Crosstalk Between Reticular Adherens Junctions and Platelet Endothelial Cell Adhesion Molecule-1 Regulates Endothelial Barrier Function
Crosstalk Between Reticular Adherens Junctions and Platelet Endothelial Cell Adhesion Molecule-1 Regulates Endothelial Barrier Function
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DOI：
10.1161/atvbaha.112.252080
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发表时间：
2012-08-01
影响因子：
8.7
通讯作者：
Millan, Jaime
中科院分区：
文献类型：
--
作者：
Fernandez-Martin, Laura;Marcos-Ramiro, Beatriz;Millan, Jaime
内皮细胞在血液和组织之间提供屏障，在炎症期间减少，以允许分子和细胞选择性通过。粘附连接（AJ）在调节这种屏障中起着核心作用。我们的目的是研究一个独特的三维网状网络AJ中发现endothelial.Methods和Results-In内皮AJ，血管内皮钙粘蛋白招聘的细胞质蛋白β-连环蛋白和p120-连环蛋白的作用。β-连环蛋白与α-连环蛋白结合，α-连环蛋白将AJ连接到肌动蛋白丝。AJ通常被描述为沿着富含肌动蛋白的细胞间接触的线性结构。在这里，我们表明，这些AJ组件也可以组织在含有低水平的肌动蛋白的网状结构域。网状AJ位于相邻细胞重叠的区域，并包含细胞粘附受体血小板内皮细胞粘附分子-1（PECAM-1）。超分辨率显微镜显示，PECAM-1形成离散的结构不同，并沿着AJ分布，在网状结构域的空隙内。炎症性肿瘤坏死因子-α通过不依赖于肌动球蛋白介导的张力的机制增加通透性，并且仍然不完全清楚。网状AJ，而不是肌动蛋白丰富的线性AJ，被肿瘤坏死因子α破坏。这与PECAM-1从细胞边界的扩散有关。用阻断抗体或小干扰RNA抑制PECAM-1特异性地破坏网状AJ，留下完整的线性AJ。这种破坏概括了典型的肿瘤坏死因子-α诱导的屏障功能的改变，包括增加β-连环蛋白磷酸化，而不改变actomyosin cytokerelastics.Conclusion-We建议，网状AJ与PECAM-1协调行动，以维持低肌动球蛋白介导的张力区域的内皮屏障功能。网状AJ的选择性破坏有助于响应于肿瘤坏死因子-α的渗透性增加。（Arterioscler Thromb Vasc Biol.2012;32：e90-102。）
Objective-Endothelial cells provide a barrier between the blood and tissues, which is reduced during inflammation to allow selective passage of molecules and cells. Adherens junctions (AJ) play a central role in regulating this barrier. We aim to investigate the role of a distinctive 3-dimensional reticular network of AJ found in the endothelium.Methods and Results-In endothelial AJ, vascular endothelial-cadherin recruits the cytoplasmic proteins beta-catenin and p120-catenin. beta-catenin binds to alpha-catenin, which links AJ to actin filaments. AJ are usually described as linear structures along the actin-rich intercellular contacts. Here, we show that these AJ components can also be organized in reticular domains that contain low levels of actin. Reticular AJ are localized in areas where neighboring cells overlap and encompass the cell adhesion receptor platelet endothelial cell adhesion molecule-1 (PECAM-1). Superresolution microscopy revealed that PECAM-1 forms discrete structures distinct from and distributed along AJ, within the voids of reticular domains. Inflammatory tumor necrosis factor-alpha increases permeability by mechanisms that are independent of actomyosin-mediated tension and remain incompletely understood. Reticular AJ, but not actin-rich linear AJ, were disorganized by tumor necrosis factor-alpha. This correlated with PECAM-1 dispersal from cell borders. PECAM-1 inhibition with blocking antibodies or small interfering RNA specifically disrupted reticular AJ, leaving linear AJ intact. This disruption recapitulated typical tumor necrosis factor-alpha-induced alterations of barrier function, including increased beta-catenin phosphorylation, without altering the actomyosin cytoskeleton.Conclusion-We propose that reticular AJ act coordinately with PECAM-1 to maintain endothelial barrier function in regions of low actomyosin-mediated tension. Selective disruption of reticular AJ contributes to permeability increase in response to tumor necrosis factor-alpha. (Arterioscler Thromb Vasc Biol. 2012;32:e90-102.)