MicroRNA-149-5p regulates blood-brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes
MicroRNA-149-5p regulates blood-brain barrier permeability after transient middle cerebral artery occlusion in rats by targeting S1PR2 of pericytes
复制标题
MicroRNA-149-5p 通过靶向周细胞的 S1PR2 调节大鼠短暂大脑中动脉闭塞后的血脑屏障通透性。
DOI：
10.1096/fj.201701121r
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发表时间：
2018-06-01
期刊：
影响因子：
4.8
通讯作者：
Hu, Bo
中科院分区：
文献类型：
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作者：
Wan, Yan;Jin, Hui-Juan;Hu, Bo
缺血性脑卒中后再灌注损伤引起的血脑屏障（BBB）破坏是一个有利于进一步损伤的难治性事件。脑周细胞通过与血脑屏障的其他成分相互作用，在维持血脑屏障完整性方面起着至关重要的作用。在本研究中，我们发现鞘氨醇-1-磷酸受体（S1PR）2在体内和体外缺血后在周细胞中表达明显上调。通过使用S1PR2拮抗剂（JTE-013），我们发现S1PR2在诱导短暂性大脑中动脉闭塞（tMCAO）大鼠和体外血脑屏障模型的血脑屏障通透性中起关键作用。此外，我们发现S1PR2可通过NF-kappa B p65信号降低N-cadherin的表达，增加周细胞的迁移，并发现S1PR2可受miR-149-5p的负调控，在缺血边界区和培养周细胞中，miR-149-5p在缺血后降低。在体外培养的周细胞中过表达miR-149-5p可显著增加N-cadherin的表达，减少周细胞的迁移，从而减少体外模型中的血脑屏障渗漏。脑室内注射agomir-149-5p上调miR-149-5p可显著降低脑屏障通透性，改善tMCAO大鼠的预后。因此，我们的数据表明miR-149-5p可能作为治疗缺血性卒中后血脑屏障破坏的潜在靶点。
Blood-brain barrier (BBB) disruption caused by reperfusion injury after ischemic stroke is an intractable event conducive to further injury. Brain pericytes play a vital role in maintaining BBB integrity by interacting with other components of the BBB. In this study, we found that sphingosine-1-phosphate receptor (S1PR)2 expressed in pericytes was significantly up-regulated after ischemia in vivo and in vitro. By using a S1PR2 antagonist (JTE-013), we showed that S1PR2 plays a critical role in the induction of BBB permeability of transient middle cerebral artery occlusion (tMCAO) rats and the in vitro BBB model. Furthermore, we discovered that S1PR2 may decrease N-cadherin expression and increase pericyte migration via NF-kappa B p65 signal and found that S1PR2 could be regulated by miR-149-5p negatively, which was decreased in the ischemic boundary zone and cultured pericytes after ischemia. Overexpression of miR-149-5p in cultured pericytes substantially increased N-cadherin expression and decreased pericyte migration, which decreased BBB leakage in the in vitro model. Up-regulating miR-149-5p by intracerebroventricular injection of agomir-149-5p attenuated BBB permeability and improved the outcomes of tMCAO rats significantly. Thus, our data suggest that miR-149-5p may serve as a potential target for treatment of BBB disruption after ischemic stroke.