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

Maier-Begandt, Daniela; Comstra, Heather Skye; Molina, Samuel A.; Krueger, Nenja; Ruddiman, Claire A.; Chen, Yen-Lin; Chen, Xiaobin; Biwer, Lauren A.; Johnstone, Scott R.; Lohman, Alexander W.; Good, Miranda E.; DeLalio, Leon J.; Hong, Kwangseok; Bacon, Hannah M.; Yan, Zhen; Sonkusare, Swapnil K.; Koval, Michael und Isakson, Brant E. (2021): A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNF alpha-induced increases in endothelial permeability. In: Science Signaling, Bd. 14, Nr. 672, eaba2940

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 TNF alpha on transendothelial permeability and electrophysiology in ex vivo murine veins and arteries. We found that TNF alpha 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, TNF alpha increased the permselectivity of Cl- over Na+ in venous but not arterial endothelium. The vein-specific effects of TNF alpha also required the activation of Pannexin 1 (Panx1) channels and the CD39-mediated hydrolysis of ATP to adenosine, which subsequently stimulated A(2A )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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1945-0877
• Sprache: Englisch