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

Why this study matters for heart health

Atherosclerosis—the buildup of fatty plaques in our arteries—is the root cause of many heart attacks and strokes. These events often happen when a plaque suddenly ruptures. Doctors therefore care not only about how big a plaque is, but also whether it is stable or fragile. This study explores an unexpected way in which the cells lining our blood vessels can change their identity and, rather than making plaques more dangerous, actually help reinforce them against rupture.

How artery-lining cells can change their identity

Arteries are lined by a thin sheet of endothelial cells that normally form a smooth, protective barrier between blood and the vessel wall. Under stress—such as disturbed, swirling blood flow and inflammation—these cells can switch into a more mobile, builder-like state in a process called endothelial-to-mesenchymal transition (EndMT). In this state they move into the growing plaque, produce structural proteins like collagen, and start to resemble scar-forming cells. Earlier work suggested that this transformation simply worsens atherosclerosis by adding to plaque growth and inflammation. The new study asks a more nuanced question: can some forms of this transformation actually make plaques tougher and less likely to burst?

A key switch called TWIST1

The researchers focused on TWIST1, a gene that acts as a molecular switch controlling EndMT in several diseases. Using mice prone to high cholesterol and plaque formation, they engineered animals in which TWIST1 could be turned off specifically in endothelial cells after plaques had already formed. Single-cell RNA sequencing—an approach that reads the activity of thousands of genes in individual cells—showed that TWIST1 drives several distinct subgroups of transformed endothelial cells inside advanced plaques. Some of these cell clusters displayed only partial identity change, while others showed a more complete shift away from the original endothelial state, highlighting that EndMT is not an all-or-nothing event but a spectrum.

From cell migration and growth to a stronger plaque cap

When TWIST1 was deleted from endothelial cells in male mice, plaques became smaller but also showed more worrisome features: less collagen, fewer smooth muscle–like cells, more immune cells, larger dead cores, and more breaks in the elastic layer of the artery wall. Together, these are classic hallmarks of fragile, rupture-prone plaques. In contrast, when TWIST1 was present, transformed endothelial cells contributed to a thicker, collagen-rich cap over the plaque’s soft center. Studies in cultured human artery cells helped explain how. Under disturbed flow, TWIST1 boosted two key behaviors—cell migration and cell division—by activating downstream partners. Through the protein PELP1, it encouraged cells to move into the plaque; through an AEBP1–COL4A1 pathway, it helped them multiply and lay down collagen type IV, an important structural component of the vessel wall.

Differences between males and females and links to human disease

Interestingly, the same genetic switch-off of TWIST1 in endothelial cells had little effect on plaque size, EndMT, or stability features in female mice. This sex-specific pattern fits broader clinical observations: women more often show more diffuse, relatively stable plaque disease, whereas men are more prone to focal, vulnerable plaques. In human carotid artery samples, TWIST1 levels in the vessel lining were higher in plaques from patients without recent symptoms, and higher expression was linked to a lower risk of future cardiovascular events. These human data echo the mouse findings and suggest that TWIST1 activity in endothelial cells may mark a more stable plaque state.

What this means for future treatments

Overall, the study reshapes how we think about identity changes in artery-lining cells. Rather than being purely harmful, the TWIST1-driven form of EndMT appears to help build and maintain a tougher fibrous cap that shields the plaque’s soft core from the bloodstream, reducing the chance of rupture—at least in male animals. By mapping out the TWIST1–PELP1 and TWIST1–AEBP1–COL4A1 pathways, the work highlights new molecular targets that might one day be tuned to stabilize vulnerable plaques. Any future therapy would need to respect sex differences and the complex spectrum of cell states within plaques, but this research offers a promising blueprint for strengthening the artery wall from within.

Citation: Tardajos Ayllon, B., Diagbouga, M., Das, A. et al. TWIST1 drives endothelial-to-mesenchymal-transition to stabilize atherosclerotic plaques. Nat Commun 17, 2905 (2026). https://doi.org/10.1038/s41467-026-69808-z

Keywords: atherosclerosis, plaque stability, endothelial cells, TWIST1, EndMT