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

TL;DR

This study shows that TWIST1 promotes a cell change in blood vessels that can stabilize dangerous cholesterol plaques in arteries, challenging previous assumptions.

Contribution

The study reveals that TWIST1-driven endothelial-to-mesenchymal transition can stabilize atherosclerotic plaques rather than destabilize them.

Findings

TWIST1 promotes endothelial-to-mesenchymal transition in advanced atherosclerotic plaques.

Endothelial TWIST1 increases plaque stability by boosting collagen and reducing necrosis and macrophage accumulation.

TWIST1 enhances endothelial cell migration and proliferation via PELP1 and AEBP1-dependent pathways.

Abstract

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.

Endothelial-to-mesenchymal transition contributes to plaque progression in atherosclerosis. Here, Ayllon et al. show that the protein TWIST1 drives endothelial cell plasticity in atherosclerosis, promoting plaque growth and stability while reducing features linked to rupture, challenging the view that these cell changes always worsen disease.

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