VSMC phenotypic switching in thoracic aortic aneurysm at single‐cell resolution: Trajectories, regulatory circuits, and spatial niches

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Abstract Thoracic aortic aneurysm (TAA) is a life‐threatening cardiovascular disorder characterized by progressive aortic dilation that often culminates in dissection or rupture, with few effective pharmacological interventions currently available. Vascular smooth muscle cells (VSMCs)‐the predominant cellular component of the aortic media‐undergo extensive phenotypic modulation during TAA development. However, the heterogeneity of VSMC populations and the molecular mechanisms regulating their fate decisions remained poorly understood until the emergence of single‐cell technologies. Single‐cell RNA sequencing, single‐nucleus assay for transposase‐accessible chromatin sequencing, and spatial transcriptomics have revolutionized the understanding of VSMC diversity at an unprecedented resolution. These approaches have revealed a complex spectrum of VSMC phenotypic states that extend beyond the classical contractile–synthetic dichotomy, including fibroblast‐like, macrophage‐like, and chondrocyte‐like subpopulations that arise through distinct differentiation trajectories. This review systematically summarizes recent progress in elucidating VSMC phenotypic switching in TAA, emphasizing developmental trajectories reconstructed through pseudotime analyses, the gene regulatory networks controlling fate decisions, and the spatial microenvironmental cues influencing VSMC behaviour. Furthermore, it discusses the translational implications of these insights for identifying novel diagnostic biomarkers and developing therapeutic strategies aimed at stabilizing VSMC phenotypes.

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