title: Stimulation of Transforming Growth Factor-β1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1.
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.
authors: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States of America.
authors: Peter J
authors: PJ
authors: Wermuth
authors: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States of America.
authors: Zhaodong
authors: Z
authors: Li
authors: Division of Rheumatology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, United States of America.
authors: Fabian A
authors: FA
authors: Mendoza
authors: Jefferson Institute of Molecular Medicine, Thomas Jefferson University, Philadelphia, PA, United States of America.
authors: Sergio A
authors: SA
authors: Jimenez
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D024061:Collagen Type III / Q000378:metabolism; D004347:Drug Interactions; D042783:Endothelial Cells / Q000166:cytology* / Q000187:drug effects*; D019332:Endothelin-1 / Q000494:pharmacology*; D005355:Fibrosis; D005786:Gene Expression Regulation / Q000187:drug effects; D008168:Lung / Q000098:blood supply / Q000473:pathology; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000166:cytology; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D012867:Skin / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D000199:Actins; D024042:Collagen Type I; D024061:Collagen Type III; D019332:Endothelin-1; D010980:Platelet Membrane Glycoproteins; D053773:Transforming Growth Factor beta1; C544013:alpha-smooth muscle actin, mouse; C028254:von Willebrand factor receptor