Small Extracellular Vesicles From Hypoxia-Neuron Maintain Blood-Brain Barrier Integrity

BACKGROUND: Acute ischemic stroke disrupts communication between neurons and blood vessels in penumbral areas. How neurons and blood vessels cooperate to achieve blood-brain barrier repair remains unclear. Here, we reveal crosstalk between ischemic penumbral neurons and endothelial cells (ECs) mediated by circular RNA originating from oxoglutarate dehydrogenase (CircOGDH). METHODS: We analyzed clinical data from patients with acute ischemic stroke to explore the relationship between CircOGDH levels and hemorrhagic transformation events. In addition, a middle cerebral artery occlusion and reperfusion mouse model with neuronal CircOGDH suppression was used to assess endothelial permeability. ECs with increased CircOGDH expression were analyzed for changes in COL4A4 (collagen type IV alpha 4) levels, and in vitro coculture experiments were conducted to examine small extracellular vesicle–mediated CircOGDH transfer between neurons and ECs. RESULTS: Clinical data indicated that reduced CircOGDH levels were correlated with increased hemorrhagic transformation in patients with acute ischemic stroke. In the middle cerebral artery occlusion and reperfusion model, neuronal CircOGDH suppression impaired the restoration of endothelial permeability. ECs with increased CircOGDH expression exhibited higher COL4A4 levels, which helped maintain vascular stability. In vitro, hypoxic neurons transferred CircOGDH to ECs via small extracellular vesicles, leading to elevated COL4A4 expression and enhanced endothelial integrity. CONCLUSIONS: Our findings highlight the significance of CircOGDH in neuron-EC crosstalk via small extracellular vesicles in the ischemic penumbra, emphasizing the need for balanced intervention strategies in acute ischemic stroke management.