Ephrin-A3 and Ephrin-A4 Contribute to Microglia-Induced Angiogenesis in Brain Endothelial Cells
Ephrin-A3 and Ephrin-A4 Contribute to Microglia-Induced Angiogenesis in Brain Endothelial Cells
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Ephrin-A3 和 Ephrin-A4 有助于小胶质细胞诱导的脑内皮细胞血管生成
DOI：
10.1002/ar.22998
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发表时间：
2014-10-01
影响因子：
2
通讯作者：
Chen, Yu-Hua
中科院分区：
文献类型：
--
作者：
Li, Ying;Liu, Dong-Xin;Chen, Yu-Hua
小胶质细胞在发育过程中与脑血管系统的关联以及小胶质细胞缺陷小鼠脑血管复杂性的降低表明小胶质细胞在脑血管生成中的作用。然而，潜在的分子机制仍不清楚。在这里，利用体外血管生成模型，我们发现BV2小胶质细胞的培养上清液显着增强了毛细血管样管的形成和脑微血管内皮细胞（BMEC）的迁移。暴露于 BV2 衍生培养物上清液的 BMEC 中，血管生成因子 ephrin-A3 和 ephrin-A4 的表达特异性上调。通过 siRNA 敲低 BMEC 中的 ephrin-A3 和 ephrin-A4，可显着减弱 BV2 上清液诱导的 BMEC 增强的血管生成和迁移。我们的进一步结果表明，BV2上清液促进内皮血管生成的能力是由BV2小胶质细胞释放的可溶性肿瘤坏死因子α（TNF-α）引起的。此外，BMEC 中 Ephrin-A3 和 ephrin-A4 响应 BV2 上清液的上调分别被针对 TNF-α 和 TNF 受体 1 的中和抗体有效消除。本研究提供的证据表明，小胶质细胞上调内皮肝配蛋白-A3和肝配蛋白-A4，以促进脑内皮细胞的体外血管生成，这是由小胶质细胞释放的TNF-α介导的。 (C) 2014 年 Wiley 期刊公司。
The association of microglia with brain vasculature during development and the reduced brain vascular complexity in microglia-deficient mice suggest the role of microglia in cerebrovascular angiogenesis. However, the underlying molecular mechanism remains unclear. Here, using an in vitro angiogenesis model, we found the culture supernatant of BV2 microglial cells significantly enhanced capillary-like tube formation and migration of brain microvascular endothelial cells (BMECs). The expression of angiogenic factors, ephrin-A3 and ephrin-A4, were specifically upregulated in BMECs exposed to BV2-derived culture supernatant. Knockdown of ephrin-A3 and ephrin-A4 in BMECs by siRNA significantly attenuated the enhanced angiogenesis and migration of BMECs induced by BV2 supernatant. Our further results indicated that the ability of BV2 supernatant to promote endothelial angiogenesis was caused by the soluble tumor necrosis factor alpha (TNF-alpha) released from BV2 microglial cells. Moreover, the upregulations of ephrin-A3 and ephrin-A4 in BMECs in response to BV2 supernatant were effectively abolished by neutralization antibody against TNF-alpha and TNF receptor 1, respectively. The present study provides evidence that microglia upregulates endothelial ephrin-A3 and ephrin-A4 to facilitate in vitro angiogenesis of brain endothelial cells, which is mediated by microglia-released TNF-alpha. (C) 2014 Wiley Periodicals, Inc.