A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability.
A venous-specific purinergic signaling cascade initiated by Pannexin 1 regulates TNFα-induced increases in endothelial permeability.
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DOI：
10.1126/scisignal.aba2940
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发表时间：
2021-03-02
影响因子：
7.3
通讯作者：
Isakson BE
中科院分区：
文献类型：
--
作者：
Maier-Begandt D;Comstra HS;Molina SA;Krüger N;Ruddiman CA;Chen YL;Chen X;Biwer LA;Johnstone SR;Lohman AW;Good ME;DeLalio LJ;Hong K;Bacon HM;Yan Z;Sonkusare SK;Koval M;Isakson BE
内皮细胞屏障调节血流和下层组织之间的流体通过，并且屏障功能损伤加剧炎性损伤的严重性。为了了解炎症如何改变血管通透性，我们研究了促炎细胞因子TNFα对离体小鼠静脉和动脉的跨内皮通透性和电生理学的影响。我们发现TNFα特异性地降低静脉内皮的屏障功能，而不影响动脉内皮的屏障功能。基于RNA表达谱和蛋白质分析，我们发现CLDN11是静脉内皮细胞中的主要密蛋白，并且在动脉内皮细胞中几乎没有CLDN11。与claudin组成的差异一致，TNFα增加了静脉内皮细胞中Cl−相对于Na+的选择性渗透，但动脉内皮细胞中没有。TNFα的静脉特异性作用还需要激活泛联蛋白1（Panx 1）通道和CD 39介导的ATP水解为腺苷，随后刺激A2A腺苷受体。此外，静脉通透性的增加需要激活Panx1激活下游的Ca2+通道TRPV4。Panx1基因缺陷小鼠抵抗盲肠结扎和穿孔诱导的脓毒症对寿命和肺血管通透性的病理影响。这些数据提供了一种靶向途径，具有促进静脉屏障功能和预防炎症反应中血管渗漏的有害影响的潜力。
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. Based on RNA expression profiling and protein analysis, we found that 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 lifespan 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.
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