Endothelial to Mesenchymal Transition in Pulmonary Vascular Diseases

Abstract

Lung diseases, such as pulmonary hypertension and pulmonary fibrosis, are life-threatening diseases and have common features of vascular remodeling. During progression, extracellular matrix protein deposition and dysregulation of proteolytic enzymes occurs, which results in vascular stiffness and dysfunction. Although vasodilators or anti-fibrotic therapy have been mainly used as therapy owing to these characteristics, their effectiveness does not meet expectations. Therefore, a better understanding of the etiology and new therapeutic approaches are needed. Endothelial cells (ECs) line the inner walls of blood vessels and maintain vascular homeostasis by protecting vascular cells from pathological stimuli. Chronic stimulation of ECs by various factors, including pro-inflammatory cytokines and hypoxia, leads to ECs undergoing an imbalance of endothelial homeostasis, which results in endothelial dysfunction and is closely associated with vascular diseases. Emerging studies suggest that endothelial to mesenchymal transition (EndMT) contributes to endothelial dysfunction and plays a key role in the pathogenesis of vascular diseases. EndMT is a process by which ECs lose their markers and show mesenchymal-like morphological changes, and gain mesenchymal cell markers. Despite the efforts to elucidate these molecular mechanisms, the role of EndMT in the pathogenesis of lung disease still requires further investigation. Here, we review the importance of EndMT in the pathogenesis of pulmonary vascular diseases and discuss various signaling pathways and mediators involved in the EndMT process. Furthermore, we will provide insight into the therapeutic potential of targeting EndMT.

Keywords: endothelial to mesenchymal transition; lung disease; pulmonary fibrosis; pulmonary hypertension.

Figure 1

A schematic representation of endothelial-to-mesenchymal transition (EndMT) involved in lung diseases. Endothelial cells stimulated by transforming growth factor-β (TGFβ), interleukin 1 beta (IL-1β), tumor necrosis factor alpha (TNFα), and hypoxia undergo EndMT. EndMT is characterized by phenotypic change from a cobblestone into an elongated shape, loss of endothelial markers, and the acquisition of mesenchymal markers. EndMT contributes to the pathogenesis of lung diseases, including pulmonary arterial hypertension (PAH), radiation-induced pulmonary fibrosis (RIPF), and idiopathic pulmonary fibrosis (IPF). Various mediators and transcription factors are identified in this process.

Figure 2

Molecular signaling pathways involved in endothelial-to-mesenchymal transition (EndMT). Stimulation with transforming growth factor-β (TGFβ), bone morphogenic protein (BMP), Notch ligands, inflammatory stress, and hypoxia induce expression of transcription factors, such as Twist1, Slug, and Snail, resulting in EndMT. During this process, mediators including microRNAs (miRNAs), Smad, Akt/nuclear factor kappa B (NF-κB), and hypoxia-inducible factor (HIF) play important roles in EndMT.

Figure 3

The novel therapeutic approach for lung diseases by targeting EndMT. The modulation of signaling pathways involved in EndMT by miRNAs, inhibitors, and agonists has therapeutic effects in vitro and in vivo. Targeting EndMT reduces mesenchymal marker expression and pulmonary vascular remodeling, which ultimately ameliorates the hemodynamic phenotypes in the animal model of PH. In addition, the inhibition of EndMT decreases fibrotic lesion in various PF animal models. This provides insight into the therapeutic potential of targeting EndMT.