Robert M. Berne Cardiovascular Research Center, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
Walter Brendel Center of Experimental Medicine, University Hospital, and Institute of Cardiovascular Physiology and Pathophysiology, Biomedical Center, LMU Munich, 82152 Planegg-Martinsried, Germany.
Sci Signal. 2021 Mar 2;14(672):eaba2940. doi: 10.1126/scisignal.aba2940.
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 A adenosine receptors. Moreover, the increase in vein permeability required the activation of the Ca 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.
内皮细胞屏障调节着血液与组织之间的液体交换，屏障功能的损伤会加剧炎症损伤的严重程度。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 对体外培养的小鼠静脉和动脉内皮细胞通透性和电生理学的影响。我们发现，TNFα 特异性地降低了静脉内皮细胞的屏障功能，而对动脉内皮细胞没有影响。基于 RNA 表达谱和蛋白质分析，我们发现 Claudin-11（CLDN11）是静脉内皮细胞中主要的紧密连接蛋白，而动脉内皮细胞中几乎没有 CLDN11。与紧密连接蛋白组成的差异一致，TNFα 增加了静脉内皮细胞中 Cl 相对于 Na 的选择性通透性，但对动脉内皮细胞没有影响。TNFα 对静脉的特异性作用还需要 Pannexin 1（Panx1）通道的激活以及 CD39 介导的 ATP 水解为腺苷，随后刺激 A 型腺苷受体。此外，静脉通透性的增加需要 Panx1 激活下游的 Ca 通道 TRPV4 的激活。Panx1 缺陷小鼠抵抗了盲肠结扎穿刺诱导的脓毒症对寿命和肺血管通透性的病理影响。这些数据提供了一个有潜力的靶向途径，可以促进静脉屏障功能，并防止血管渗漏在炎症反应中的有害影响。
