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<p>Rupture of unstable atherosclerotic plaques is a major cause of mortality. Endothelial-to-mesenchymal transition associates with advanced atherosclerotic plaques and contributes to plaque progression. We examined the role of <i>Twist1</i>, a transcription factor that drives endothelial-to-mesenchymal transition, in plaque progression by inducible deletion from endothelial cells in hypercholesterolemic mice (<i>Twist1</i><sup><i>ECKO</i></sup> <i>Apo</i><sup><i>-/-</i></sup>). Single-cell RNA sequencing coupled to endothelial cell-tracking reveals that <i>Twist1</i> promotes endothelial-to-mesenchymal transition in advanced atherosclerotic plaques. Histological analyses demonstrate that endothelial <i>Twist1</i> promotes plaque growth and hallmarks of plaque stability (collagen, ACTA2-positive cells) and reduces features of instability (necrosis, macrophage accumulation). Analysis of cultured human aortic endothelial cells shows that TWIST1 contributes to endothelial-to-mesenchymal transition by promoting migration and proliferation through the transcriptional coactivator PELP1. Additionally, TWIST1 promotes endothelial cell proliferation via AEBP1-dependent upregulation of COL4A1. These findings challenge the prevailing view that endothelial-to-mesenchymal transition uniquely destabilizes plaques, by suggesting that TWIST1-driven endothelial-to-mesenchymal transition can promote plaque stability, offering new insights into atherosclerosis pathophysiology and therapeutic potential.</p>

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TWIST1 drives endothelial-to-mesenchymal-transition to stabilize atherosclerotic plaques

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月18日

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  • Blanca Tardajos Ayllon,
  • Mannekomba Diagbouga,
  • Ankita Das,
  • Siyu Tian,
  • Andreas Edsfeldt,
  • Joanna Kalucka,
  • Jovana Serbanovic-Canic,
  • Emily Chambers,
  • Jiangming Sun,
  • Chrysostomi Gialeli,
  • Mark Dunning,
  • Sheila E. Francis,
  • Xiuying Li,
  • Akiko Mammoto,
  • Michael Simons,
  • Helle F. Jørgensen,
  • Isabel Goncalves,
  • Suowen Xu,
  • Paul C. Evans

摘要

Rupture of unstable atherosclerotic plaques is a major cause of mortality. Endothelial-to-mesenchymal transition associates with advanced atherosclerotic plaques and contributes to plaque progression. We examined the role of Twist1, a transcription factor that drives endothelial-to-mesenchymal transition, in plaque progression by inducible deletion from endothelial cells in hypercholesterolemic mice (Twist1ECKO Apo-/-). Single-cell RNA sequencing coupled to endothelial cell-tracking reveals that Twist1 promotes endothelial-to-mesenchymal transition in advanced atherosclerotic plaques. Histological analyses demonstrate that endothelial Twist1 promotes plaque growth and hallmarks of plaque stability (collagen, ACTA2-positive cells) and reduces features of instability (necrosis, macrophage accumulation). Analysis of cultured human aortic endothelial cells shows that TWIST1 contributes to endothelial-to-mesenchymal transition by promoting migration and proliferation through the transcriptional coactivator PELP1. Additionally, TWIST1 promotes endothelial cell proliferation via AEBP1-dependent upregulation of COL4A1. These findings challenge the prevailing view that endothelial-to-mesenchymal transition uniquely destabilizes plaques, by suggesting that TWIST1-driven endothelial-to-mesenchymal transition can promote plaque stability, offering new insights into atherosclerosis pathophysiology and therapeutic potential.