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

Abstract

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 for the first time in vascular disease, integrating it with single-cell transcriptomics to map protein regulation in healthy and Marfan syndrome (MFS) aortas. Results: This approach uncovered cell type– and 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 (modSMC) states enriched for matrix effectors (AEBP1, HTRA1, FN1) and uniquely protein-level regulators (GLIPR2, ITGB2, CD151). Conclusions: Together, these findings establish the first human single-cell proteomic atlas of the aorta, reveal altered FBN1 protein regulation in both human and mouse MFS, and position single-cell proteomics as a transformative framework for decoding vascular plasticity and identifying actionable effectors in disease.