COL10A1+ fibroblasts define rupture-prone abdominal aortic aneurysms and enable molecular risk stratification.

BACKGROUND: Abdominal aortic aneurysm (AAA) rupture remains the leading cause of AAA-related mortality, while current clinical management relies primarily on aneurysm diameter, which inadequately predicts rupture risk. Increasing evidence suggests that stromal cell heterogeneity critically shapes vascular remodeling; however, the specific fibroblast states associated with AAA rupture predisposition remain poorly defined.

METHODS: We integrated cross-species single-cell RNA-sequencing datasets spanning the full spectrum of AAA progression to systematically characterize fibroblast heterogeneity and state transitions. Pseudotime trajectory analysis, transcriptional regulatory network inference, and ligand-receptor interaction modeling were applied to delineate fibroblast-associated microenvironmental programs. Based on these findings, a fibroblast-derived molecular signature was constructed and validated in an independent human AAA cohort.

RESULTS: Single-cell analysis revealed a progressive transition from homeostatic IGFBP6+ fibroblasts to a disease-associated COL10A1+ fibroblast state during AAA progression. COL10A1+ fibroblasts were selectively enriched in rupture-prone lesions and exhibited transcriptional programs linked to extracellular matrix remodeling and osteogenic-like activation. Intercellular communication analysis indicated that COL10A1+ fibroblasts were predicted to engage macrophage populations through coordinated ligand-receptor signaling pathways, including MDK, CSF1, and CXCL12, collectively delineating a rupture-associated vascular microenvironment. Translationally, leveraging this fibroblast state enabled the development of a minimal two-gene risk score (COL10A1-IGFBP6), which stratified AAA patients by molecular rupture risk independently of aneurysm diameter in the validation cohort.

CONCLUSIONS: This study identifies a COL10A1+ fibroblast-associated transcriptional state that defines a rupture-prone vascular microenvironment in abdominal aortic aneurysm. The derived COL10A1-IGFBP6 signature establishes a biologically informed framework for molecular risk stratification, complementing anatomical size-based assessment and providing a foundation for future development of mechanism-guided strategies to refine AAA risk evaluation.