A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNF alpha-induced increases in endothelial permeability

• Type of Material: Article
• Authors: Daniela Maier-Begandt, University of Virginia; Heather Comstra, Emory University; Samuel Molina, Emory University; Nenja Krüger, University of Virginia; Claire A Ruddiman, University of Virginia; Yen-Lin Chen, University of Virginia; Xiaobin Chen, University of Virginia; Lauren A Biwer, University of Virginia; Scott R Johnstone, Virginia Tech; Alexander W Lohman, University of Calgary; Miranda E Good, Tufts Medical Center; Leon J DeLalio, University of Virginia; Kwangseok Hong, Chung Ang University; Hannah M Bacon, University of Virginia; Zhen Yan, University of Virginia; Swapnil K Sonkusare, University of Virginia; Michael Koval, Emory University; Brant E Isakson, University of Virginia
• Language: English
• Date: 2021-03-02
• Publisher: AMER ASSOC ADVANCEMENT SCIENCE
• Publication Version: Final Published Version
• Copyright Statement: © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
• Final Published Version (URL): http://dx.doi.org/10.1126/scisignal.aba2940
• Title of Journal or Parent Work: SCIENCE SIGNALING
• Volume: 14
• Issue: 672
• Keywords: SEVERE SEPSIS; Biochemistry & Molecular Biology; TARGETED DISRUPTION; TIGHT JUNCTIONS; INFLAMMATION; PROTECTS; Cell Biology; CHANNELS; ATP RELEASE; CD39; TRPV4; TUMOR-NECROSIS-FACTOR; Life Sciences & Biomedicine; Science & Technology

Abstract

The endothelial cell barrier regulates the passage of fluid between the bloodstream and underlying tissues, and barrier function impairment exacerbates the severity of inflammatory insults. To understand how inflammation alters vessel permeability, we studied the effects of the proinflammatory cytokine TNFα on transendothelial permeability and electrophysiology in ex vivo murine veins and arteries. We found that TNFα specifically decreased the barrier function of venous endothelium without affecting that of arterial endothelium. On the basis of RNA expression profiling and protein analysis, we found that claudin-11 (CLDN11) was the predominant claudin in venous endothelial cells and that there was little, if any, CLDN11 in arterial endothelial cells. Consistent with a difference in claudin composition, TNFα increased the permselectivity of Cl− over Na+ in venous but not arterial endothelium. The vein-specific effects of TNFα also required the activation of Pannexin 1 (Panx1) channels and the CD39-mediated hydrolysis of ATP to adenosine, which subsequently stimulated A2A adenosine receptors. Moreover, the increase in vein permeability required the activation of the Ca2+ channel TRPV4 downstream of Panx1 activation. Panx1-deficient mice resisted the pathologic effects of sepsis induced by cecal ligation and puncture on life span and lung vascular permeability. These data provide a targetable pathway with the potential to promote vein barrier function and prevent the deleterious effects of vascular leak in response to inflammation.