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.
Highlights
The mechanisms by which oligodendroglia modulate central nervous system (CNS) angiogenesis remain elusive
Endothelial cell (EC) proliferation is an essential step of angiogenesis and the blood vessel density is an end-point reflection of angiogenesis
To determine whether oligodendroglial Hypoxia-inducible factor α (HIFα) is required for angiogenesis throughout the postnatal CNS, Cre-LoxP approach was used to genetically ablate or stabilize HIFα and EC proliferation and vessel density were analyzed in the brain and the spinal cord
Summary
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. Our in vivo genetic knockout data reveal that oligodendroglial HIFα regulates endothelial cell proliferation and angiogenesis in a VEGF-dependent but Wntindependent manner and this regulation is independent of CNS regions during postnatal development. This data demonstrate that postnatal astroglia regulate CNS angiogenesis at least in part through HIFα-activated Wnt signaling, unveiling a glial cell type-specific HIFα-Wnt connection in the CNS
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