Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium.
Rab5-mediated VE-cadherin internalization regulates the barrier function of the lung microvascular endothelium.
复制标题
Rab5介导的VE-钙粘蛋白内化调节肺微血管内皮的屏障功能
DOI：
10.1007/s00018-015-1973-4
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Wang G
中科院分区：
文献类型：
--
作者：
Yang J;Yao W;Qian G;Wei Z;Wu G;Wang G
小GTdR ab 5已被很好地定义为控制囊泡介导的质膜蛋白转运到内体区室。然而，其在血管内皮（VE）-钙粘蛋白，粘附连接的重要组成部分，并因此调节内皮细胞极性和屏障功能的内化功能仍然未知。在这里，我们证明了脂多糖（LPS）模拟显着增强Rab 5在人肺微血管内皮细胞（HPMEC），这是伴随着VE-钙粘蛋白内化的激活和表达。同时，LPS刺激也可诱导细胞极性异常和内皮屏障功能障碍。LPS刺激促进了VE-钙粘蛋白从质膜向细胞内转运，并且细胞内表达的VE-钙粘蛋白与Rab 5广泛共定位。小干扰RNA（siRNA）介导的Rab 5a表达缺失减弱了LPS诱导的VE-钙粘蛋白内化的破坏和细胞极性的紊乱。此外，Rab 5的敲低抑制血管内皮细胞的高通透性和保护内皮屏障功能，从LPS损伤，在体外和体内。这些结果表明，Rab 5是LPS诱导的内皮屏障功能障碍的关键介质，这可能是通过调节VE-钙粘蛋白内化介导的。这些发现提供了证据，暗示Rab 5a是预防内皮屏障破坏和血管炎症的潜在治疗靶点。
The small GTPase Rab5 has been well defined to control the vesicle-mediated plasma membrane protein transport to the endosomal compartment. However, its function in the internalization of vascular endothelial (VE)-cadherin, an important component of adherens junctions, and as a result regulating the endothelial cell polarity and barrier function remain unknown. Here, we demonstrated that lipopolysaccharide (LPS) simulation markedly enhanced the activation and expression of Rab5 in human pulmonary microvascular endothelial cells (HPMECs), which is accompanied by VE-cadherin internalization. In parallel, LPS challenge also induced abnormal cell polarity and dysfunction of the endothelial barrier in HPMECs. LPS stimulation promoted the translocation of VE-cadherin from the plasma membrane to intracellular compartments, and intracellularly expressed VE-cadherin was extensively colocalized with Rab5. Small interfering RNA (siRNA)-mediated depletion of Rab5a expression attenuated the disruption of LPS-induced internalization of VE-cadherin and the disorder of cell polarity. Furthermore, knockdown of Rab5 inhibited the vascular endothelial hyperpermeability and protected endothelial barrier function from LPS injury, both in vitro and in vivo. These results suggest that Rab5 is a critical mediator of LPS-induced endothelial barrier dysfunction, which is likely mediated through regulating VE-cadherin internalization. These findings provide evidence, implicating that Rab5a is a potential therapeutic target for preventing endothelial barrier disruption and vascular inflammation.