ArticleProceedings of the National Academy of Sciences of the United States of America2015
CFTR and sphingolipids mediate hypoxic pulmonary vasoconstriction.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 95 citations in OpenAlex.
- Home Oxygen Therapy for Children. An Official American Thoracic Society Clinical Practice Guideline.American journal of respiratory and critical care medicine · 2019Guideline
- Plasma Levels of the Bioactive Sphingolipid Metabolite S1P in Adult Cystic Fibrosis Patients: Potential Target for Immunonutrition?Nutrients · 2020Trial
- Sildenafil improves vascular endothelial function in patients with cystic fibrosis.American journal of physiology. Heart and circulatory physiology · 2018Trial
- PM2.5 toxin benzo[a]pyrene induces life-limiting inflammation and oxidative stress in the airway by up-regulation of TRPC6 and inactivation of β2AR/CFTR signaling.bioRxiv : the preprint server for biology · 2026Article
- Ceramide as a Biomarker for HFpEF in Women: Menopause, Aging, and Pregnancy.International journal of molecular sciences · 2025Review
- Pulmonary vascular remodeling in Fra-2 transgenic mice is driven by type 2 inflammation and accompanied by pulmonary vascular hyperresponsiveness.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- GQ style: a multipronged therapeutic approach to pulmonary arterial hypertension.Pflugers Archiv : European journal of physiology · 2025Article
- Enhancing Quercetin's Potential: A Nanoliposome Delivery System for High Altitude Pulmonary Edema.Drug design, development and therapy · 2025Article
- The Role of Ion Channels in Pulmonary Hypertension: A Review.Pulmonary circulation · 2025Review
- Article
- [Platycodin D improves pulmonary fibrosis in mice by down-regulating TRPC6 expression and reducing ROS production in lung fibroblasts].Nan fang yi ke da xue xue bao = Journal of Southern Medical University · 2024Article
- Review
- Sphingolipid Levels and Signaling via Resveratrol and Antioxidant Actions in Cardiometabolic Risk and Disease.Antioxidants (Basel, Switzerland) · 2023Review
- Cystic fibrosis transmembrane conductance regulator in COPD: a role in respiratory epithelium and beyond.The European respiratory journal · 2023Review
- Pannexin 1: a novel regulator of acute hypoxic pulmonary vasoconstriction.Cardiovascular research · 2022Article
- Oxylipin profile in saliva from patients with cystic fibrosis reveals a balance between pro-resolving and pro-inflammatory molecules.Scientific reports · 2022Article
- Role of Ion Channel Remodeling in Endothelial Dysfunction Induced by Pulmonary Arterial Hypertension.Biomolecules · 2022Review
- Mitochondrial Metabolism, Redox, and Calcium Homeostasis in Pulmonary Arterial Hypertension.Biomedicines · 2022Review
- Therapeutic CFTR Correction Normalizes Systemic and Lung-Specific S1P Level Alterations Associated with Heart Failure.International journal of molecular sciences · 2022Article
- Trpc6 gain-of-function disease mutation enhances phosphatidylserine exposure in murine platelets.PloS one · 2022Article
Corrections and comments
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Authors and funding
17 authors at 6 institutions in 3 countries.
Funding
Abstract
Hypoxic pulmonary vasoconstriction (HPV) optimizes pulmonary ventilation-perfusion matching in regional hypoxia, but promotes pulmonary hypertension in global hypoxia. Ventilation-perfusion mismatch is a major cause of hypoxemia in cystic fibrosis. We hypothesized that cystic fibrosis transmembrane conductance regulator (CFTR) may be critical in HPV, potentially by modulating the response to sphingolipids as mediators of HPV. HPV and ventilation-perfusion mismatch were analyzed in isolated mouse lungs or in vivo. Ca(2+) mobilization and transient receptor potential canonical 6 (TRPC6) translocation were studied in human pulmonary (PASMCs) or coronary (CASMCs) artery smooth muscle cells. CFTR inhibition or deficiency diminished HPV and aggravated ventilation-perfusion mismatch. In PASMCs, hypoxia caused CFTR to interact with TRPC6, whereas CFTR inhibition attenuated hypoxia-induced TRPC6 translocation to caveolae and Ca(2+) mobilization. Ca(2+) mobilization by sphingosine-1-phosphate (S1P) was also attenuated by CFTR inhibition in PASMCs, but amplified in CASMCs. Inhibition of neutral sphingomyelinase (nSMase) blocked HPV, whereas exogenous nSMase caused TRPC6 translocation and vasoconstriction that were blocked by CFTR inhibition. nSMase- and hypoxia-induced vasoconstriction, yet not TRPC6 translocation, were blocked by inhibition or deficiency of sphingosine kinase 1 (SphK1) or antagonism of S1P receptors 2 and 4 (S1P2/4). S1P and nSMase had synergistic effects on pulmonary vasoconstriction that involved TRPC6, phospholipase C, and rho kinase. Our findings demonstrate a central role of CFTR and sphingolipids in HPV. Upon hypoxia, nSMase triggers TRPC6 translocation, which requires its interaction with CFTR. Concomitant SphK1-dependent formation of S1P and activation of S1P2/4 result in phospholipase C-mediated TRPC6 and rho kinase activation, which conjointly trigger vasoconstriction.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.