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

Sheng Zhang, Bokyung Kim, Xiaoqing Zhu, Xuehong Gui, Yan Wang, Zhaohui Lan, Preeti Prabhu, Kenneth Fond, Aijun Wang and Fuzheng Guo ()
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Sheng Zhang: Shriners Hospitals for Children/UC Davis School of Medicine
Bokyung Kim: Shriners Hospitals for Children/UC Davis School of Medicine
Xiaoqing Zhu: Shriners Hospitals for Children/UC Davis School of Medicine
Xuehong Gui: Shriners Hospitals for Children/UC Davis School of Medicine
Yan Wang: Shriners Hospitals for Children/UC Davis School of Medicine
Zhaohui Lan: Shriners Hospitals for Children/UC Davis School of Medicine
Preeti Prabhu: Shriners Hospitals for Children/UC Davis School of Medicine
Kenneth Fond: Shriners Hospitals for Children/UC Davis School of Medicine
Aijun Wang: Shriners Hospitals for Children/UC Davis School of Medicine
Fuzheng Guo: Shriners Hospitals for Children/UC Davis School of Medicine

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-15656-4

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