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

Pei-Yu Chen,Martin A Schwartz,Michael Simons

doi:10.3389/fcvm.2020.00053

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.

Highlights

Atherosclerosis is a chronic progressive disease characterized by vascular inflammation and growth of atherosclerotic plaque that eventually lead to compromise of blood flow
Recent evidence has pointed to endothelial-to-mesenchymal transition (EndMT) as a key process in vascular inflammation in atherosclerosis [6, 7]
Continued fibroblast growth factor (FGF) signaling input, high endothelial let-7 levels, and suppression of TGFβRs expression maintain endothelial normalcy (Figure 1). This reciprocal relationship between Transforming growth factor receptor β (TGFβ) and FGF signaling outputs becomes important in atherosclerosis because vascular inflammation effectively suppresses FGF signaling by profoundly reducing expression of FGF receptor 1 (FGFR1, the principal endothelial FGF receptor), thereby increasing TGFβR1 expression and initiating EndMT [6]

Summary

INFLAMMATION AND ATHEROSCLEROSIS

Atherosclerosis is a complex, slowly developing disease characterized by a gradual transformation of intimal fatty streaks into full-blown plaques composed of activated endothelial and smooth muscle cells, macrophages, lymphocytes, and large amounts of extracellular matrix. Normal adult quiescent endothelial cells have a very low expression of TGFβR1, rendering these cells nearly completely resistant to TGFβ stimulation and EndMT [6] This is controlled by continuous fibroblast growth factor (FGF) signaling that maintains high expression of let-7 family of microRNAs (miRs). Continued FGF signaling input, high endothelial let-7 levels, and suppression of TGFβRs expression maintain endothelial normalcy (Figure 1) This reciprocal relationship between TGFβ and FGF signaling outputs becomes important in atherosclerosis because vascular inflammation effectively suppresses FGF signaling by profoundly reducing expression of FGF receptor 1 (FGFR1, the principal endothelial FGF receptor), thereby increasing TGFβR1 expression and initiating EndMT [6]

FLUID SHEAR STRESS

EndMT AND ATHEROSCLEROSIS

Findings

CONCLUSIONS