OBJECTIVE Vascular endothelial (VE)-cadherin is of dominant importance for the formation and stability of endothelial junctions, yet induced gene inactivation enhances vascular permeability in the lung but does not cause junction rupture. This study aims at identifying the junctional adhesion molecule, which is responsible for preventing endothelial junction rupture in the pulmonary vasculature in the absence of VE-cadherin. Approach and Results: We have compared the relevance of ESAM (endothelial cell-selective adhesion molecule), JAM (junctional adhesion molecule)-A, PECAM (platelet endothelial cell adhesion molecule)-1, and VE-cadherin for vascular barrier integrity in various mouse tissues. Gene inactivation of ESAM enhanced vascular permeability in the lung but not in the heart, skin, and brain. In contrast, deletion of JAM-A or PECAM-1 did not affect barrier integrity in any of these organs. Blocking VE-cadherin with antibodies caused lethality in ESAM-/- mice within 30 minutes but had no such effect in JAM-A-/-, PECAM-1-/- or wild-type mice. Likewise, induced gene inactivation of VE-cadherin caused rapid lethality only in the absence of ESAM. Ultrastructural analysis revealed that only combined interference with VE-cadherin and ESAM disrupted endothelial junctions and caused massive blood coagulation in the lung. Mechanistically, we could exclude a role of platelet ESAM in coagulation, changes in the expression of other junctional proteins or a contribution of cytoplasmic signaling domains of ESAM. CONCLUSIONS Despite well-documented roles of JAM-A and PECAM-1 for the regulation of endothelial junctions, only for ESAM, we detected an essential role for endothelial barrier integrity in a tissue-specific way. In addition, we found that it is ESAM which prevents endothelial junction rupture in the lung when VE-cadherin is absent.

中文翻译：

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干扰ESAM（内皮细胞选择性粘附分子）加上血管内皮钙黏着蛋白会立即导致致命性和特定于肺的血液凝结。

目的血管内皮钙粘蛋白对内皮连接的形成和稳定性起着至关重要的作用，而诱导的基因失活可增强肺部的血管通透性，但不会引起连接破裂。这项研究旨在鉴定连接黏附分子，该黏附分子可在缺乏VE-钙黏着蛋白的情况下防止肺血管系统中的内皮连接破裂。方法和结果：我们比较了ESAM（内皮细胞选择性粘附分子），JAM（结缔粘附分子）-A，PECAM（血小板内皮细胞粘附分子）-1和VE-钙黏着蛋白在各种血管屏障完整性中的相关性小鼠组织。ESAM的基因失活可增强肺部的血管通透性，但不能增强心脏，皮肤和脑部的通透性。相比之下，删除JAM-A或PECAM-1不会影响任何这些器官的屏障完整性。用抗体阻断VE-钙粘蛋白会在30分钟内在ESAM-/-小鼠中造成致命性，但在JAM-A-/-，PECAM-1-/-或野生型小鼠中则没有这种作用。同样，仅在没有ESAM的情况下，诱导的VE-钙黏着蛋白基因失活才导致快速致死性。超微结构分析显示，仅对VE-钙粘蛋白和ESAM的联合干扰会破坏内皮连接，并导致肺部大量凝血。从机制上讲，我们可以排除血小板ESAM在凝血中的作用，其他连接蛋白表达的变化或ESAM胞质信号传导域的贡献。结论尽管JAM-A和PECAM-1在血管内皮连接的调节中有充分的文献记载作用，但仅对ESAM有用，我们以组织特异性方式检测了内皮屏障完整性的重要作用。此外，我们发现，当缺少VE-钙黏着蛋白时，ESAM可以防止肺中的内皮连接破裂。