Twist1 Drives Atherosclerotic Plaque Stability, Challenging Conventional Views

New preclinical research indicates that atherosclerotic plaques driven by the transcription factor Twist1 exhibit surprising stability, challenging the long-held assumption that endothelial-to-mesenchymal transition solely contributes to cardiovascular disease progression. Plaque rupture remains a leading cause of heart attack and stroke, making plaque stability a critical area of research.

Historically, atherosclerosis has been characterized by lipid accumulation and inflammation, leading to plaque formation. Unstable plaques, prone to rupture, feature large necrotic cores and inflammatory cells. Endothelial-to-mesenchymal transition, where endothelial cells gain mesenchymal characteristics, was previously linked to advanced, unstable plaques. However, the precise role of this transition has been debated.

A study using hypercholesterolaemic mice revealed that Twist1 actively promotes endothelial-to-mesenchymal transition within advanced atherosclerotic plaques. While Twist1 expression contributed to plaque growth, it simultaneously enhanced hallmarks of plaque stability, including increased collagen deposition and a greater number of smooth muscle-like cells. Conversely, features associated with instability, such as necrotic core formation and macrophage accumulation, were reduced.

Further in vitro experiments demonstrated that Twist1 facilitates endothelial-to-mesenchymal transition by driving migration and proliferation. These findings suggest that Twist1-driven plaques may undergo structural remodeling that reinforces fibrous cap integrity, potentially lowering rupture risk.

This research challenges the notion that endothelial-to-mesenchymal transition uniformly destabilizes plaques, indicating that Twist1-mediated transition can offer protective effects under specific conditions. If validated in human studies, targeting Twist1 pathways could offer a novel therapeutic strategy focused on enhancing plaque stability, complementing existing treatments by shifting the focus from plaque burden reduction to rupture prevention.