Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement
Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement
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DOI：
10.1172/jci12450
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发表时间：
2001-09-01
影响因子：
15.9
通讯作者：
English, D
中科院分区：
文献类型：
--
作者：
Garcia, JGN;Liu, F;English, D
血小板在血液凝固过程中释放的物质是连接止血和血管生成并确保伤口充分愈合和组织损伤修复的重要参与者。我们评估了 1-磷酸鞘氨醇 (Sph-1-P)（一种从活化血小板释放的生物活性磷酸化脂质生长因子）在调节内皮单层屏障完整性中的参与，而内皮单层屏障完整性是血管生成和血管稳态的关键。 Sph-1-P 在人和牛肺动脉和肺微血管内皮细胞中产生快速、持续和剂量依赖性的跨单层电阻 (TER) 增加。这种物质还可以逆转由水肿剂凝血酶引起的屏障功能障碍。 Sph-1-P 介导的屏障增强依赖于 G(i α) 受体与内皮分化基因 (Edg) 受体家族（Edg-1 和 Edg-3）特定成员的偶联、Rho 激酶和酪氨酸激酶依赖性激活以及肌动蛋白丝重排。 Sph-l-P 增强的 TER 与 Rac GTPase 和 p21 相关的激酶依赖性内皮皮质肌动蛋白组装以及肌动蛋白丝调节蛋白 cofilin 的募集一起发生。血小板释放的 Sph-1-P 与 Rac 和 Rho 依赖性细胞骨架重排有关，可能在血管生成后期发挥作用，以稳定新形成的血管，这些血管通常表现出异常增加的血管通透性。
Substances released by platelets during blood clotting are essential participants in events that link hemostasis and angiogenesis and ensure adequate wound healing and tissue injury repair. We assessed the participation of sphingosine 1-phosphate (Sph-1-P), a biologically active phosphorylated lipid growth factor released from activated platelets, in the regulation of endothelial monolayer barrier integrity, which is key to both angiogenesis and vascular homeostasis. Sph-1-P produced rapid, sustained, and dose-dependent increases in transmonolayer electrical resistance (TER) across both human and bovine pulmonary artery and lung microvascular endothelial cells. This substance also reversed barrier dysfunction elicited by the edemagenic agent thrombin. Sph-1-P-mediated barrier enhancement was dependent upon G(i alpha)-receptor coupling to specific members of the endothelial differentiation gene (Edg) family of receptors (Edg-1 and Edg-3), Rho kinase and tyrosine kinase-dependent activation, and actin filament rearrangement. Sph-l-P-enhanced TER occurred in conjunction with Rac GTPase- and p21-associated kinase-dependent endothelial cortical actin assembly with recruitment of the actin filament regulatory protein, cofilin. Platelet-released Sph-1-P, linked to Rac- and Rho-dependent cytoskeletal rearrangement, may act late in angiogenesis to stabilize newly formed vessels, which often display abnormally increased vascular permeability.