TWIST1 drives endothelial-to-mesenchymal-transition to stabilize atherosclerotic plaques
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 (Twist1<sup>ECKO</sup> Apo<sup>-/-</sup>). 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.
Authors
- Xiuying Li (ORCID: https://orcid.org/0000-0003-4194-0843)
- Andreas Edsfeldt (ORCID: https://orcid.org/0000-0002-2691-9192)
- Akiko Mammoto (ORCID: https://orcid.org/0000-0003-3448-7331)
- Emily V. Chambers (ORCID: https://orcid.org/0000-0003-1252-8059)
- Helle F. Jørgensen (ORCID: https://orcid.org/0000-0002-7909-2977)
- S. Xu
- Mannekomba R. Diagbouga (ORCID: https://orcid.org/0000-0002-2641-5445)
- Joanna Kalucka (ORCID: https://orcid.org/0000-0003-4887-7672)
- Jiangming Sun (ORCID: https://orcid.org/0000-0001-6814-1297)
- Chrysostomi Gialeli (ORCID: https://orcid.org/0000-0003-4290-9610)
- Mark Dunning (ORCID: https://orcid.org/0000-0001-7694-0427)
- Sheila Francis (ORCID: https://orcid.org/0000-0001-6552-0339)
- Paul C. Evans (ORCID: https://orcid.org/0000-0001-7975-681X)
- Michael Simons
- Siyu Tian
- Jovana Serbanovic-Canic
- Ankita Das
Institutions
- University of Science and Technology of China (CN)
- Steno Diabetes Centers (DK)
- Queen Mary University of London (GB)
- Lund University (SE)
- Medical College of Wisconsin (US)
- Aarhus University (DK)
- Royal Papworth Hospital (GB)
- Aarhus University Hospital (DK)
- Southwest Medical University (CN)
- Yale University (US)
- Affiliated Hospital of Southwest Medical University (CN)
- Skåne University Hospital (SE)
- Insigneo (GB)
- William Harvey Research Institute (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2026-02-18
- DOI
- https://doi.org/10.1038/s41467-026-69808-z
- Primary Topic
- Single-cell and spatial transcriptomics
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- British Heart Foundation
- Fondation Leducq
- Stiftelsen för Strategisk Forskning
- National Natural Science Foundation of China
- Lunds Universitet
- Svenska Sällskapet för Medicinsk Forskning
- Knut och Alice Wallenbergs Stiftelse
- Vetenskapsrådet
- STROKE-Riksförbundet
- National Institutes of Health