Early matrix softening contributes to vascular smooth muscle cell phenotype switching and aortic dissection through down-regulation of microRNA-143/145

• Published in: Journal of molecular and cellular cardiology 2024-07, Vol.192, p.1-12
• Main Authors: Ye, Zhaofei, Zhu, Shuolin, Li, Guoqi, Lu, Jie, Huang, Shan, Du, Jie, Shao, Yihui, Ji, Zhili, Li, Ping
• Format: Article
• Language: English
• Subjects: Animals; Aortic Dissection - genetics; Aortic Dissection - metabolism; Aortic Dissection - pathology; Down-Regulation - genetics; Extracellular matrix; Extracellular Matrix - metabolism; Female; Gene Expression Regulation; Humans; Male; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; miR-143/145; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Phenotype; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Synthetic phenotype; TEA Domain Transcription Factors; Thoracic aortic dissection; Transcription Factors - genetics; Transcription Factors - metabolism; Vascular smooth muscle cell
• ISSN: 0022-2828; 1095-8584; 1095-8584
• DOI: 10.1016/j.yjmcc.2024.05.002

Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection. [Display omitted] •ECM softening down-regulates miR-143/145 expression via AKT phosphorylation.•TEAD1 as a target of miR-143/145 linking ECM softening to VSMC phenotype switching.•miR-143/145 levels correlate with TAD severity and prognosis, suggesting biomarker potential.