Protection of Vascular Endothelial Growth Factor to Brain Edema Following Intracerebral Hemorrhage and Its Involved Mechanisms: Effect of Aquaporin-4.
Protection of Vascular Endothelial Growth Factor to Brain Edema Following Intracerebral Hemorrhage and Its Involved Mechanisms: Effect of Aquaporin-4.
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血管内皮生长因子对脑出血后脑水肿的保护作用及其机制：Aquaporin-4的作用。
DOI：
10.1371/journal.pone.0066051
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dong Q
中科院分区：
文献类型：
--
作者：
Chu H;Tang Y;Dong Q
血管内皮生长因子（VEGF）对许多神经系统疾病具有保护作用。然而，VEGF是否作用于脑出血（ICH）后的脑水肿在很大程度上是未知的。本课题组前期研究表明，水通道蛋白4（AQP 4）在脑出血后脑水肿的消除中起重要作用。同时，VEGF与AQP 4之间存在着密切的关系。在这项研究中，我们的目的是测试VEGF对脑出血后脑水肿的影响，并检查它们是否依赖于AQP 4。采用自体全血纹状体内微量注射法诱导脑出血后1d，侧脑室注射重组人VEGF 165（rhVEGF 165）。我们检测了AQP 4蛋白的表达，然后研究了rhVEGF 165对野生型（AQP 4 +/+）和AQP 4敲除（AQP 4-/-）小鼠注射后1 d、3 d和7 d血肿周围脑水肿的影响。此外，我们评估了可能的信号转导途径激活VEGF调节AQP 4表达通过星形胶质细胞培养。我们发现rhVEGF 165可显著增加血肿周围AQP 4蛋白的表达。rhVEGF 165在每个时间点减轻AQP 4 +/+小鼠的血肿周围脑水肿，但对AQP 4 −/−小鼠没有影响。在AQP 4-/-小鼠中，rhVEGF 165可增加血肿周围EB外渗，但对AQP 4 +/+小鼠无影响。rhVEGF 165可减少两种小鼠的神经功能缺损，并增加血肿周围的尼氏染色细胞，这些作用与AQP 4有关。rhVEGF 165可上调培养星形胶质细胞中C-Jun氨基末端激酶（p-JNK）、细胞外信号调节激酶（p-ERK）和AQP 4蛋白的磷酸化。后者可被JNK和ERK抑制剂抑制。总之，VEGF可减少血肿周围的神经功能缺损、脑水肿和神经元死亡，但对血脑屏障通透性无影响。这些作用与AQP 4上调密切相关，可能通过激活JNK和ERK通路。目前的研究可能为ICH后脑水肿的治疗提供新的见解。
Vascular endothelial growth factor (VEGF) has protective effects on many neurological diseases. However, whether VEGF acts on brain edema following intracerebral hemorrhage (ICH) is largely unknown. Our previous study has shown aquaporin-4 (AQP4) plays an important role in brain edema elimination following ICH. Meanwhile, there is close relationship between VEGF and AQP4. In this study, we aimed to test effects of VEGF on brain edema following ICH and examine whether they were AQP4 dependent. Recombinant human VEGF165 (rhVEGF165) was injected intracerebroventricularly 1 d after ICH induced by microinjecting autologous whole blood into striatum. We detected perihemotomal AQP4 protein expression, then examined the effects of rhVEGF165 on perihemotomal brain edema at 1 d, 3 d, and 7 d after injection in wild type (AQP4+/+) and AQP4 knock-out (AQP4−/−) mice. Furthermore, we assessed the possible signal transduction pathways activated by VEGF to regulate AQP4 expression via astrocyte cultures. We found perihemotomal AQP4 protein expression was highly increased by rhVEGF165. RhVEGF165 alleviated perihemotomal brain edema in AQP4+/+ mice at each time point, but had no effect on AQP4−/− mice. Perihemotomal EB extravasation was increased by rhVEGF165 in AQP4−/− mice, but not AQP4+/+ mice. RhVEGF165 reduced neurological deficits and increased Nissl’s staining cells surrounding hemotoma in both types of mice and these effects were related to AQP4. RhVEGF165 up-regulated phospharylation of C-Jun amino-terminal kinase (p-JNK) and extracellular signal-regulated kinase (p-ERK) and AQP4 protein in cultured astrocytes. The latter was inhibited by JNK and ERK inhibitors. In conclusion, VEGF reduces neurological deficits, brain edema, and neuronal death surrounding hemotoma but has no influence on BBB permeability. These effects are closely related to AQP4 up-regulation, possibly through activating JNK and ERK pathways. The current study may present new insights to treatment of brain edema following ICH.
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DOI：
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