Title :

Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension

Author(s) :

Le Ribeuz, Hélène [Auteur]
Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
Hypertension pulmonaire : physiopathologie et innovation thérapeutique [HPPIT]
Faculté de Médecine Paris-Saclay
To, Lucie [Auteur]
Ghigna, Maria-Rosa [Auteur]
Hypertension pulmonaire : physiopathologie et innovation thérapeutique [HPPIT]
Martin, Clémence [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Nagaraj, Chandran [Auteur]
Dreano, Elise [Auteur]
Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 [PhLAM]
Rucker-Martin, Catherine [Auteur]
Centre Chirurgical Marie Lannelongue [CCML]
Adhésion et Inflammation [LAI]
Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
Girerd, Barbara [Auteur]
Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
Université Paris-Saclay
Bouligand, Jérôme [Auteur]
Physiologie et physiopathologie endocriniennes [PHYSENDO]
Service de Génétique Moléculaire Pharmacogénétique et Hormonologie [CHU Bicêtre]
Pechoux, Christine [Auteur]
Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement [INRAE]
Lambert, Mélanie [Auteur]
Karolinska Institutet [Stockholm]
Adaptateurs de signalisation en hématologie [ASIH]
Boet, Angèle [Auteur]
Centre Chirurgical Marie Lannelongue [CCML]
Adhésion et Inflammation [LAI]
Hôpital Bicêtre [AP-HP, Le Kremlin-Bicêtre]
Issard, Justin [Auteur]
Hypertension pulmonaire : physiopathologie et innovation thérapeutique [HPPIT]
Mercier, Olaf [Auteur]
Hôpital Marie-Lannelongue
Université Paris-Saclay
Hypertension pulmonaire : physiopathologie et innovation thérapeutique [HPPIT]
Hoetzenecker, Konrad [Auteur]
Manoury, Boris [Auteur]
Université Paris-Saclay
Signalisation et physiopathologie cardiovasculaire [CARPAT (UMRS1180)]
Becq, Frédéric [Auteur]
Signalisation et Transports Ioniques Membranaires [STIM [Poitiers]]
Burgel, Pierre-Régis [Auteur]
Institut Cochin [IC UM3 (UMR 8104 / U1016)]
Service de pneumologie [CHU Cochin]
Cottart, Charles-Henry [Auteur]
Laboratoire de Physique des Lasers, Atomes et Molécules - UMR 8523 [PhLAM]
Olschewski, Andrea [Auteur]
Sermet-Gaudelus, Isabelle [Auteur]
Perros, Frédéric [Auteur]
Humbert, Marc [Auteur]
Montani, David [Auteur]
Antigny, Fabrice [Auteur]
Hypertension pulmonaire : physiopathologie et innovation thérapeutique [HPPIT]

Journal title :

European Respiratory Journal

Pages :

2000653

Publisher :

European Respiratory Society

Publication date :

2021-11-29

ISSN :

0903-1936

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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.Show less >

Language :

Anglais

Popular science :

Non

Collections :

• Laboratoire de Physique des Lasers, Atomes et Molécules (PhLAM) - UMR 8523

Source :

Harvested from HAL