MicroRNA-126 Regulates Angiogenesis and Neurogenesis in a Mouse Model of Focal Cerebral Ischemia
MicroRNA-126 Regulates Angiogenesis and Neurogenesis in a Mouse Model of Focal Cerebral Ischemia
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MicroRNA-126 调节局灶性脑缺血小鼠模型中的血管生成和神经发生
DOI：
10.1016/j.omtn.2019.02.002
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发表时间：
2019-06-07
影响因子：
8.8
通讯作者：
Yang, Guo-Yuan
中科院分区：
文献类型：
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作者：
Qu, Meijie;Pan, Jiaji;Yang, Guo-Yuan
研究表明，microRNA-126在促进血管生成中起着关键作用。然而，其对缺血性卒中后血管生成的影响尚不清楚。在此，我们探讨了microRNA-126- 3 p和microRNA-126- 5 p对脑缺血后血管生成和神经发生的影响。我们证明，与乱序miRNA对照相比，microRNA（miRNA）-126-3p和microRNA-126- 5 p都增加了人脐静脉内皮细胞（HUVECs）的增殖、迁移和管形成（p < 0.05）。通过慢病毒将microRNA-126转移到小鼠大脑中动脉闭塞模型中，我们发现microRNA-126过表达增加了CD 31（+）/BrdU（+）的数量。（5-溴-2 '-脱氧尿苷阳性）增殖内皮细胞和DCX+/BrdU（+）神经母细胞在缺血小鼠脑中，改善神经行为结果（p < 0.05），并且与对照小鼠相比减少脑萎缩体积（p < 0.05）。Western blot结果显示，在慢病毒-microRNA-126处理组中，AKT和ERK信号通路被激活（p < 0.05）。PCR和蛋白质印迹结果均表明，在慢病毒-microRNA-126处理组中，酪氨酸蛋白磷酸酶非受体9型（PTPN 9）降低（p < 0.05）。双荧光素酶报告基因检测也表明PTPN 9是缺血脑中microRNA-126- 3 p和microRNA-126- 5 p的直接靶点。我们证明microRNA-126- 3 p和microRNA-126- 5 p促进缺血小鼠脑中的血管生成和神经发生，并进一步改善神经行为结果。我们的机制研究进一步表明microRNA-126通过直接抑制其靶点PTPN 9并激活AKT和ERK信号通路介导血管生成。
Studies demonstrate that microRNA-126 plays a critical role in promoting angiogenesis. However, its effects on angiogenesis following ischemic stroke are unclear. Here, we explored the effect of microRNA-126-3p and microRNA-126-5p on angiogenesis and neurogenesis after brain ischemia. We demonstrated that both microRNA (miRNA)-126-3p and microRNA-126-5p increased the proliferation, migration, and tube formation of human umbilical vein endothelial cells (HUVECs) compared with the scrambled miRNA control (p < 0.05). Transferring microRNA-126 into a mouse middle cerebral artery occlusion model via lentivirus, we found that microRNA-126 overexpression increased the number of CD31(+)/BrdU(+) (5-bromo-2'-deoxyuridine-positive) proliferating endothelial cells and DCX+/BrdU(+) neuroblasts in the ischemic mouse brain, improved neurobehavioral outcomes (p < 0.05), and reduced brain atrophy volume (p < 0.05) compared with control mice. Western blot results showed that AKT and ERK signaling pathways were activated in the lentiviral-microRNA-126-treated group (p < 0.05). Both P CR and western blot results demonstrated that tyrosine-protein phosphatase non-receptor type 9 (PTPN9) was decreased in the lentiviral-microRNA-126-treated group (p < 0.05). Dual-luciferase gene reporter assay also showed that PTPN9 was the direct target of microRNA-126-3p and microRNA-126-5p in the ischemic brain. We demonstrated that microRNA-126-3p and microRNA-126-5p promoted angiogenesis and neurogenesis in ischemic mouse brain, and further improved neurobehavioral outcomes. Our mechanistic study further showed that microRNA-126 mediated angiogenesis through directly inhibiting its target PTPN9 and activating AKT and ERK signaling pathways.