Endothelial-to-mesenchymal transition in systemic sclerosis

Abstract

Systemic sclerosis (SSc) is an autoimmune disease characterized by significant vascular alterations and multi-organ fibrosis. Microvascular alterations are the first event of SSc and injured endothelial cells (ECs) may transdifferentiate towards myofibroblasts, the cells responsible for fibrosis and collagen deposition. This process is identified as endothelial-to-mesenchymal transition (EndMT), and understanding of its development is pivotal to identify early pathogenetic events and new therapeutic targets for SSc. In this review, we have highlighted the molecular mechanisms of EndMT and summarize the evidence of the role played by EndMT during the development of progressive fibrosis in SSc, also exploring the possible therapeutic role of its inhibition.

Keywords: endothelial cells; endothelial-to-mesenchymal transition; systemic sclerosis.

Fig. 1

Outline of the endothelial‐to‐mesenchymal transition (EndMT) process. (a) In physiological conditions, endothelial cells (ECs) express von Willebrand factor (vWF), Tie‐1 and Tie‐2 receptors, CD31 and vascular endothelial‐cadherin (VE‐cadherin), displaying cobblestone morphology and surrounded by pericytes. (b) After pathological stimuli, such as transforming growth factor (TGF)‐β, endothelin‐1 (ET‐1), tumour necrosis factor (TNF)‐α, interleukin (IL)‐1, interferon (IFN), hypoxia, reactive oxygen species (ROS) and microRNAs (miRs), ECs acquire invasive properties and express mesenchymal markers such as α‐smooth muscle actin (α‐SMA), smooth muscle 22 (Sm22), CD44, N‐cadherin, vimentin and fibroblast‐specific protein‐1 (FSP‐1) (S100A4) and collagen. In these conditions, ECs show the typical elongated shape of mesenchymal cells and, together with surrounding pericytes, may transdifferentiate toward myofibroblasts. (c) ECs, differentiated towards mesenchymal cells, increase their migratory and proliferative capacity, losing their barrier skill. During EndMT, resident ECs disaggregate from the organized cells layer of the vessel walls and invade the surrounding tissue. In this phase, the transdifferentiated cells may release collagen in the tissue, contributing to fibrosis.

Fig. 2

Role of endothelin‐1 (ET‐1) and transforming growth factor (TGF)‐β during endothelial‐to‐mesenchymal transition (EndMT). Both TGF‐β and ET‐1, which are largely over‐expressed in systemic sclerosis (SSc), may promote the decrease of endothelial markers, such as CD31, von Willebrand factor (vWF) and vascular endothelial‐cadherin (VE‐cadherin) and the increase of mesenchymal markers, such as α‐smooth muscle actin (α‐SMA), smooth muscle 22 (Sm22) and collagen (Col1A1). ET‐1 may promote the TGF‐β mRNA transcription which, in turn, further promote ET‐1 mRNA, in a vicious loop. Both these molecules may modulate fibrogenic responses.