Abstract
TGF-β-induced endothelial-to-mesenchymal transition (EndoMT) is a newly recognized source of profibrotic activated myofibroblasts and has been suggested to play a role in the pathogenesis of various fibrotic processes. Endothelin-1 (ET-1) has been implicated in the development of tissue fibrosis but its participation in TGF-β-induced EndoMT has not been studied. Here we evaluated the role of ET-1 on TGF-β1-induced EndoMT in immunopurified CD31+/CD102+ murine lung microvascular endothelial cells. The expression levels of α-smooth muscle actin (α-SMA), of relevant profibrotic genes, and of various transcription factors involved in the EndoMT process were assessed employing quantitative RT-PCR, immunofluorescence histology and Western blot analysis. TGF-β1 caused potent induction of EndoMT whereas ET-1 alone had a minimal effect. However, ET-1 potentiated TGF-β1-induced EndoMT and TGF-β1-stimulated expression of mesenchymal cell specific and profibrotic genes and proteins. ET-1 also induced expression of the TGF-β receptor 1 and 2 genes, suggesting a plausible autocrine mechanism to potentiate TGF-β-mediated EndoMT and fibrosis. Stimulation of TGF-β1-induced skin and lung fibrosis by ET-1 was confirmed in vivo in an animal model of TGF-β1-induced tissue fibrosis. These results suggest a novel role for ET-1 in the establishment and progression of tissue fibrosis.
Highlights
Activated myofibroblasts comprise a unique population of mesenchymal cells that play a crucial role in the development of pathologic fibrotic processes and are considered to be the ultimate effector cells in various fibrotic disorders including Systemic Sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF), and cardiac, liver and kidney fibrosis [1,2]
We examined here the possibility that ET-1 may participate in the fibrotic process through potentiation of TGF-β1-induced endothelial-to-mesenchymal transition (EndoMT) in immunopurified murine lung microvascular endothelial cells
The data revealed that ET-1 alone had no effect on αSMA expression (ET-1 in Fig 1B, top right), it displayed a potentiating effect on TGF-β1-induced α-smooth muscle actin (α-SMA) expression as evidenced by a greater intensity of fluorescence in cultures treated with ET-1 plus TGF-β1 (TGF-β1 plusET1 in Fig 1A, bottom right) in comparison with cultures treated with TGF-β1 alone
Summary
Activated myofibroblasts comprise a unique population of mesenchymal cells that play a crucial role in the development of pathologic fibrotic processes and are considered to be the ultimate effector cells in various fibrotic disorders including Systemic Sclerosis (SSc), Idiopathic Pulmonary Fibrosis (IPF), and cardiac, liver and kidney fibrosis [1,2]. ET-1 Stimulates TGF-β1-Induced EndoMT including type I and type III collagens Owing to their crucial role in the pathogenesis of tissue fibrosis and various fibrotic diseases there has been intense investigation of their cellular origins [3,4]. EndoMT has been shown to occur in organ-specific fibrotic disorders including cardiac, kidney, and intestinal fibrosis [16,17,18,19,20,21], in cancer-associated fibrosis [22], and in Systemic Sclerosis (SSc)-associated pulmonary fibrosis and Pulmonary Arterial Hypertension (PAH) as well as in Primary PAH [23,24,25,26]
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