Endothelial-to-Mesenchymal Transition, Vascular Inflammation, and Atherosclerosis

Abstract

Atherosclerosis is a chronic progressive disease characterized by vascular inflammation and growth of atherosclerotic plaque that eventually lead to compromise of blood flow. The disease has proven to be remarkably resistant to multiple attempts at meaningful reversal including recent strategies targeting selective inflammatory mediators. Endothelial-to-mesenchymal transition (EndMT) has emerged as a key driver of both vascular inflammation and plaque growth. A deeper understanding of EndMT provides new insights into the underlying biology of atherosclerosis, suggests likely molecular mechanism of atherosclerotic resistance, and identifies potential new therapeutic targets.

Keywords: FGF (fibroblast growth factor); TGFβ (transforming growth factor β); atherosclerotic plaques; endothelial-to-mesenchymal transition (EndMT); endothelium; inflammation.

Figure 1

Inflammation and endothelial-to-mesenchymal transition (EndMT). Inflammatory mediators including interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), and interleukin 1β (IL-1β) induce downregulation of endothelial fibroblast growth factor (FGF) receptors, reducing FGF signaling input. This leads to a large fall in let-7 miRNA levels and activation of transforming growth factor receptor β (TGFβ) signaling, initiating EndMT. Restoration of FGF signaling, endothelial let-7 miRNA levels, or suppression of endothelial TGFβ receptor expression arrest EndMT development.

Figure 2

Endothelial-to-mesenchymal transition (EndMT) in atherosclerosis. Endothelial cells in atherosclerotic vessels can, as a result of chronic vessel wall inflammation, undergo EndMT. This is a gradual process, with the majority of endothelial cells progressing to an intermediate phenotype characterized by a partial loss of endothelial-specific gene expression and acquisition of “mesenchymal” features. However, a significant number can progress to a fully blown mesenchymal phenotype characterized by a near-complete loss of endothelial fate gene expression and acquisition of mesenchymal fate gene expression. This results in breakdown of endothelial cell junctions, increased vascular leakiness, and promotion of inflammation, thereby establishing a feed forward loop and driving atherosclerosis progression.