title: Ephrin-A3 and ephrin-A4 contribute to microglia-induced angiogenesis in brain endothelial cells.
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.
authors: Department of Developmental Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, China Medical University, Shenyang, 110001, China; Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, 110001, China.
authors: Ying
authors: Y
authors: Li
authors: Dong-Xin
authors: DX
authors: Liu
authors: Mei-Yang
authors: MY
authors: Li
authors: Xiao-Xue
authors: XX
authors: Qin
authors: Wen-Gang
authors: WG
authors: Fang
authors: Wei-Dong
authors: WD
authors: Zhao
authors: Yu-Hua
authors: YH
authors: Chen
mesh_terms: D001921:Brain / Q000378:metabolism*; D002196:Capillaries / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000378:metabolism*; D036384:Ephrin-A3 / Q000378:metabolism*; D036385:Ephrin-A4 / Q000378:metabolism*; D006801:Humans; D017628:Microglia / Q000378:metabolism*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D036384:Ephrin-A3; D036385:Ephrin-A4; D014409:Tumor Necrosis Factor-alpha
keywords: angiogenesis; brain microvascular endothelial cells; ephrin-A3; ephrin-A4; microglia