Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia
Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia
复制标题
组织纤溶酶原激活剂通过增加脑缺血后周细胞介导的炎症反应来破坏血脑屏障
DOI：
10.18632/aging.102431
复制
发表时间：
2019-11-30
期刊：
影响因子：
5.2
通讯作者：
Wu, Jialing
中科院分区：
文献类型：
--
作者：
Yang, Eryan;Cai, Ying;Wu, Jialing
周细胞是血脑屏障(BBB)的重要组成部分，在维持血脑屏障的完整性、调节止血、血管生成、炎症和吞噬功能等方面发挥着重要作用。我们研究了周细胞是否参与了重组组织型纤溶酶原激活剂(rt-PA)诱导的炎症反应，从而破坏了血脑屏障，并探讨了可能的机制。采用大脑中动脉闭塞(MCAO)和缺糖缺氧组(OGD)模拟大鼠缺氧缺血状态。小鼠大脑中动脉阻塞1h后静脉注射rt-PA，OGD后4h在培养液中加入rt-PA。与低氧处理相比，rt-PA处理加重了血脑屏障的破坏，而依那西普(肿瘤坏死因子-α抑制剂)联合rt-PA在体内和体外均减轻了rt-PA诱导的血脑屏障破坏。体内、体外RT-PA处理组与缺氧处理组比较，肿瘤坏死因子-α和单核细胞趋化蛋白-1水平升高，转化生长因子-β、p-Smad2/3和PDGFR-β水平降低。与rt-PA相比，转化生长因子-β联合rt-PA可减少肿瘤坏死因子-α和单核细胞趋化蛋白-1的分泌，减轻血脑屏障的破坏，这些变化可被TPO427736HCl(转化生长因子-β/p-Smad2/3途径抑制剂)共同作用所阻断。Rt-PA不降低去卵巢后PDGFR-β高表达的周细胞转化生长因子-β和p-Smad2/3的表达。这些发现证实周细胞中的PDGFR-β/转化生长因子-β/p-Smad2/3信号通路是治疗rt-PA诱导的血脑屏障损伤的新靶点。
Pericytes, important elements of the blood-brain barrier (BBB), play critical roles in maintaining BBB integrity and modulating hemostasis, angiogenesis, inflammation and phagocytic function. We investigated whether pericytes are involved in the recombinant tissue plasminogen activator (rt-PA)-induced inflammatory response, which disrupts the BBB, and investigated the potential mechanisms. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) were employed to mimic hypoxic-ischemic conditions. Rt-PA was intravenously injected into mice 1 h after 1 h MCAO, and Rt-PA was added to the culture medium after 4 h OGD. Rt-PA treatment aggravated the disruption of the BBB compared with hypoxia treatment, and etanercept (TNF-α inhibitor) combined with rt-PA alleviated the rt-PA-induced BBB disruption in vivo and in vitro. Rt-PA treatment increased the TNF-α and MCP-1 levels and decreased the TGF-β, p-Smad2/3 and PDGFR-β levels compared with hypoxia treatment in vivo and vitro. TGF-β combined with rt-PA decreased TNF-α and MCP-1 secretion and alleviated BBB disruption compared with rt-PA; these changes were abrogated by TPO427736 HCL (a TGF-β/p-Smad2/3 pathway inhibitor) cotreatment in vitro. Rt-PA did not decrease TGF-β and p-Smad2/3 expression in PDGFR-β-overexpressing pericytes after OGD. These findings identify PDGFR-β/TGF-β/p-Smad2/3 signaling in pericytes as a new therapeutic target for the treatment of rt-PA-induced BBB damage.