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

Area of Science:

• Neuroscience
• Vascular Biology
• Ischemic Stroke Research

Background:

• Ischemic stroke (IS) is a leading cause of disability, often linked to cerebral microcirculatory dysfunction.
• Hypoxia can promote angiogenesis to improve blood flow but may compromise blood-brain barrier (BBB) integrity.
• The effect of intermittent hypoxia (IH) on BBB integrity during angiogenesis remains unclear.

Purpose of the Study:

• To investigate whether IH maintains BBB integrity during hypoxia-induced angiogenesis.
• To elucidate the underlying molecular mechanisms responsible for BBB integrity during IH.
• To compare the effects of IH and continuous hypoxia (CH) on BBB integrity and angiogenesis.

Main Methods:

• Establishment of mouse models for intermittent hypoxia (IH) and continuous hypoxia (CH).
• Assessment of cerebrovascular permeability, angiogenesis markers, and BBB components (astrocyte end-feet, pericytes, ZO-1).
• Analysis of hypoxia-inducible factor (HIF)-1α and HIF-2α activation and downstream signaling pathways, including vascular endothelial growth factor (VEGF)-B and VEGFA.

Main Results:

• Both IH and CH initially increased cerebrovascular permeability due to angiogenesis.
• IH treatment led to the restoration of BBB integrity over time, comparable to controls.
• CH failed to restore vascular leakage and BBB integrity within the study period.
• IH uniquely activated both HIF-1α and HIF-2α, while CH activated only HIF-2α.
• HIF-1α activation in IH promoted VEGF-B, antagonizing VEGFA-induced barrier disruption.

Conclusions:

• Intermittent hypoxia preserves neovascular blood-brain barrier integrity via the HIF-1α/VEGF-B pathway.
• This mechanism contrasts with continuous hypoxia, which impairs BBB integrity.
• Findings provide a theoretical basis for developing novel therapeutic strategies for ischemic stroke.