Brain perivascular macrophages regulate endothelial cell function via a cMAF-dependent transcriptional program in mouse and human [scRNA-seq brain vascular cells]

ABSTRACT: Brain perivascular macrophages maintain brain physiology, yet their transcriptional regulators and functions in health and disease remain unclear. Using single-cell multi-omics and functional experiments, we identify cMAF as a key transcription factor for brain perivascular macrophages. Conditional deletion of cMAF disrupts the phenotype of perivascular macrophages, while sparing microglia. Functionally, cMAF drives IGF1 expression in perivascular macrophages, enabling communication with endothelial cells. Consistently, cMAF deletion in perivascular macrophages causes transcriptional alterations in cerebral arteries affecting vascular functions. Notably, cMAF emerges as the main transcription factor for human perivascular macrophages, suggesting conservation of this transcriptional module. During Alzheimer’s Disease (AD), human perivascular macrophages upregulate cMAF and IGF1 to enhance communications with vascular cells, and this response is abrogated in APOE4 carriers. Lastly, we explore an uncharacterized polymorphism in cMAF providing evidence that the cMAF program is protective against AD. Targeting cMAF in perivascular macrophages may offer new therapeutic strategies for neurodegenerative and cerebrovascular diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE289367 | GEO | 2026/08/14

REPOSITORIES: GEO