Targeting TBX20 to Restore Contractile Function in Thoracic Aortic Aneurysm

All articles of this category (opens in new window) Background: Thoracic aortic aneurysms (TAA) are characterized by progressive vascular smooth muscle cell (VSMC) dysfunction, yet the molecular mechanisms remain poorly understood. Here, we identify TBX20, a transcription factor, as a potential regulator of VSMC dedifferentiation in thoracic aortic aneurysm and therapeutic target. Methods: This study utilized comprehensive transcriptomic profiling using bulk RNA-sequencing (RNA-seq, n = 195) and single-cell RNA-seq (scRNA-seq, n = 34) on ascending aortic specimens from TAA patients and healthy heart transplant donors (controls). TAA tissues were stratified by valve phenotype (bicuspid/tricuspid aortic valve), clinical presentation (aortic stenosis/insufficiency), and anatomical location (outer/inner curvature). Datasets were integrated using deconvolution analysis, followed by differential expression, RNA velocity, and pathway enrichment analyses. Validation included immunohistochemistry (IHC) and qPCR in human tissue samples. Functional studies used siRNA-mediated knockdown in patient-derived and commercial VSMC. Results: Bulk RNA-seq revealed significant TBX20 upregulation in TAA (2.3-fold, p < 0.05), independent of valve phenotype, clinical presentation, or anatomical location, which was validated by qPCR (2.7-fold, p < 0.001). Single-cell analysis demonstrated TBX20 upregulation specifically in VSMCs, with the highest expression in the pathological fibroblast-like subpopulation (5.7-fold, p < 0.001), confirmed by IHC. This correlated with a phenotypic shift where contractile VSMC decreased from 79 to 69% and fibroblast-like VSMC increased from 16 to 29% (both p < 0.001) in TAA tissue. RNA velocity demonstrated that this shift represents a unidirectional contractile-to-fibroblast-like transition. Functional validation directly linked TBX20 to this process, as siRNA-mediated knockdown in primary VSMC restored contractile marker expression (ACTA2 1.9-fold, TAGLN 1.8-fold, CNN1 1.3-fold, all p < 0.05) and enhanced contractile force in collagen gel assays, supporting its therapeutic relevance. Conclusion: TBX20 functions as a molecular switch driving VSMC dedifferentiation in TAA by suppressing contractile gene programs while promoting fibrotic transformation. Its upregulation across different TAA etiologies suggests a common pathological pathway. Therapeutic targeting of TBX20 could restore VSMC contractile function and preserve aortic wall integrity, representing a potential treatment strategy. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany