Glial type specific regulation of CNS angiogenesis by HIFα-activated different signaling pathways

• Published in: Nature communications 2020-04, Vol.11 (1), p.2027-2027, Article 2027
• Main Authors: Zhang, Sheng, Kim, Bokyung, Zhu, Xiaoqing, Gui, Xuehong, Wang, Yan, Lan, Zhaohui, Prabhu, Preeti, Fond, Kenneth, Wang, Aijun, Guo, Fuzheng
• Format: Article
• Language: English
• Subjects: 13/51; 14/1; 14/32; 14/63; 38/77; 631/136; 631/136/16; 631/378/368/2430; 82/29; Angiogenesis; Animals; Animals, Newborn; Astrocytes; Astrocytes - metabolism; Blood vessels; Cell Proliferation; Cells, Cultured; Central nervous system; Endothelial cells; Endothelial Cells - metabolism; Female; Glial cells; Humanities and Social Sciences; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Male; Mice; Mice, Knockout; multidisciplinary; Neovascularization, Physiologic; Oligodendrocytes; Oligodendroglia - metabolism; Primary Cell Culture; Prosencephalon - blood supply; Prosencephalon - cytology; Science; Science (multidisciplinary); Signaling; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - metabolism; Wnt protein; Wnt Signaling Pathway - physiology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15656-4

The mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIFα)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIFα in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIFα stabilization in oligodendroglia does not perturb Wnt signaling but rather activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIFα-regulated CNS angiogenesis. Blocking astroglia-derived Wnt signaling reduces astroglial HIFα-regulated CNS angiogenesis. Together, our in vivo data demonstrate that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. These findings suggest an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIFα-Wnt axis in regulating CNS vessel formation. In the central nervous system, the maturation of glial cells is temporally and functionally coupled with that of the vascular network during postnatal development. Here the authors show that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling, while astroglial HIFα participates through Wnt-dependent signaling.