Institute of Medical Biochemistry, Centre for Molecular Biology of Inflammation, University of Münster, Von-Esmarch-Strasse 56, 48149 Münster, Germany.
Int J Mol Sci. 2018 Jun 13;19(6):1752. doi: 10.3390/ijms19061752.
Endothelial cells serve as gatekeepers of vascular hemostasis and local inflammatory reactions. They can rapidly respond to changes in the environment, caused, for example, by blood vessel injury, tissue damage or infection, by secreting in a strictly regulated manner factors regulating these processes. These factors include adhesion receptors for circulating leukocytes and platelets, P-selectin and von-Willebrand factor (VWF) that are stored in specialized secretory granules of endothelial cells, the Weibel-Palade bodies (WPB). Acute exposure of these adhesion molecules converts the endothelial cell surface from an anti-adhesive state enabling unrestricted flow of circulating blood cells to an adhesive one capable of capturing leukocytes (through P-selectin) and platelets (through VWF). While these are important (patho)physiological responses, compromised or dysregulated WPB secretion can cause pathologies such as excessive bleeding or vascular occlusion. Several factors are involved in regulating the exocytosis of WPB and thus represent potential targets for therapeutic interventions in these pathologies. Among them, the annexin A2 (AnxA2)-S100A10 complex has been shown to participate in the tethering/docking of secretion-competent WPB at the plasma membrane, and interference with AnxA2/S100A10 expression or complex formation significantly reduces acute WPB exocytosis and VWF release. Thus, developing specific means to efficiently block AnxA2-S100A10 complex formation in endothelial cells could lead to novel avenues towards interfering with acute vascular thrombosis.
内皮细胞作为血管止血和局部炎症反应的守门员。它们可以迅速响应环境变化，例如血管损伤、组织损伤或感染，通过以严格调节的方式分泌调节这些过程的因子。这些因子包括循环白细胞和血小板的粘附受体、储存于内皮细胞特殊分泌颗粒 Weibel-Palade 小体 (WPB) 中的 P-选择素和血管性血友病因子 (VWF)。这些粘附分子的急性暴露将内皮细胞表面从允许循环血细胞无限制流动的抗粘附状态转化为能够捕获白细胞 (通过 P-选择素) 和血小板 (通过 VWF) 的粘附状态。虽然这些是重要的（病理）生理反应，但 WPB 分泌受损或失调可导致病理性出血或血管阻塞等疾病。有几种因素参与调节 WPB 的胞吐作用，因此代表了这些疾病治疗干预的潜在靶点。其中，膜联蛋白 A2 (AnxA2)-S100A10 复合物已被证明参与了具有分泌能力的 WPB 在质膜上的系留/对接，干扰 AnxA2/S100A10 的表达或复合物形成显著减少急性 WPB 胞吐作用和 VWF 释放。因此，开发有效的方法特异性阻断内皮细胞中 AnxA2-S100A10 复合物的形成可能会为干扰急性血管血栓形成开辟新途径。
