Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells
Monocyte-derived microparticles and exosomes induce procoagulant and apoptotic effects on endothelial cells
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DOI：
10.1160/th07-11-0691
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发表时间：
2008-11-01
影响因子：
6.7
通讯作者：
Brenner, Benjamin
中科院分区：
文献类型：
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作者：
Aharon, Anat;Tamari, Tal;Brenner, Benjamin
微囊泡（MV）包括微粒（MP）和外泌体，其在正常生理条件下存在于血液循环中，并且在多种疾病中增加。本研究从形态学、细胞凋亡和血栓形成等方面探讨了MVs对体外培养的人脐静脉内皮细胞（HUVEC）的影响。单核细胞系（THP-I）通过饥饿或通过内毒素和钙离子载体A23187刺激导致MV的释放，所述MV表达外泌体标志物Tsg 101、其小叶中的阴性磷脂、单核细胞标志物（CD 18、CD 14）和活性组织因子（TF）。发现MV破坏EC完整性并快速诱导膜起泡。短暂暴露于MV（2-4小时）导致EC膜磷脂“翻转”，而较长的刺激（20小时）导致两个矛盾的结果-管形成以及凋亡，如通过核碎裂评估的。此外，MV暴露导致细胞表面血栓形成性增加和内皮止血平衡紊乱，这在较长的暴露时间内得到增强。凝血起始因子TF的活性、抗原水平和mRNA表达升高是由于（i）MV衍生的TF粘附到EC膜，和（ii）内皮TF表达增加。此外，抗凝剂组织因子途径抑制物（TFPI）和血栓调节蛋白（TM）水平降低。这些发现表明，单核细胞MV增加内皮血栓形成和细胞凋亡。此外，它们诱导管形成，这可能表明它们的血管生成作用。这些发现可能部分阐明了MV在与炎症性疾病和高凝状态相关的EC功能障碍中的作用。
Microvesicles (MVs) which include microparticles (MPs) and exosomes are found in blood circulation in normal physiologic conditions and are increased in a variety of diseases. This study evaluated the effects of MVs on human umbilical vein endothelial cells (HUVEC) by morphologic changes, apoptosis, and thrombogenicty, in vitro. Stimulation of monocyte cell line (THP-I) by starvation or by endotoxin and calcium ionophore A23187 resulted in the release of MVs which express exosome marker Tsg 101, negative phospholipids in their leaflets, monocyte markers (CD18, CD14) and active tissue factor (TF). MVs were found to disrupt EC integrity and rapidly induce membrane blebbing. Brief exposure (2-4 hours) to MVs resulted in EC membrane phospholipids "flip-flop" while longer stimulation (20 hours) led to two contradicting outcomes-tube formation as well as apoptosis, as assessed by nuclear fragmentation. Additionally, MVs exposure resulted in increased cell surface thrombogenicity and perturbation of the endothelial haemostatic balance, which were enhanced during longer exposure time. Activity, antigen level and mRNA expression of the coagulation initiator TF were elevated due to (i) adherence of MVs derived TF to the EC membrane, and (ii) an increase in endothelial TF expression. Furthermore, levels of the anticoagulant tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) were decreased. These findings demonstrate that monocyte MVs increase endothelial thrombogenicity and apoptosis. In addition, they induce tube formation which may indicate their angiogenic effect. These findings may clarify, in part, the role of MVs in EC dysfunction associated with inflammatory diseases and hyper-coagulable states.