Defective CFTR modulates mechanosensitive channels TRPV4 and PIEZO1 and drives endothelial barrier failure

• Published in: iScience 2024-09, Vol.27 (9), p.110703, Article 110703
• Main Authors: Amoakon, Jean-Pierre, Lee, Jesun, Liyanage, Pramodha, Arora, Kavisha, Karlstaedt, Anja, Mylavarapu, Goutham, Amin, Raouf, Naren, Anjaparavanda P.
• Format: Article
• Language: English
• Subjects: Cell biology; Functional aspects of cell biology; Pathophysiology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.110703

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. [Display omitted] •CFTR deficiency promotes barrier failure in the pulmonary microvascular endothelium•CFTR deficiency alters endothelial cells lipid metabolism and membrane fluidity•CFTR deficiency sensitizes TRPV4 to fluid shear stress•CFTR directly interacts with PIEZO1 Cell biology; Functional aspects of cell biology; Pathophysiology