Related Experiment Video
Updated: Apr 26, 2026
Retinal Explant of the Adult Mouse Retina as an Ex Vivo Model for Studying Retinal Neurovascular Diseases
Published on: December 9, 2022
Ephrin-A3 and ephrin-A4 contribute to microglia-induced angiogenesis in brain endothelial cells
Ying Li1, Dong-Xin Liu, Mei-Yang Li
1Department 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.
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.
Insights
Microglia promote brain endothelial cell angiogenesis by releasing tumor necrosis factor-α (TNF-α). This process upregulates ephrin-A3 and ephrin-A4, enhancing capillary-like tube formation and cell migration.
Area of Science:
- Neuroscience
- Cell Biology
- Angiogenesis Research
Background:
- Microglia are associated with brain vasculature, and their absence reduces vascular complexity, suggesting a role in cerebrovascular angiogenesis.
- The precise molecular mechanisms by which microglia influence brain blood vessel formation remain largely unknown.
Purpose of the Study:
- To investigate the molecular mechanisms by which microglia influence brain endothelial cell angiogenesis in vitro.
- To identify key factors and pathways involved in microglia-mediated cerebrovascular development.
Main Methods:
- Utilized an in vitro angiogenesis model with brain microvascular endothelial cells (BMECs) and BV2 microglial cell culture supernatant.
- Employed siRNA to knockdown ephrin-A3 and ephrin-A4 expression in BMECs.
- Used neutralization antibodies against tumor necrosis factor-α (TNF-α) and TNF receptor 1.
Main Results:
- BV2 microglial supernatant significantly enhanced capillary-like tube formation and migration of BMECs.
- Expression of angiogenic factors ephrin-A3 and ephrin-A4 was upregulated in BMECs exposed to BV2 supernatant.
- Knockdown of ephrin-A3/A4 or neutralization of TNF-α/TNF receptor 1 attenuated the pro-angiogenic effects.
Conclusions:
- Microglia promote in vitro angiogenesis of brain endothelial cells by upregulating ephrin-A3 and ephrin-A4.
- This microglial-mediated angiogenesis is dependent on the release of tumor necrosis factor-α (TNF-α).
Related Concept Videos
01:24Regulation of Angiogenesis and Blood Supply
01:22Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
01:10Mechanism of Angiogenesis