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An integrated analysis of three transcriptome sequencing datasets from mouse middle cerebral artery occlusion\/reperfusion (MCAO\/R) models identified eight downregulated genes in endothelial cells. Additionally, transcriptome analysis of BBB (cortex) and non-BBB (lung) endothelium of E13.5 mice revealed 2,102 upregulated genes potentially associated with BBB integrity. The eight downregulated genes were intersected with the 2,102 BBB-related genes and mapped using single-cell RNA sequencing data, revealing that solute carrier family 22 member 8 (Slc22a8) is specifically expressed in endothelial cells and pericytes and significantly decreases after MCAO\/R. This finding was validated in the mouse MCAO\/R model at both protein and mRNA levels in this study. External overexpression of Slc22a8 using a lentivirus carrying Tie2 improved Slc22a8 and tight junction protein levels and reduced BBB leakage after MCAO\/R, accompanied by Wnt\/\u03b2-catenin signaling activation. In conclusion, this study suggested that MCAO\/R-induced downregulation of Slc22a8 expression may be a crucial mechanism underlying BBB disruption. 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