ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Cell Adhesion and Migration
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1592594
SOX9 mediates the phenotypic transformation of vascular smooth muscle cells in restenosis after carotid artery injury
Provisionally accepted
- 1Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China
- 2Southwest Medical University, Luzhou, Sichuan, China
- 3Xindu District People's Hospital of Chengdu., Chengdu, China
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In-stent restenosis (ISR) remains a significant public health challenge globallysince millions of stents are implanted annually. Elucidating the mechanismsunderlying ISR is essential for developing effective preventive and therapeuticstrategies. In this study, we identified SOX9, a transcription factor, as a key factorinvolved in the pathogenesis of ISR. Morphological and histological analysis ofhuman carotid atherosclerotic plaques revealed high expression of SOX9 at theinterface between the fibrous cap, predominantly composed of α-SMA-positivevascular smooth muscle cells (VSMCs), and the lipid-rich necrotic core (LRNC), enriched with CD68-positive macrophages. This region is characterized by a highfrequency of the phenotypic transformation of VSMCs. Using a carotid artery ballooninjury model, we observed high expression of SOX9 in the neointima, and SOX9knockdown significantly attenuated intimal hyperplasia. In vitro, SOX9 knockdownin primary VSMCs suppressed PDGF-BB-induced phenotypic transformation, proliferation, and migration. Further studies using CUT&Tag analysis indicated thatPDGF-BB promoted the AMPK signaling pathway, leading to the nucleartranslocation of SOX9. Dual-luciferase reporter assay revealed that SOX9 directlybinds to the motif of the STAT3 promoter, thereby enhancing the phenotypictransformation of VSMCs. This study uncovered a novel molecular mechanism inwhich AMPK-mediated SOX9 activation facilitates its interaction with STAT3 toregulate the transformation, proliferation, and migration of VSMCs. These findingssuggest that targeting the SOX9-STAT3 axis can serve as a promising therapeuticstrategy for the prevention and treatment of ISR.
Keywords: SOX9, stat3, VSMCs, transformation, proliferation, Migration, restenosis, carotid artery injury
Received: 12 Mar 2025; Accepted: 22 May 2025.
Copyright: © 2025 Yuan, Jiang, Ye, Chen, Huang, Gao, Guo and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Chuan Jiang, Southwest Medical University, Luzhou, Sichuan, China
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