometric tension measurements are used to analyze contraction and relaxation responses of pulmonary arterial rings. PA remodeling is quantified by the muscularization of PA (SM-α-actin labeling on lung sections).

In SM-Rac1-KO mice, hypoxia-induced elevation in RV systolic pressure and RV hypertrophy were significantly decreased by 32.5% and 60%, respectively, compared to WT mice (n=5–7). In addition, hypoxia-induced loss of endothelium-dependent relaxation was prevented in PA from SM-Rac1-KO mice, while Rac1 deletion in SMC did not affect PA responses to vasoconstrictors (KCl, endothelin-1). SMC Rac1 deletion also limited hypoxia-induced PA remodeling as shown by a decrease of the number of muscularized PA in SM-Rac1-KO compared to WT mice (21.1±5.2% vs. 53.9±7.1%; P<0.05; n=5–7).

Surprisingly, and in contrast to that previously observed for systemic blood pressure, Rac1 deletion protects against hypoxic PAH. Our results suggest that Rac1 activity in PA smooth muscle cells plays a causal role in PAH by favoring the alteration of endothelium-dependent vasodilation and PA remodelling induced by chronic hypoxia.