Hypoxia-Induced Neural-BBB Coupling via Extracellular Vesicles Delivering CircOGDH

Many nervous system diseases involve changes in neurovascular coupling, the connection between neurons and the blood-brain barrier(BBB). CircOGDH is a circular RNA linked to hypoxic neurons. In this study, we investigated how neuron-derived CircOGDH affects BBB-associated endothelial cells under hypoxic conditions. We reduced neuronal CircOGDH expression in MCAO/R(middle cerebral artery occlusion/reperfusion) mice using a neuron-specific AAV, which led to compromised BBB structure and maintenance in ischemic stroke mice. We found that giving CircOGDH-rich sEVs(small extracellular vesicles) to brain tumors helped blood vessels stay integrity in a glioblastoma model. In addition, we revealed that hypoxic neurons transfer CircOGDH from sEVs to ECs in vitro co-culture system, leading to increased COL4A4 expression and improved ECs functionality. Additionally, analyzing CircOGDH levels in AIS patients' plasma(with and without hemorrhagic transformation) showed a strong link between CircOGDH expression and BBB damage. These findings indicate that neurons under hypoxic stress release sEVs containing CircOGDH into the microenvironment, which interact with ECs and regulate COL4A4 expression, strengthening vascular integrity.