Grimsey Neil J, Trejo JoAnn
Department of Pharmacology, School of Medicine, University of California, San Diego, La Jolla, California, USA.
Curr Opin Hematol. 2016 May;23(3):274-9. doi: 10.1097/MOH.0000000000000232.
The maintenance and integrity of the endothelial barrier is essential for vascular homeostasis. Endothelial barrier dysfunction is mediated by various inflammatory factors, many of which act through G protein-coupled receptors including protease-activated receptors (PARs). PARs are expressed in multiple cell types in the vasculature and mediate cellular responses to thrombin, the key effector protease of the coagulation cascade. Thrombin activation of PAR1 induces endothelial barrier permeability through multiple pathways. Here, we discuss the mechanism by which thrombin activation of PAR1 promotes endothelial barrier breakdown and highlight recent advances that have provided new insight into molecular mechanisms that control endothelial barrier integrity.
Although the signal transduction pathways induced by thrombin activation of PAR1 in endothelial cells have been extensively studied, the key regulatory mechanisms remain poorly understood. Posttranslational modifications are integral to the regulation of PAR1 signaling and recent studies suggest a novel function for ubiquitination of PAR1 in regulation of endothelial barrier permeability.
An understanding of how endothelial barrier permeability is regulated by thrombin activation of PAR1 is important for the discovery of new drug targets that can be manipulated to control endothelial barrier permeability and prevent progression of vascular inflammation.
内皮屏障的维持和完整性对于血管稳态至关重要。内皮屏障功能障碍由多种炎症因子介导，其中许多通过G蛋白偶联受体发挥作用，包括蛋白酶激活受体（PARs）。PARs在脉管系统的多种细胞类型中表达，并介导细胞对凝血酶（凝血级联反应的关键效应蛋白酶）的反应。凝血酶激活PAR1通过多种途径诱导内皮屏障通透性增加。在此，我们讨论凝血酶激活PAR1促进内皮屏障破坏的机制，并强调最近的进展，这些进展为控制内皮屏障完整性的分子机制提供了新的见解。
尽管凝血酶激活内皮细胞中PAR1所诱导的信号转导途径已得到广泛研究，但关键的调控机制仍知之甚少。翻译后修饰是PAR1信号调控不可或缺的部分，最近的研究表明PAR1泛素化在调节内皮屏障通透性方面具有新功能。
了解凝血酶激活PAR1如何调节内皮屏障通透性对于发现新的药物靶点很重要，这些靶点可被操控以控制内皮屏障通透性并预防血管炎症进展。
