Tissue Plasminogen Activator Causes Brain Microvascular Endothelial Cell Injury After Oxygen Glucose Deprivation by Inhibiting Sonic Hedgehog Signaling
Tissue Plasminogen Activator Causes Brain Microvascular Endothelial Cell Injury After Oxygen Glucose Deprivation by Inhibiting Sonic Hedgehog Signaling
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DOI：
10.1007/s11064-018-2697-2
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发表时间：
2019-02-01
影响因子：
4.4
通讯作者：
Xu, Zhou
中科院分区：
文献类型：
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作者：
Gong, Pian;Li, Mingchang;Xu, Zhou
组织纤溶酶原激活剂 (tPA) 的溶栓活性具有无可争议的益处。然而，已记录的 tPA 神经毒性引发了重要问题。目前，如果外源性 tPA 能够穿过血脑屏障并进入大脑，从而增加 tPA 在脑实质内的有害作用，那么常见的中风治疗方法可能不是最佳的。在这里，我们确定了 tPA 是否会在脑缺血期间损伤脑微血管内皮细胞 (BMEC)。我们发现，用 tPA 处理 BMEC 可以降低跨内皮电阻和细胞增殖，并阻断细胞周期在 G0-G1 期。此外，Sonic Hedgehog (Shh) 信号通路参与 tPA 诱导的 BMEC 功能障碍。然而，tPA 增强的氧糖剥夺诱导的 BMEC 功能障碍可通过 Shh 给药消除，并且该影响可以通过 Shh 抑制剂逆转。综上所述，这些结果表明，由于 Shh 信号通路受阻，tPA 给药可能会导致内皮屏障受损。
The thrombolytic activity of tissue plasminogen activator (tPA) has undisputed benefits. However, the documented neurotoxicity of tPA raises important issues. Currently, common treatments for stroke might not be optimum if exogenous tPA can pass through the blood-brain barrier and enter the brain, thus adding to the deleterious effects of tPA within the cerebral parenchyma. Here, we determined whether tPA could damage brain microvascular endothelial cells (BMECs) during cerebral ischemia. We showed that treatment of BMECs with tPA decreased trans-endothelial electrical resistance and cell proliferation, and blocked the cell cycle at the G0-G1 phase. In addition, the Sonic hedgehog (Shh) signaling pathway was involved in tPA-induced BMECs dysfunction. However, tPA-enhanced oxygen glucose deprivation-induced BMECs dysfunction was eliminated by Shh administration and the effects could be reversed by Shh inhibitors. Taken together, these results demonstrate that tPA administration might result in damage to the endothelial barrier owing to blocked Shh signaling pathway.