Stimulation of Transforming Growth Factor-?1-Induced Endothelial-To-Mesenchymal Transition and Tissue Fibrosis by Endothelin-1 (ET-1): A Novel Profibrotic Effect of ET-1.

ABSTRACT: TGF-?-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-?-induced EndoMT has not been studied. Here we evaluated the role of ET-1 on TGF-?1-induced EndoMT in immunopurified CD31+/CD102+ murine lung microvascular endothelial cells. The expression levels of ?-smooth muscle actin (?-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-?1 caused potent induction of EndoMT whereas ET-1 alone had a minimal effect. However, ET-1 potentiated TGF-?1-induced EndoMT and TGF-?1-stimulated expression of mesenchymal cell specific and profibrotic genes and proteins. ET-1 also induced expression of the TGF-? receptor 1 and 2 genes, suggesting a plausible autocrine mechanism to potentiate TGF-?-mediated EndoMT and fibrosis. Stimulation of TGF-?1-induced skin and lung fibrosis by ET-1 was confirmed in vivo in an animal model of TGF-?1-induced tissue fibrosis. These results suggest a novel role for ET-1 in the establishment and progression of tissue fibrosis.

SUBMITTER: Wermuth PJ 

PROVIDER: S-EPMC5008786 | biostudies-other | 2016

REPOSITORIES: biostudies-other