Single-cell transcriptomics reveals cellular heterogeneity and phenotypic transitions of smooth muscle cells in aortic dissection.

We utilized single-cell RNA sequencing (scRNA-seq) to investigate cellular heterogeneity and signaling networks in aortic dissection (AD) tissues compared to adjacent normal tissues. The analysis identified five smooth muscle cell (SMC) subtypes, with SMC2 linked to fibrosis and SMC3 associated with inflammation. Thrombus-positive AD samples showed upregulated angiopoietin-like 4 (ANGPTL4) and increased M2 macrophages, indicating an immunosuppressive microenvironment. Cell-cell communication analysis revealed a shift in vascular endothelial growth factor A (VEGFA) signaling from SMCs to fibroblasts, disrupting vascular homeostasis. In vitro experiments confirmed SMC2-induced endothelial-to-mesenchymal transition and SMC3-driven inflammatory responses via mitogen-activated protein kinase (MAPK) pathways. Immunofluorescence validated elevated insulin-like growth factor binding protein 2 (IGFBP2), procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2), and VEGFA in AD tissues, supporting their roles in matrix remodeling and angiogenesis. These findings highlight SMC phenotypic switching and altered VEGFA signaling as key drivers of AD, proposing novel therapeutic targets to restore vascular integrity.