Endothelial Netrin-4 regulates oligodendrocyte precursor cell proliferation and differentiation via ET-1 signaling in preterm white matter injury

Perinatal hypoxia-ischemia is a leading cause of preterm white matter injury (PWMI), yet mechanisms underlying oligodendrocyte precursor cells (OPCs) dysfunction remain poorly understood. Here, we identify endothelial-derived Netrin-4 (Ntn4) as a critical regulator of OPCs proliferation and differentiation in PWMI. Developmental analysis revealed that Netrin-4, predominantly expressed in cerebrovascular endothelial cells (ECs), peaks during postnatal myelination and correlates with OPCs marker PDGFR-α. Conditional endothelial deletion of Ntn4 in mice impaired spatial memory, induced anxiety-like behavior, and reduced mature oligodendrocytes, accompanied by disrupted myelin ultrastructure. In a PWMI model, endothelial Ntn4 knockout exacerbated myelination deficits and suppressed OPCs proliferation, while inducible deletion at later stages enhanced OPCs differentiation. Mechanistically, Netrin-4-overexpressing ECs elevated ET-1 secretion, which promoted OPCs proliferation but inhibited differentiation via ET-1 receptor EDNRB. Our findings reveal that endothelial Netrin-4 is a dual regulator of OPCs dynamics in PWMI, driving proliferation via ET-1 while impairing differentiation. Targeting the Netrin-4/ET-1 axis restores OPCs maturation, offering a potential strategy to mitigate myelination deficits in PWMI.