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Death-associated protein kinase (DAPK) 1 is a critical mediator for neuronal cell death in cerebral ischemia, but its role in blood-brain barrier (BBB) disruption is incompletely understood. Here, we found that endothelial-specific deletion of Dapk1 using Tie2 Cre protected the brain of Dapk1 fl/fl mice against middle cerebral artery occlusion (MCAO), characterized by mitigated Evans blue dye (EBD) extravasation, reduced infarct size and improved behavior. In vitro experiments also indicated that DAPK1 deletion inhibited oxygen-glucose deprivation (OGD)-induced tight junction alteration between cerebral endothelial cells (CECs). Mechanistically, we revealed that DAPK1-DAPK3 interaction activated cytosolic phospholipase A 2 (cPLA 2) in OGD-stimulated CECs. Our results thus suggest that inhibition of endothelial DAPK1 specifically prevents BBB damage after stroke. • Endothelial DAPK1 deletion protected blood-brain barrier against tMCAO. • Endothelial DAPK1 deletion protected tight junction after OGD. • Endothelial DAPK1-DAPK3 interaction activated cPLA 2 after OGD. [ABSTRACT FROM AUTHOR]