PROTECTION OF GRANULOCYTE-COLONY STIMULATING FACTOR TO HEMORRHAGIC BRAIN INJURIES AND ITS INVOLVED MECHANISMS: EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND AQUAPORIN-4
PROTECTION OF GRANULOCYTE-COLONY STIMULATING FACTOR TO HEMORRHAGIC BRAIN INJURIES AND ITS INVOLVED MECHANISMS: EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND AQUAPORIN-4
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粒细胞集落刺激因子对出血性脑损伤的保护作用及其机制：血管内皮生长因子和水通道蛋白4的作用
DOI：
10.1016/j.neuroscience.2013.12.017
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发表时间：
2014-02-28
期刊：
影响因子：
3.3
通讯作者：
Dong, Q.
中科院分区：
文献类型：
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作者：
Chu, H.;Tang, Y.;Dong, Q.
粒细胞集落刺激因子（G-CSF）对许多神经系统疾病具有保护作用。在这里，我们旨在测试G-CSF对脑出血（ICH）后血肿周围组织损伤的作用，并研究其作用是否在功能上依赖于血管内皮生长因子（VEGF）和水通道蛋白-4 （AQP4）。我们在脑出血后1、3、7天检测血肿周围VEGF、VEGF受体（VEGFRs）和AQP4的表达。此外，我们还研究了G-CSF对野生型小鼠脑出血组织损伤的影响，并通过VEGFR抑制剂- su5416和AQP4敲除（AQP4(-/-)）小鼠检测了这种影响是否依赖于VEGF和AQP4。此外，我们通过星形胶质细胞培养评估了相关的信号转导途径。我们发现G-CSF显著增加了血周VEGF、VEGFR-2和AQP4。重要的是，G-CSF通过减少脑水肿、血脑屏障（BBB）通透性、神经元死亡和凋亡，导致两种类型小鼠的神经功能改善，统计分析表明，这些作用需要AQP4。此外，除缓解血脑屏障渗漏外，上述作用均被SU5416减弱但未被抵消，提示VEGF参与其中。G-CSF上调培养星形胶质细胞细胞外信号调节激酶（ERK）、信号传导和转录激活因子3 （STAT3）以及VEGF和AQP4蛋白的磷酸化。后者分别被ERK和STAT3抑制剂抑制。我们的数据表明，G-CSF对脑出血后血肿周围组织损伤的保护作用与VEGF和AQP4水平升高高度相关，可能分别通过C-Jun氨基末端激酶和ERK途径起作用。(C) 2013年作者。Elsevier Ltd.出版。版权所有。
Granulocyte-colony stimulating factor (G-CSF) has protective effects on many neurological diseases. Here, we aimed to test G-CSF's effects on perihematomal tissue injuries following intracerebral hemorrhage (ICH) and examine whether the effects were functionally dependent on vascular endothelial growth factor (VEGF) and aquaporin-4 (AQP4). We detected the expression of perihematomal VEGF, VEGF receptors (VEGFRs) and AQP4 at 1, 3 and 7 days after ICH. Also, we examined the effects of G-CSF on tissue injuries by ICH in wild type mice, and tested whether such effects were VEGF and AQP4 dependent by using VEGFR inhibitor -SU5416 and AQP4 knock-out (AQP4(-/-)) mice. Furthermore, we assessed the related signal transduction pathways via astrocyte cultures. We found G-CSF highly increased perihematomal VEGF, VEGFR-2 and AQP4. Importantly, G-CSF led to neurological functional improvement in both types of mice by associating with reduction of brain edema, blood-brain barrier (BBB) permeability and neuronal death and apoptosis and statistical analysis suggested AQP4 was required for these effects. Besides, except BBB leakage alleviation, the above effects were attenuated but not counteracted by SU5416, suggesting involvement of VEGF. G-CSF up-regulated phosphoryla-tion of extracellular signal-regulated kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) as well as VEGF and AQP4 proteins in cultured astrocytes. The latter was inhibited by ERK and STAT3 inhibitors respectively. Our data suggest the protective effects of G-CSF on perihematomal tissue injuries after ICH are highly associated with the increased levels of VEGF and AQP4, possibly act through C-Jun amino-terminal kinase and ERK pathways respectively. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.