Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension.

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.
Competing Interests: Conflict of interest: H. Le Ribeuz has nothing to disclose. Conflict of interest: L. To has nothing to disclose. Conflict of interest: M-R. Ghigna has nothing to disclose. Conflict of interest: C. Martin has nothing to disclose. Conflict of interest: C. Nagaraj has nothing to disclose. Conflict of interest: E. Dreano has nothing to disclose. Conflict of interest: C. Rucker-Martin has nothing to disclose. Conflict of interest: B. Girerd has nothing to disclose. Conflict of interest: J. Bouligand has nothing to disclose. Conflict of interest: C. Pechoux has nothing to disclose. Conflict of interest: M. Lambert has nothing to disclose. Conflict of interest: A. Boet has nothing to disclose. Conflict of interest: J. Issard has nothing to disclose. Conflict of interest: O. Mercier has nothing to disclose. Conflict of interest: K. Hoetzenecker has nothing to disclose. Conflict of interest: B. Manoury has nothing to disclose. Conflict of interest: F. Becq has nothing to disclose. Conflict of interest: P-R. Burgel reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Novartis, Pfizer, Vertex, Teva, Zambon and Mylan, outside the submitted work. Conflict of interest: C-H. Cottart reports grants from Vaincre La Mucoviscidose and Fondation Maladies Rares, during the conduct of the study. Conflict of interest: A. Olschewski has nothing to disclose. Conflict of interest: I. Sermet-Gaudelus reports grants and other (advisory board member) from Vertex therapeutics, other (advisory board member) from Eloxx and Proteostasis therapeutics, outside the submitted work. Conflict of interest: F. Perros has nothing to disclose. Conflict of interest: M. Humbert reports grants and personal fees from Actelion, Bayer, GSK and Acceleron, personal fees from Merck and United Therapeutics, outside the submitted work. Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, personal fees from GSK, Pfizer, Chiesi and Boehringer, grants, personal fees and non-financial support from MSD, non-financial support from Acceleron, outside the submitted work. Conflict of interest: F. Antigny has nothing to disclose.
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