VEGFD-VEGFR3通路在缺血性脑卒中诱导的胶质瘢痕形成中的作用
首发时间:2020-04-24
摘要:目的:研究VEGFD-VEGFR3信号通路在缺血性脑卒中诱导的胶质瘢痕形成中的作用。方法:通过建立大脑中动脉阻塞(transient middle cerebral artery occlusion,tMCAO)模型,诱导大鼠大脑皮层胶质瘢痕的形成。通过氧糖剥夺再复氧(oxygen-glucose deprivation/reoxygenation,OGD/Re)模型,诱导原代星形胶质细胞胶质瘢痕的形成。通过使用VEGFR3抑制剂Axitinib及VEGFR3特异性抑制剂SAR131675抑制VEGFD-VEGFR3通路的信号传导。免疫组化、免疫荧光、Western Blotting检测脑缺血再灌注(ischemia/reperfusion,I/R)后GFAP、neurocan、phosphacan、VEGFD、VEGFR3等蛋白表达的变化。TTC染色检测C57BL/6小鼠脑缺血再灌注后脑梗死体积。乳酸脱氢酶(lactate dehydrogenase,LDH)试剂盒检测OGD/Re诱导的原代星形胶质细胞LDH漏出率以评价细胞受损情况。结果:VEGFD与VEGFR3在tMCAO诱导的大鼠大脑皮层胶质瘢痕的形成过程中表达上调。Axitinib及SAR131675抑制VEGFR3减少tMCAO诱导的大鼠大脑皮层及OGD/Re诱导的反应性星形胶质细胞中胶质瘢痕的形成。Axitinib抑制VEGFR3能够减少tMCAO诱导的C57BL/6小鼠脑梗死体积,改善行为学症状;SAR131675抑制VEGFR3能够减少OGD/Re诱导的星形胶质细胞损伤。结论:VEGFD-VEGFR3通路参与了缺血性脑卒中诱导的胶质瘢痕的形成。
关键词: 缺血性脑卒中 胶质瘢痕 VEGFD VEGFR3?????
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The role of VEGFD-VEGFR3 pathway in glial scar formation induced by ischemic stroke
Abstract:Objective: To study the role of VEGFD-VEGFR3 signaling pathway in glial scar formation induced by ischemic stroke. Methods:Transient middle cerebral artery occlusion (tMCAO) model was established to induce the formation of glial scar in rat cerebral cortex. Oxygen-glucose deprivation/reoxygenation (OGD/Re) model was used to induce the formation of glial scar in astrocytes. VEGFR3 inhibitor Axitinib andVEGFR3-specific inhibitor SAR131675were used to inhibit VEGFD-VEGFR3 pathway. Immunohistochemistry, immunofluorescence, and Western Blotting were used to detect theexpression of GFAP, neurocan, phosphacan, VEGFDand VEGFR3after cerebral ischemia/reperfusion (I/R)in vitro and in vivo models. TTC staining was used to evaluate cerebral infarction volume after cerebral ischemia/reperfusion in C57BL/6 mice. Lactate dehydrogenase (LDH) kit was used to detect the LDH leakagein OGD/Re-induced astrocytes.Results: The expression of VEGFD and VEGFR3 wasincreased in tMCAO-induced rat cerebral cortex.Axitinib and SAR131675 inhibited VEGFR3 activityto reduce the glial scar formation in tMCAO-induced rat cerebral cortex and OGD/Re-inducedastrocytes.VEGFR3 inhibitor Axitinib reduced the volume of cerebral infarction in C57BL/6 mice induced by tMCAO and improved mice behavioral symptoms; VEGFR3-specific inhibitor SAR131675reduced OGD/Re-induced astrocytesinjury. Conclusion: The VEGFD-VEGFR3 pathwayisinvolved in the formation of glial scarafterischemic stroke.?????
Keywords: ischemic stroke glial scar VEGFD VEGFR3?????
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