Females show less hypoxia-induced blood-brain barrier disruption in aged mice: a protective role for CD11c

Abstract

Aging is associated with a decline in blood-brain barrier (BBB) integrity. Interestingly, recent reports suggest that females may be more resistant to BBB disruption than males. Using a robust model of hypoxia-induced BBB disruption, we exposed aged (20 months) male and female mice to chronic mild hypoxia (CMH; 8% O 2 ) for 4 days before evaluating BBB disruption and endothelial proliferation by immunofluorescent (IF) analysis. Bulk RNA-seq analysis was used to identify differentially expressed genes between male and female brains. Function-blocking antibody studies then evaluated the role of an identified candidate protein, CD11c. Compared with aged male mice, females show reduced levels of hypoxia-induced BBB disruption and endothelial proliferation. Bulk RNA-seq identified Itgax , which encodes the adhesion protein CD11c as the only gene showing a greater than 2-fold difference (higher in female) between the sexes. IF analysis of brain tissue revealed that CD11c is expressed predominantly by microglia and confirmed its higher expression in females. In the hypoxic brain, CD11c + microglia co-localized with vascular disruptions. Functional blockade of CD11c in females resulted in elevated BBB disruption and endothelial proliferation that was associated with enhanced microglial and vascular activation, culminating in reduced density of mature oligodendrocytes. Our data provide further evidence that the female brain is better equipped to withstand BBB disruption and suggest that the microglial receptor CD11c may play a protective role in maintaining BBB integrity.