Hélène Le Ribeuz1,2,3, Lucie To1,2,3, Maria-Rosa Ghigna1,2,3, Clémence Martin4,5, Chandran Nagaraj6, Elise Dreano7, Catherine Rucker-Martin1,2,3, Barbara Girerd1,2,3, Jérôme Bouligand8,9, Christine Pechoux10, Mélanie Lambert1,2,3, Angèle Boet1,2,3, Justin Issard1,2,3, Olaf Mercier1,2,3, Konrad Hoetzenecker11, Boris Manoury12, Frédéric Becq13, Pierre-Régis Burgel4,5, Charles-Henry Cottart7, Andrea Olschewski5,14, Isabelle Sermet-Gaudelus7, Frédéric Perros1,2,3, Marc Humbert1,2,3, David Montani1,2,3, Fabrice Antigny15,2,3. 1. Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France. 2. INSERM UMR_S 999 "Hypertension Pulmonaire: Physiopathologie et Innovation Thérapeutique", Hôpital Marie Lannelongue, Le Plessis-Robinson, France. 3. Hôpitaux de Paris (AP-HP), Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l'Hypertension Pulmonaire, Hôpital Bicêtre, Le Kremlin-Bicêtre, France. 4. Hôpitaux de Paris (AP-HP), Dept of Respiratory Medicine, Centre de Référence Maladie Rare Mucoviscidose, ERN-Lung, Cochin Hospital, Paris, France. 5. Inserm U1016, Institut Cochin, Université de Paris, Paris, France. 6. Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria. 7. Inserm U1151 - CNRS UMR 8253 - Institut Necker Enfants Malades, Centre Maladie Rare Mucoviscidose, ERN Lung, Université de Paris, Paris, France. 8. Laboratoire de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Le Kremlin-Bicêtre, France. 9. INSERM UMR-1185, Université Paris Saclay, Faculté de Médecine, Le Kremlin Bicêtre, France. 10. GABI, INRA, AgroParisTech, Université Paris-Saclay, Jouy-en-Josas, France. 11. Dept of Thoracic Surgery, Medical University of Vienna, Vienna, Austria. 12. Signalisation et Physiopathologie Cardiovasculaire - UMR_S 1180, Université Paris-Sud, INSERM, Université Paris-Saclay, Châtenay-Malabry, France. 13. Laboratoire Signalisation et Transports Ioniques Membranaires, Université de Poitiers, Poitiers Cedex 9, France. 14. Dept of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria. 15. Université Paris-Saclay, Faculté de Médecine, Le Kremlin-Bicêtre, France fabrice.antigny@universite-paris-saclay.fr.
Abstract
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.
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.