Intermittent Hypoxia Maintains Neovascular Blood-Brain Barrier Integrity Via the HIF-1α/VEGFB Axis

Ischemic stroke (IS) is the most prevalent cerebrovascular disease, with a high proportion of patients developing lifelong disability. Cerebral microcirculatory dysfunction is a key driver of poor IS prognosis. Hypoxia-induced cerebral angiogenesis could improve cerebral perfusion but risks blood-brain barrier (BBB) disruption, worsening outcomes. We previously found that intermittent hypoxia (IH) promotes cerebral angiogenesis and improves IS outcomes, but whether it maintains BBB integrity during angiogenesis and the underlying mechanism remains unclear. This study established mouse hypoxia models, including IH and continuous hypoxia (CH) treatment groups. We found that both IH and CH transiently increased cerebrovascular permeability via angiogenesis activation. However, IH restored permeability to baseline over time, with astrocyte end-foot wrapping, pericyte coverage, and tight junction protein ZO-1 level in neovessels comparable to controls. In contrast, CH failed to recover vascular leakage and BBB integrity within the same period. Mechanistically, IH uniquely activated both hypoxia-inducible factor (HIF)-1α and HIF-2α, while CH only activated HIF-2α. HIF-1α-specific activation in the IH group promoted downstream vascular endothelial growth factor (VEGF)-B transcription, which antagonized VEGFA-mediated endothelial barrier disruption and adhesion molecule upregulation. This study demonstrates that IH maintains neovascular BBB integrity via the HIF-1α/VEGFB pathway, providing a theoretical basis for novel IS interventions and targeted drug development.