Secretory VSMC-derived THBS1 promotes macrophage M1 polarization and inflammation in intracranial aneurysms via the...

Chronic vascular inflammation and immune cell infiltration are key pathogenic features of intracranial aneurysms (IAs). Although phenotypic switching of vascular smooth muscle cells (VSMCs) and macrophage M1 polarization have both been observed in IAs, the intercellular communication mechanisms linking these two processes remain incompletely understood. This study aimed to explore the potential role of the THBS1-CD47 axis in mediating crosstalk between VSMCs and macrophages within the IA microenvironment.

We analyzed bulk transcriptomic (GSE54083) and single-cell RNA-sequencing (GSE193533) datasets to characterize the cellular landscape of IAs. Weighted gene co-expression network analysis (WGCNA) and the CellChat algorithm were applied to predict key ligand-receptor interactions. To validate these predictions in vitro, human aortic VSMCs (HA-VSMCs) were induced toward a secretory phenotype and co-cultured with THP-1-derived macrophages. shRNA-mediated THBS1 knockdown, CD47-neutralizing antibodies, and NF-κB inhibitors were used to investigate the underlying mechanisms.

Bioinformatic analyses suggested enrichment of M1-like macrophages and phenotypically switched VSMCs in IA tissues compared with controls. CellChat analysis identified THBS1-CD47 as a potential key ligand-receptor pair linking secretory VSMCs and macrophages. Consistent with these predictions, in vitro experiments showed that secretory VSMCs released elevated levels of THBS1, which correlated with increased expression of M1 markers (CD86, iNOS) and pro-inflammatory cytokines in co-cultured macrophages. Mechanistic studies suggested that VSMC-derived THBS1 may promote this inflammatory response by activating the CD47/NF-κB signaling axis, as blockade of this pathway markedly attenuated macrophage M1 polarization.

Collectively, our findings support a model in where secretory VSMCs may actively regulate the immune microenvironment of IAs through paracrine secretion of THBS1. This signaling appears to drive macrophage M1 polarization via the CD47/NF-κB axis. Targeting the THBS1-CD47 interaction may represent a promising therapeutic strategy to alleviate vascular inflammation in IAs.