CFTR Expression in the Pathogenesis of Pulmonary Arterial Hypertension

X-Ray image of the human chest
Researchers sought to delineate the role of cystic fibrosis transmembrane conductance regulator (CFTR) in pulmonary arterial hypertension pathogenesis through observational and interventional experiments in human tissues and animal models.

Cystic fibrosis transmembrane conductance regulator (CFTR) expression is lost in the pulmonary arteries of patients with pulmonary arterial hypertension (PAH), therefore pharmacological inhibition of CFTR increases vascular cell proliferation and reduces pulmonary artery relaxation, contributing to PAH pathogenesis, according to a study published in the European Respiratory Journal.

A significant event in PAH pathogenesis is a reduction in pulmonary artery (PA) relaxation. CFTR dysfunction in airway epithelial cells plays a central role in cystic fibrosis (CF), and CFTR is also expressed in PAs and has been shown to control endothelium-independent relaxation. Researchers sought to delineate the role of CFTR in PAH pathogenesis through observational and interventional experiments in human tissues and animal models.

They found that CFTR expression was reduced in PAs from patients with idiopathic PAH (iPAH) and in rats with monocrotaline-induced pulmonary hypertension (PH). Inhuman, pig, and rat PAs, the researchers found that CFTR activation induces relaxation of PAs. CFTR-mediated PA relaxation was also reduced in PAs 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 neomuscularization. Pathologic assessment of the lungs from patients with severe CF (F508del-CFTR) revealed severe PA remodeling with intimal fibrosis and medial hypertrophy.

Lungs from homozygous F508delCftr rats exhibited pulmonary vessel neomuscularization. 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.

“In conclusion, we provide evidence that the CFTR channel contributes to PA tone in humans, pigs and rats; that PA CFTR expression is reduced in iPAH and in 2 different experimental models of PAH; and that CFTR inhibition increases vascular cell proliferation,” stated the authors.

Disclosure: One study author declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures. 


Le Ribeuz H, To L, Ghigna MR, et al. Involvement of CFTR in the pathogenesis of pulmonary arterial hypertension. Eur Respir J. 2021. Published online May 28, 2021. doi:10.1183/13993003.00653-2020