Single-Cell Proteomics Uncovers Cell-Specific Proteins in Vascular Health and Marfan Syndrome Disease.

BACKGROUND: The vascular system is the largest organ in the body and underlies most chronic diseases, yet the molecular mechanisms that govern its plasticity remain poorly defined. METHODS: We applied single-cell proteomics in vascular disease, integrating it with single-cell transcriptomics to map protein regulation in healthy and Marfan syndrome aortas. RESULTS: This approach uncovered cell type-specific and cell state-specific proteins missed at the transcriptional level. Notably, we identified a decoupling of fibrillin-1 RNA and protein abundance, suggesting altered protein regulation as a potential contributor to aortic degeneration. Single-cell proteomics further resolved modulated smooth muscle cell states enriched for matrix effectors (AEBP1 [adipocyte enhancer binding protein 1], HTRA1 [high-temperature requirement A serine peptidase 1], FN1 [fibronectin 1]) and uniquely protein-level regulators (GLIPR2 [GLI pathogenesis-related 2], ITGB2 [integrin beta-2], and CD151 [cluster of differentiation 151 antigen]). CONCLUSIONS: Together, these findings establish the human single-cell proteomic atlas of the aorta, reveal altered FBN1 (fibrillin-1) protein regulation in both human and mouse Marfan syndrome, and position single-cell proteomics as a transformative framework for decoding vascular plasticity and identifying actionable effectors in disease.