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Journal Articles British Journal of Pharmacology Year : 2022

Smooth muscle Rac1 contributes to pulmonary hypertension

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Abstract

Background and purpose: 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 signaling in PA play 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 thus to analyze the role of SMC Rac1 in PH. Experimental approach: 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 analyzed by isometric tension measurements. PA remodeling is quantified by immunofluorescence in lung sections and ROS are detected using the DHE probe and electronic paramagnetic resonance analysis. Rac1 activity is determined by immunofluorescence. Key results: Rac1 activation is observed 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 remodeling and ROS production in PASMCs. Conclusion and implications: 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 favoring ROS-dependent PA remodeling and endothelial dysfunction induced by chronic hypoxia.
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Dates and versions

inserm-03558860 , version 1 (05-02-2022)

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Florian Dilasser, Marc Rio, Lindsay Rose, Angela Tesse, Christophe Guignabert, et al.. Smooth muscle Rac1 contributes to pulmonary hypertension. British Journal of Pharmacology, 2022, Online ahead of print. ⟨10.1111/bph.15805⟩. ⟨inserm-03558860⟩
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