Abstract 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.
Dong et al. (Wed,) studied this question.