Astrocytic PDE7B Drives Blood-Brain Barrier Breakdown via Extracellular Vesicles in Demyelinating Disease.

Blood-brain barrier (BBB) dysfunction is a critical driver of neuroinflammation and demyelination, yet its cellular and molecular underpinnings remain poorly defined. Here, we identify a pathogenic subpopulation of astrocytes expressing phosphodiesterase 7B (PDE7B) that contributes to BBB disruption. Using a colitis-induced BBB opening model and single-cell RNA sequencing, we found PDE7Bhigh astrocytes enriched at sites of BBB breakdown. In both human demyelinated lesions and the experimental autoimmune encephalomyelitis mouse model, elevated astrocytic PDE7B expression correlated with vascular leakage. In vivo and in vitro experiments confirmed that astrocytic PDE7B impairs BBB integrity, in part via effects on endothelial cells. Mechanistically, elevated PDE7B promotes BBB disruption through astrocyte-derived extracellular vesicles enriched in miR-155-5p, which disrupts endothelial tight junction integrity and focal adhesion-associated signaling. These findings identify astrocytic PDE7B as a regulatory and therapeutic target of neurovascular integrity and provide new insight into how glial signaling contributes to BBB dysfunction in demyelinating diseases.