Tert-butylhydroquinone enhanced angiogenesis and astrocyte activation by activating nuclear factor-E2-related factor 2/heme oxygenase-1 after focal cerebral ischemia in mice
Tert-butylhydroquinone enhanced angiogenesis and astrocyte activation by activating nuclear factor-E2-related factor 2/heme oxygenase-1 after focal cerebral ischemia in mice
复制标题
叔丁基氢醌通过激活小鼠局灶性脑缺血后核因子-E2相关因子2/血红素加氧酶-1增强血管生成和星形胶质细胞活化
DOI：
10.1016/j.mvr.2019.103891
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发表时间：
2019-11-01
影响因子：
3.1
通讯作者：
He, Weiliang
中科院分区：
文献类型：
--
作者：
Chen, Yanxia;Zhang, Xiangjian;He, Weiliang
脑缺血后的血管生成在神经功能恢复中起着关键作用，是治疗的靶点。核因子E2相关因子2(Nrf2)的血管生成作用是近年来发现的。然而，Nrf2诱导剂叔丁基对苯二酚对卒中后血管生成和星形胶质细胞激活的影响尚不清楚。在这项研究中，我们研究了叔丁基对苯二酚是否通过Nrf2途径促进血管生成和星形胶质细胞的激活。野生型(Nrf2(+/+))和缺陷型(Nrf2(-/-))小鼠造成大脑中动脉远端永久性闭塞(DMCAO)。共设6个实验组(Sham Nrf2(+/+)组、Vehicle Nrf2(+/+)组、TBHQ Nrf2(+/+)组、Sham Nrf2组、Vehicle Nrf2(-/-)组、TBHQ Nrf2组)。观察不同时间点脑缺血再灌注后各时间点的脑梗塞体积、神经功能、微血管密度(MVD)、星形细胞终末覆盖率及Nrf2、HO-1、VEGF的表达。与载体Nrf2(+/+)组相比，TBHQ可显著缩小梗死灶体积，增加卒中后血管生成，增加梗死灶周围星形细胞终足覆盖率。在血管生成过程中，TbHQ激活了Nrf2/HO-1/VEGF通路。然而，在Nrf2(-/-)小鼠中，Nrf2缺乏阻断了TBHQ对血管生成过程和神经恢复的影响，并取消了促血管生成因子的中介作用。提示TBHQ通过激活Nrf2通路促进脑缺血后血管生成和星形胶质细胞活化。
Angiogenesis after cerebral ischemia plays a pivotal role in neurological recovery and represents a therapeutic target. The angiogenic effect of nuclear factor E2-related factor 2 (Nrf2) was identified in recent years. However, the effects of tert-butylhydroquinone, an Nrf2 inducer, on angiogenesis and astrocyte activation after stroke remain unclear. In this study, we investigated whether tert-butylhydroquinone enhanced angiogenesis and astrocyte activation through Nrf2 pathway. Wild-type (Nrf2(+/+)) and Nrf2-deficient (Nrf2(-/-)) mice were subjected to permanent distal middle cerebral artery occlusion (dMCAO). We established 6 experimental groups (sham Nrf2(+/+)) group, vehicle Nrf2(+/+) group, tBHQ Nrf2(+/+) group; sham Nrf2 group, vehicle Nrf2(-/-) group, and tBHQ Nrf2 group). The infarct volume, neurological function, microvessel density (MVD), astrocytic endfeet covered ratio and the expression of Nrf2, HO-1 and VEGF in the ischemic brain were measured at different time points. Compared with that observed in the vehicle Nrf2(+/+) group, tBHQ significantly reduced the infarct volume, enhanced post-stroke angiogenesis and astrocytic endfeet covered ratio in the peri-infarct area. The Nrf2/HO-1/VEGF pathway was activated by tBHQ in the angiogenesis process. However, in Nrf2(-/-) mice, Nrf2 deficiency blocked the effects of tBHQ on angiogenesis process and neurological recovery as well as abolished the mediation of proangiogenic factors. These results suggested that tBHQ enhanced angiogenesis and astrocyte activation through activating Nrf2 pathway after cerebral ischemia.