Garcia J G, Liu F, Verin A D, Birukova A, Dechert M A, Gerthoffer W T, Bamberg J R, English D
Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21224, USA.
J Clin Invest. 2001 Sep;108(5):689-701. doi: 10.1172/JCI12450.
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(ialpha)-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-1-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.
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。我们评估了鞘氨醇-1-磷酸（Sph-1-P），一种从活化血小板释放的具有生物活性的磷酸化脂质生长因子，在调节内皮单层屏障完整性中的作用，内皮单层屏障完整性对于血管生成和血管稳态均至关重要。Sph-1-P可使人和牛肺动脉及肺微血管内皮细胞的跨单层电阻（TER）迅速、持续且呈剂量依赖性增加。该物质还可逆转由致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（αi）受体与内皮分化基因（Edg）受体家族（Edg-1和Edg-3）的特定成员偶联、Rho激酶和酪氨酸激酶依赖性激活以及肌动蛋白丝重排。Sph-1-P增强TER的同时伴有Rac GTP酶和p21相关激酶依赖性内皮皮质肌动蛋白组装，并伴有肌动蛋白丝调节蛋白cofilin的募集。血小板释放的Sph-1-P与Rac和Rho依赖性细胞骨架重排相关，可能在血管生成后期起作用，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。
