Glial heterogeneity shapes region-specific angiogenesis and neurovascular integrity in the CNS.

Abstract

Proper function of the central nervous system (CNS) requires adequate blood supply to both gray and white matter, yet the mechanisms governing the region-specific angiogenesis remain poorly understood. Through analyzing glial cell profiles combined with genetic ablation approaches, we uncover distinct pro-angiogenic programs in astrocytic and oligodendroglial lineages that differentially regulate gray and white matter vascularization. Astrocyte depletion selectively disrupted gray matter angiogenesis, whereas oligodendrocyte lineage loss caused white matter hypovascularization. Gray matter astrocytes are selectively enriched for the hypoxia-inducible factor HIF1α and promote vascular growth via VEGF-dependent signaling, while the oligodendrocyte-enriched chromatin-remodeler CHD8 directly activated pro-angiogenic genes, including <i>Tgfa</i> and <i>Sema5a</i>, to promote white matter vascularization. Conditional <i>Chd8</i> deletion recapitulated white matter vascular defects and visual dysfunction without neuronal loss. These findings define lineage-specific mechanisms of CNS angiogenesis and establish astrocytes and oligodendrocytes as distinct drivers of region-specific vascular development, providing a conceptual framework for targeted therapies in neurovascular and neurodevelopmental disorders.