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

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 (HIF alpha)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIF alpha in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIF alpha 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 HIF alpha -regulated CNS angiogenesis. Blocking astroglia-derived Wnt signaling reduces astroglial HIF alpha -regulated CNS angiogenesis. Together, our in vivo data demonstrate that oligodendroglial HIF alpha 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 HIF alpha -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 HIF alpha regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling, while astroglial HIF alpha participates through Wnt-dependent signaling.