Novel Pannexin-1-Coupled Signaling Cascade Involved in the Control of Endothelial Cell Function and NO-Dependent Relaxation

We evaluated the participation of Panx-1-formed channels in the control of membrane potential and i of endothelial cells

Mauricio A. Lillo; Pablo S. Gaete; Mariela Puebla; Pía C. Burboa; Inés Poblete; Xavier F. Figueroa

2021

Scholarcy highlights

  • Control of blood flow distribution relies on coordinated changes in the diameter of resistance arteries through a complex interplay between the vasoconstrictor and vasodilator signals that determines the degree of smooth muscle constriction
  • A basal P-eNOSS1177 was detected in control conditions, and the larger vasodilation observed in the presence of probenecid was associated with an increment in the P-eNOSS1177 level) and in Akt phosphorylation at serine 473), suggesting that the endothelial Nitric oxide synthase phosphorylation triggered by the Panx-1 channel blockade was mediated by the activation of the PI3K/Akt signaling pathway, as previously observed in response to different stimuli such as shear stress or bradykinin
  • Control of membrane potential plays an important role in the regulation of endothelial cell signaling and in the Ca2+-dependent eNOS activation; we evaluated the effect of the Panx-1 channel blockade on endothelial cell membrane potential
  • 3(d)) that showed the same temporal characteristics of the change in membrane potential) and, as expected, was abolished by Ni2+, and by TTX), supporting the notion that the activation of the Ca2+ signal was triggered by TTX-sensitive Nav channels. These findings suggest that TTX-sensitive Nav channels and Cav3.2 channels are present in endothelial cells and the expression of the isoforms Nav1.2 and Nav1.6 of TTXsensitive Nav channels as well as the isoform Cav3.2 of Cav3 channels has been detected in the endothelium, which we confirmed by immunocytochemistry analysis in mesenteric resistance arteries
  • The NADPH oxidasederived O2⋅– production initiated by the Panx-1 channel blockade may lead to the activation of Akt-mediated signaling ; we evaluated if the NADPH oxidase/O2⋅–/Akt pathway was involved in the P-eNOSS1177associated increase in NO-dependent vasodilation
  • Caveolae provide a signaling platform for the functional association ebfunertdtwohetehernelaiacthtliecveaPltliaodnnexp-oo1flaartnihzdeatiNNonaAvDancPhdHaai Tsienh/cOere2ca⋅–osensceigolinmcaiitltiatnhnget, which triggers the PI3K/Akt pathway and the subsequent increase in the ACh-induced NO-mediated vasodilation through the modulation of eNOS activity by the phosphorylation of the enzyme at serine 1177
  • This Panx-1-dependent signaling pathway is likely to play a critical role in the tonic, endothelial control of arterial blood pressure and, may contribute to the design of new therapeutic strategies for the treatment of cardiovascular-related diseases such as hypertension

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