Smooth muscle Rac1 contributes to pulmonary hypertension.

Florian Dilasser, Marc Rio, Lindsay Rose, Angela Tesse, Christophe Guignabert, Gervaise Loirand, Vincent Sauzeau

British journal of pharmacology 2022 Jul

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Pulmonary hypertension (PH) is a multifactorial chronic disease characterized by an increase in pulmonary artery (PA) resistance leading to right ventricle (RV) failure. Endothelial dysfunction and alteration of NO/cGMP signalling in PA plays a major role in PH. We recently described the involvement of the Rho protein 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 to analyse the role of SMC Rac1 in PH. PH is induced by exposure of control and SMC Rac1-deficient (SM-Rac1-KO) mice to chronic hypoxia (10% O2 , 4 weeks). PH is assessed by the measurement of RV systolic pressure and hypertrophy. PA reactivity is analysed by isometric tension measurements. PA remodelling is quantified by immunofluorescence in lung sections and ROS are detected using the dihydroethidium probe and electronic paramagnetic resonance analysis. Rac1 activity is determined by immunofluorescence. Rac1 activation in PA of hypoxic mice and patients with idiopathic PH. Hypoxia-induced rise in RV systolic pressure, RV hypertrophy and loss of endothelium-dependent relaxation were significantly decreased in SM-Rac1-KO mice compared to control mice. SMC Rac1 deletion also limited hypoxia-induced PA remodelling and ROS production in pulmonary artery smooth muscle cells (PASMCs). Our results provide evidence for a protective effect of SM Rac1 deletion against hypoxic PH. Rac1 activity in PASMCs plays a causal role in PH by favouring ROS-dependent PA remodelling and endothelial dysfunction induced by chronic hypoxia. © 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Citation

Florian Dilasser, Marc Rio, Lindsay Rose, Angela Tesse, Christophe Guignabert, Gervaise Loirand, Vincent Sauzeau. Smooth muscle Rac1 contributes to pulmonary hypertension. British journal of pharmacology. 2022 Jul;179(13):3418-3429