Distinct gene expression profiles in blood–brain barrier capillary endothelial cells between mice and humans

Endothelial cells (ECs) are key structural and functional components of the blood–brain barrier (BBB). Mouse models are frequently used to study EC biology within the BBB, yet the extent to which human and mouse BBB ECs share conserved transcriptomic features remains unclear. Here, we systematically compare transcriptomic profiles of BBB capillary ECs from adult mice and humans. We analyzed single-cell and single-nucleus RNA-sequencing datasets from adult mouse and human BBB capillary ECs. Candidate species-specific genes were further validated using two whole brain vasculature datasets, along with data from Allen Brain Atlas and Human Protein Atlas. Despite substantial overall conservation between species, 169 genes were consistently enriched in human BBB capillary ECs compared to mouse, whereas 386 genes were enriched in mouse BBB capillary ECs compared to human. Several genes, including A2M , RUNDC3B , BTNL9 and SPOCK3 exhibited predominant expression in human BBB capillary ECs, with minimal or undetected expression in mouse. Conversely, Tspan13 , Pglyrp1 , Ucp2 and Slco1c1 were specifically expressed in mouse BBB capillary ECs compared with human. Notably, a considerable proportion of differentially expressed genes belonged to the solute carrier (SLC) transporter family. Our cross-species in-depth analysis reveals both broad conservation and distinct transcriptomic differences between human and mouse BBB capillary ECs. Together, our findings provide a valuable framework for interpreting mouse BBB data in a translational context and for guiding future studies of endothelial biology in the human brain.