Defective CFTR modulates mechanosensitive channels TRPV4 and PIEZO1 and drives endothelial barrier failure
Jean-Pierre Amoakon,
Jesun Lee,
Pramodha Liyanage,
Kavisha Arora,
Anja Karlstaedt,
Goutham Mylavarapu,
Raouf Amin,
Anjaparavanda P. Naren.
Affiliations
Jean-Pierre Amoakon
Department of Systems Biology and Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Corresponding author
Jesun Lee
Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Pramodha Liyanage
Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Kavisha Arora
Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Anja Karlstaedt
Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Goutham Mylavarapu
Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Raouf Amin
Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Anjaparavanda P. Naren.
Department of Systems Biology and Physiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Pulmonary Medicine and Critical Care, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Division of Pulmonary Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA; Corresponding author
Summary: Cystic fibrosis (CF) is a genetic disease caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Despite reports of CFTR expression on endothelial cells, pulmonary vascular perturbations, and perfusion deficits in CF patients, the mechanism of pulmonary vascular disease in CF remains unclear. Here, our pilot study of 40 CF patients reveals a loss of small pulmonary blood vessels in patients with severe lung disease. Using a vessel-on-a-chip model, we establish a shear-stress-dependent mechanism of endothelial barrier failure in CF involving TRPV4, a mechanosensitive channel. Furthermore, we demonstrate that CFTR deficiency downregulates the function of PIEZO1, another mechanosensitive channel involved in angiogenesis and wound repair, and exacerbates loss of small pulmonary blood vessel. We also show that CFTR directly interacts with PIEZO1 and enhances its function. Our study identifies key cellular targets to mitigate loss of small pulmonary blood vessels in CF.
