Single-cell atlas of intracranial arteries reveals sex-specific gene regulation linked to intracranial aneurysm risk

BACKGROUNDRupture of an intracranial aneurysm (IA) results in aneurysmal subarachnoid hemorrhage, a severe form of stroke that is more prevalent in women than in men. The biological mechanisms underlying IA formation and the observed sex differences in prevalence in women remain poorly understood. Here, we present a single-cell RNA sequencing (scRNA-seq) atlas of intracranial arteries and use it to analyze sex-specific differences in gene expression and cell type composition. We further apply this atlas as a reference for deconvolution of IA bulk RNA-seq samples to study the effect of sex- and rupture status on cell type composition. METHODSscRNA-seq was performed on human intracranial artery samples (n=7) from the circle of Willis without IAs, yielding high-quality transcriptomic profiles from 55,371 cells. We characterized cell types and examined sex differences in gene expression and cell type proportions. Using this dataset as a reference, we performed bulk RNA-seq deconvolution on IA samples to assess differences in cell type proportions associated with sex or rupture status. RESULTSWe identified seven distinct cell types, as well as multiple subpopulations within structural arterial cell types. While cell type proportions were comparable between male (n=3) and female (n=4) arterial samples and IA samples after RNA deconvolution, multiple biological pathways showed sex-specific regulation. Also, ruptured IAs had higher proportions of myeloid lineage cells compared to unruptured IAs. CONCLUSIONSAnalysis of our publicly available single-cell atlas of intracranial arteries revealed no substantial sex differences in cell-type composition. However, pronounced sex-specific gene expression differences within the structural arterial cell types were observed, which may contribute to the higher prevalence of IAs in women. This single-cell atlas provides a valuable resource for further research into the pathogenesis of IAs, as well as other diseases of the intracranial arteries.