Breaking News:TWIST1 Increases Atherosclerotic Plaque Stability– What Just Happened

ATHEROSCLEROTIC plaques driven by the transcription factor Twist1 were associated with features of increased stability, challenging long-held assumptions about endothelial-to-mesenchymal transition in cardiovascular disease. 

A new preclinical study revealed that TWIST1-driven endothelial-to-mesenchymal transition can promote plaque stability, overturning the prevailing view that endothelial-to-mesenchymal transition is purely detrimental in atherosclerosis. Plaque rupture remains a leading cause of myocardial infarction and stroke, making mechanisms that influence plaque stability a major focus in cardiovascular research. 

Atherosclerosis is characterised by lipid accumulation and chronic inflammation within arterial walls, leading to plaque formation. Unstable plaques, defined by large necrotic cores and inflammatory cell infiltration, are prone to rupture. Endothelial-to-mesenchymal transition, a process in which endothelial cells acquire mesenchymal characteristics, has previously been linked to advanced and potentially unstable plaques. However, the precise role of this transition has remained controversial. 

TWIST1-Driven Atherosclerotic Plaques Promote Stability 

To clarify the function of Twist1, researchers used inducible endothelial-specific deletion of Twist1 in hypercholesterolaemic mice lacking apolipoprotein E. Single-cell RNA sequencing combined with endothelial cell tracking demonstrated that Twist1 actively promoted endothelial-to-mesenchymal transition within advanced atherosclerotic plaques. 

Histological analyses revealed a complex picture. Endothelial Twist1 expression promoted plaque growth but simultaneously enhanced hallmarks of plaque stability, including increased collagen deposition and a greater number of ACTA2-positive smooth muscle–like cells. At the same time, features typically associated with instability, such as necrotic core formation and macrophage accumulation, were reduced. 

Complementary in vitro experiments in cultured human aortic endothelial cells showed that TWIST1 facilitated endothelial-to-mesenchymal transition by driving migration and proliferation through the transcriptional coactivator PELP1. Further mechanistic work identified an AEBP1-dependent pathway that upregulated COL4A1, promoting endothelial cell proliferation. 

These findings suggest that TWIST1-driven atherosclerotic plaques may undergo structural remodelling that reinforces fibrous cap integrity, potentially lowering rupture risk. 

Rethinking Endothelial-to-Mesenchymal Transition in Atherosclerosis 

The study challenges the concept that endothelial-to-mesenchymal transition uniformly destabilises plaques. Instead, the data indicate that TWIST1-mediated endothelial-to-mesenchymal transition can exert protective effects under certain conditions. 

The findings were derived from murine models and cell culture systems, which may not fully recapitulate human disease. Nevertheless, the integration of single-cell transcriptomics with histological and functional analyses provides mechanistic insight. 

If validated in human studies, targeting TWIST1 pathways could represent a novel therapeutic strategy aimed not at shrinking plaques, but at enhancing their stability. Such an approach may complement existing lipid-lowering and anti-inflammatory therapies, shifting the focus of atherosclerosis management towards preventing rupture rather than simply reducing plaque burden. 

Reference 

Tardajos Ayllon B et al. TWIST1 drives endothelial-to-mesenchymal-transition to stabilise atherosclerotic plaques. Sci Rep. 2026; DOI:10.1038/s41467-026-69808-z. 

Featured image: lurii on Adobe Stock