Ephrin-A3 and Ephrin-A4 Contribute to Microglia-Induced Angiogenesis in Brain Endothelial Cells

Authors

  • Ying Li,

    1. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, China
    2. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
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  • Dong-Xin Liu,

    1. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, China
    2. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
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  • Mei-Yang Li,

    1. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, China
    2. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
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  • Xiao-Xue Qin,

    1. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, China
    2. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
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  • Wen-Gang Fang,

    1. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, China
    2. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
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  • Wei-Dong Zhao,

    Corresponding author
    1. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, China
    2. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
    • Correspondence to: Wei-Dong Zhao, Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, 92 Bei-Er Road, Heping District, Shenyang 110001, China. Fax: 86-24-23260246. E-mail: dzhao@mail.cmu.edu.cn or Yu-Hua Chen, Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, 92 Bei-Er Road, Heping District, Shenyang 110001, China. Fax: 86-24-23260246. E-mail: yhchen@mail.cmu.edu.cn

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  • Yu-Hua Chen

    Corresponding author
    1. Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, China
    2. Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
    • Correspondence to: Wei-Dong Zhao, Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, 92 Bei-Er Road, Heping District, Shenyang 110001, China. Fax: 86-24-23260246. E-mail: dzhao@mail.cmu.edu.cn or Yu-Hua Chen, Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, 92 Bei-Er Road, Heping District, Shenyang 110001, China. Fax: 86-24-23260246. E-mail: yhchen@mail.cmu.edu.cn

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ABSTRACT

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 α (TNF-α) 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-α 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-α. Anat Rec, 297:1908–1918, 2014. © 2014 Wiley Periodicals, Inc.

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