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Review
. 2019 Oct:168:100-107.
doi: 10.1016/j.bcp.2019.06.021. Epub 2019 Jun 26.

Endothelial-to-mesenchymal transition: Pathogenesis and therapeutic targets for chronic pulmonary and vascular diseases

Xuexin Lu  1 , Jiannan Gong  2 , Phyllis A Dennery  3 , Hongwei Yao  4
Affiliations
Review

Endothelial-to-mesenchymal transition: Pathogenesis and therapeutic targets for chronic pulmonary and vascular diseases

Xuexin Lu et al. Biochem Pharmacol. 2019 Oct.

Abstract

Endothelial-to-mesenchymal transition (EndoMT) is a process of transdifferentiation where endothelial cells gradually adopt the phenotypic characteristics of mesenchymal cells. This phenomenon was first discovered in embryonic heart development. The mechanisms underlying EndoMT are due to the activation of transforming growth factor-β, bone morphogenetic protein, Wingless/Integrated, or Notch signaling pathways. The EndoMT can be modulated by pathological processes, including inflammation, disturbed shear stress, vascular stiffness, and metabolic dysregulation. Recent studies have shown that EndoMT is implicated in the pathogenesis of chronic lung diseases, including pulmonary hypertension and lung fibrosis. Lung pathology of bronchopulmonary dysplasia can be mimicked in rodents exposed to hyperoxia as neonates. Although hyperoxic exposure reduces an endothelial cell marker platelet and endothelial cell adhesion molecule but increases a mesenchymal cell biomarker α-smooth muscle actin in vitro in human pulmonary endothelial cells, there is no direct evidence showing EndoMT in the development of bronchopulmonary dysplasia. Both pulmonary hypertension and lung fibrosis occur in long-term survivors with bronchopulmonary dysplasia. In this review, we discuss the EndoMT and its modulation by pathological processes. We then focus on the role of EndoMT in the pathogenesis of these chronic lung diseases, and discuss therapeutic approaches targeting the EndoMT using its negative regulators.

Keywords: Bronchopulmonary dysplasia; EndoMT; Lung fibrosis; Pulmonary hypertension; Therapeutics.

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Conflict of interest statement

Conflict of interests

The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Figure 1.
Figure 1.. Signaling pathways for EndoMT.
EndoMT results from the integration of a variety of signaling pathways, including TGF-β, BMP, Wnt/β-catenin and notch. These cascades interact with transcription factors, including Snail, Slug, ZEB1, ZEB2 and TWIST1. This suppresses the expression of endothelial cell genes (e.g., VE-cadherin, vWF, and CD31) but increases mesenchymal cell gene expression (e.g., α-SMA, vimentin, FSP-1, and fibronectin), leading to EndoMT. Activin receptor-like kinase (ALK) is a family of TGF-β type I receptors, which are responsible for TGF-β and BMP signal transduction.
Figure 2.
Figure 2.. Signaling pathways for EndoMT by pathological processes.
Pathologic processes, including inflammatory responses, disturbed shear stress, vascular stiffness, and metabolic reprogramming, cause EndoMT via different signaling pathways. ERK: extracellular signal-regulated kinase; FAO: fatty acid oxidation; FGFR1: fibroblast growth factor receptor 1; MEK: mitogen-activated protein kinase kinase; SRF: serum response factor; TAZ: transcriptional co-activator with PDZ-binding motif; YAP: Yes-associated protein.
Figure 3.
Figure 3.. EndoMT and pulmonary/vascular diseases.
Pathologic process-mediated EndoMT plays important roles in the pathogenesis of pulmonary hypertension, lung fibrosis and hyperoxic lung injury. Blocking and reversing EndoMT would be a potential therapeutic strategy in these diseases. Green boxes show the existing chemicals or approaches which target EndoMT thereby
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