Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension

Hélène Le Ribeuz (1) , Lucie To (1) , Maria-Rosa Ghigna (1) , Clémence Martin (2) , Chandran Nagaraj , Elise Dreano (3) , Catherine Rucker-Martin (1) , Barbara Girerd (1) , Christine Pechoux (4) , Mélanie Lambert (1) , Angèle Boet (1) , Justin Issard (1) , Olaf Mercier (1) , Konrad Hoetzenecker , Boris Manoury , Frédéric Becq , Pierre- Régis Burgel (2) , Charles-Henry Cottart (3) , Andrea Olschewski , Isabelle Sermet-Gaudelus (3) , Frédéric Perros (1) , Marc Humbert (1) , David Montani (1) , Fabrice Antigny (1) , Jérôme Bouligand , Pierre-Régis Burgel

1 HPPIT - Hypertension pulmonaire : physiopathologie et innovation thérapeutique
2 IC UM3 (UMR 8104 / U1016) - Institut Cochin
3 PhLAM - Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523
4 INRAE - Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement

Introduction A reduction in pulmonary artery relaxation is a key event in the pathogenesis of pulmonary arterial hypertension (PAH). Cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction in airway epithelial cells plays a central role in cystic fibrosis; CFTR is also expressed in pulmonary arteries and has been shown to control endothelium-independent relaxation. Aim and objectives We aimed to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models. Methods and results Reverse-transcriptase quantitative PCR, confocal imaging and electron microscopy showed that CFTR expression was reduced in pulmonary arteries from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Moreover, using myography on human, pig and rat pulmonary arteries, we demonstrated that CFTR activation induces pulmonary artery relaxation. CFTR-mediated pulmonary artery relaxation was reduced in pulmonary arteries from iPAH patients and rats with monocrotaline- or chronic hypoxia-induced PH. Long-term in vivo CFTR inhibition in rats significantly increased right ventricular systolic pressure, which was related to exaggerated pulmonary vascular cell proliferation in situ and vessel neomuscularisation. Pathologic assessment of lungs from patients with severe cystic fibrosis ( F508del-CFTR ) revealed severe pulmonary artery remodelling with intimal fibrosis and medial hypertrophy. Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularisation. The elevations in right ventricular systolic pressure and end diastolic pressure in monocrotaline-exposed rats with chronic CFTR inhibition were more prominent than those in vehicle-exposed rats. Conclusions CFTR expression is strongly decreased in pulmonary artery smooth muscle and endothelial cells in human and animal models of PH. CFTR inhibition increases vascular cell proliferation and strongly reduces pulmonary artery relaxation.

Domaines: Sciences du Vivant [q-bio]

Hélène Le Ribeuz, Lucie To, Maria-Rosa Ghigna, Clémence Martin, Chandran Nagaraj, et al.. Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension. European Respiratory Journal, 2021, 58 (5), pp.2000653. ⟨10.1183/13993003.00653-2020)⟩. ⟨hal-03499886⟩