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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE266881 | GEO | 2026/04/20

REPOSITORIES: GEO

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Project description:Bacterial meningitis is a deadly disease most commonly caused by Streptococcus pneumoniae that leads to severe neurological sequelae including cerebral edema, seizures, stroke, and mortality when untreated. Meningitis is initiated by the transfer of S. pneumoniae from hematogenous source into the brain across the blood-brain barrier (BBB); the mechanisms however are still poorly understood. Current treatment strategies include adjuvant dexamethasone therapy for cerebral edema, the prime reason for neurological complications and mortality, which is followed up by antibiotics. The success of corticosteroids is however inconclusive, necessitating the development of new therapies for controlling cerebral edema. We have previously shown a general activation of hypoxia inducible factor (HIF-1α) in bacterial infections, we therefore hypothesized that HIF-1α, via induction of vascular endothelial growth factor (VEGF) is critically involved in the transmigration of pathogens across the BBB. In human and murine meningitis brain samples, HIF-1 activation was observed by immunohistochemistry. HIF-1α/VEGF expression and permeability was therefore analyzed in vitro in infected brain endothelial cells (ECs). Localization of S. pneumoniae in brain ECs from mouse/human sources was visualized in vitro and in vivo by confocal, super-resolution, and electron microscopy. S. pneumoniae infection in brain ECs resulted in upregulation of HIF-1α/VEGF by Western blotting and qRT-PCR that was associated with increased paracellular permeability, which was supported by bacterial localization at cell-cell junctions. RNA sequencing of brain microvessels from hematogenously infected mice with increased permeability and S. pneumoniae deposition in the brain showed upregulation of genes in HIF-1α/VEGF pathway. Inhibition of HIF-1α with echinomycin, siRNA in bEnd5 cells and by using primary brain ECs from HIF-1α KO mice revealed a reduced endothelial permeability and transmigration of S. pneumoniae. We thus demonstrate a critical role for HIF-1α/VEGF in transmigration of S. pneumoniae across the BBB and propose targeting this pathway to prevent BBB dysfunction in infections.

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

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