机构：[1]Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology,[2]Department of Neurology, Jinshan Hospital, Fudan University,[3]Department of Neurology, Tongren Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Background: Apelin-13 has been found to have protective effects on many neurological diseases, including cerebral ischemia. However, whether Apelin-13 acts on blood-brain barrier (BBB) disruption following cerebral ischemia is largely unknown. Aquaporin-4 (AQP4) has a close link with BBB due to the high concentration in astrocyte foot processes and regulation of astrocytes function. Here, we aimed to test Apelin-13's effects on ischemic BBB injury and examine whether the effects were dependent on AQP4. Methods: We detected the expression of AQP4 induced by Apelin-13 injection at 1, 3, and 7 days after middle cerebral artery occlusion. Meanwhile, we examined the effects of Apelin-13 on neurological function, infarct volume, and BBB disruption owing to cerebral ischemia in wild type mice, and tested whether such effects were AQP4 dependent by using AQP4 knock-out mice. Furthermore, we assessed the possible signal transduction pathways activated by Apelin-13 to regulate AQP4 expression via astrocyte cultures. Results: It was found that Apelin-13 highly increased AQP4 expression as well as reduced neurological scores and infarct volume. Importantly, Apelin-13 played a role of BBB protection in both types of mice by reducing BBB permeability, increased vascular endothelial growth factor, upregulated endothelial nitric oxide synthase, and downregulated inducible NOS. In morphology, we demonstrated Apelin-13 suppressed tight junction opening and endothelial cell swelling via electron microscopy detection. Meanwhile, Apelin-13 also alleviated apoptosis of astrocytes and promoted angiogenesis. Interestingly, effects of AQP4 on neurological function and infarct volume varied with time course, while AQP4 elicited protective effects on BBB at all time points. Statistical analysis of 2-way analysis of variance with replication indicated that AQP4 was required for these effects. In addition, Apelin-13 upregulated phosphorylation of extracellular signal-regulated kinase (ERK) and Akt as well as AQP4 protein in cultured astrocytes. The latter was inhibited by ERK and phosphatidylinositol 3'-kinase (PI3K) inhibitors. Conclusion: Our data suggest that Apelin-13 protects BBB from disruption after cerebral ischemia both morphologically and functionally, which is highly associated with the increased levels of AQP4, possibly through the activation of ERK and PI3K/Akt pathways. This study provides double targets to protection of ischemic BBB damage, which can present new insights to drugs development. (C) 2017 S. Karger AG, Basel
基金：
This research was supported by grants from the National Natural
Science Foundation (No. 81171129; 81500998) of China, National
Basic Research Program (973 Program, No. 2012CB518602) of
China and Science and Technology Commission of Shanghai Municipality
grant (No. 16140903200).
第一作者机构：[1]Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology,
共同第一作者：
通讯作者：
通讯机构：[1]Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology,[*1]Department of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Fudan University No.12 Mid. Wulumuqi Road, Shanghai 200040 (China)
推荐引用方式(GB/T 7714)：
Chu Heling,Yang Xiaobo,Huang Chuyi,et al.Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4[J].CEREBROVASCULAR DISEASES.2017,44(1-2):10-25.doi:10.1159/000460261.
APA：
Chu, Heling,Yang, Xiaobo,Huang, Chuyi,Gao, Zidan,Tang, Yuping&Dong, Qiang.(2017).Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4.CEREBROVASCULAR DISEASES,44,(1-2)
MLA：
Chu, Heling,et al."Apelin-13 Protects against Ischemic Blood-Brain Barrier Damage through the Effects of Aquaporin-4".CEREBROVASCULAR DISEASES 44..1-2(2017):10-25
