Profiling the mouse brain endothelial transcriptome in health and disease models reveals a core blood–brain barrier dysfunction module

Blood vessels in the CNS form a specialized and critical structure, the blood–brain barrier (BBB). We present a resource to understand the molecular mechanisms that regulate BBB function in health and dysfunction during disease. Using endothelial cell enrichment and RNA sequencing, we analyzed the gene expression of endothelial cells in mice, comparing brain endothelial cells with peripheral endothelial cells. We also assessed the regulation of CNS endothelial gene expression in models of stroke, multiple sclerosis, traumatic brain injury and seizure, each having profound BBB disruption. We found that although each is caused by a distinct trigger, they exhibit strikingly similar endothelial gene expression changes during BBB disruption, comprising a core BBB dysfunction module that shifts the CNS endothelial cells into a peripheral endothelial cell-like state. The identification of a common pathway for BBB dysfunction suggests that targeting therapeutic agents to limit it may be effective across multiple neurological disorders. Munji et al. analyzed the transcriptomes of endothelial cells from multiple organs and in neural tissue of neurological disease models. They identified a blood–brain barrier dysfunction module in seizure, multiple sclerosis, stroke and brain trauma.