载脂蛋白E拟肽在脑血管痉挛中的保护机制

Protective role of apoE-mimetic peptide on vasospasm and its mechanism

目的：研究血管内皮生长因子（VEGF）-细胞外信号调节激酶（ERK）信号转导通路在脑血管痉挛后早期脑损伤中的作用,探讨载脂蛋白E（apoE）拟肽通过此途径发挥的保护机制.方法：采用非开颅血管内穿线法制备小鼠蛛网膜下腔出血（SAH）和脑血管痉挛模型,给予apoE-1410肽,术后脑血管铸型检测大脑中动脉（MCA）直径变化,分别在术后12、 24、 48h 3个时相点取右侧大脑动脉标本,应用免疫印迹法检测各组VEGF、 p-ERK1/2蛋白表达,TUNEL法检测MCA内皮细胞凋亡.结果：模型组MCA出现严重的血管痉挛,管腔直径减小,随脑血管痉挛时间延长,各组小鼠VEGF、 p-ERK1/2蛋白均有不同程度上调,凋亡细胞增多.与模型组比较,治疗组MCA管腔直径增加,各时相点3项指标的表达均不同程度下调.蛛网膜下腔出血12～48h VEGF表达与p-ERK1/2呈正相关;p-ERK1/2与TUNEL呈正相关.结论：脑血管痉挛后VEGF表达增强可通过激活ERK信号途径诱导大脑动脉内皮细胞凋亡;拟apoE-1410肽对脑血管痉挛具有一定的治疗作用,其机制之一可能是通过部分阻抑VEGF/ERK通路活化减少凋亡实现的.

Objective： To investigate the protective role of apoE-1410 in nervous system and molecular mechanism of vascular endothelial growth factor （VEGF）-extracellular signal regulated kinase （ERK） signaling pathway on vasospasm Methods： We made a stable and reliable mice cerebral vasospasm （CVS） model by endovascular perforation without opening cranium At different time points （12, 24, 48 h） after operation, vascular casting technique was performed to observe diameter changes of middle cerebral arteries （MCA）, Western blotting assay was used to examine the VEGF, p-ERK1/2 expression, and the apoptotic cell number was determined by TUNEL. Results： In subarachnoid hemorrhage （SAH） group, the diameters of MCA were smaller than those of control mice, and the VEGF, p-ERK1/2 level and the number of apoptosis cells were significantly increased. The expression of VEGF, p-ERK1/2 and the number of apoptosis cells were lower in the apoE group than those in the SAH group, and vasospasm was relieved. The quantification of VEGF expression was positively correlated with p-ERK1/2, and the expression of p-ERK1/2 was positively correlated with the TUNEL positive cells after CVS. Conclus/on：The increased expression of VEGF in the cerebral arteries may induce apoptosis by activation of ERK signaling pathway after CVS. The apoE-1410 reduces apoptosis of cerebral arteries endothelial cells by inhibiting the activation of the VEGF/ERK signaling pathway.