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Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor
OBJECTIVES: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less cl...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867407/ https://www.ncbi.nlm.nih.gov/pubmed/29259049 http://dx.doi.org/10.1136/annrheumdis-2017-212120 |
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author | Liakouli, Vasiliki Elies, Jacobo El-Sherbiny, Yasser Mohamed Scarcia, Margherita Grant, Gary Abignano, Giuseppina Derrett-Smith, Emma C Esteves, Filomena Cipriani, Paola Emery, Paul Denton, Christopher P Giacomelli, Roberto Mavria, Georgia Del Galdo, Francesco |
author_facet | Liakouli, Vasiliki Elies, Jacobo El-Sherbiny, Yasser Mohamed Scarcia, Margherita Grant, Gary Abignano, Giuseppina Derrett-Smith, Emma C Esteves, Filomena Cipriani, Paola Emery, Paul Denton, Christopher P Giacomelli, Roberto Mavria, Georgia Del Galdo, Francesco |
author_sort | Liakouli, Vasiliki |
collection | PubMed |
description | OBJECTIVES: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-β and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis. METHODS: PEDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast–endothelial cell co-cultures and matrigel assays were employed to assess angiogenesis. RESULTS: PEDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-β in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-β receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density. CONCLUSIONS: Our data reveal a new pathway by which TGF-β suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc. |
format | Online Article Text |
id | pubmed-5867407 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-58674072018-03-27 Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor Liakouli, Vasiliki Elies, Jacobo El-Sherbiny, Yasser Mohamed Scarcia, Margherita Grant, Gary Abignano, Giuseppina Derrett-Smith, Emma C Esteves, Filomena Cipriani, Paola Emery, Paul Denton, Christopher P Giacomelli, Roberto Mavria, Georgia Del Galdo, Francesco Ann Rheum Dis Basic and Translational Research OBJECTIVES: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-β) plays a major role in tissue fibrosis, including downregulation of caveolin-1 (Cav-1); however, its role in defective angiogenesis is less clear. Pigment epithelium-derived factor (PEDF), a major antiangiogenic factor, is abundantly secreted by SSc fibroblasts. Here, we investigated the effect of TGF-β and Cav-1 on PEDF expression and the role of PEDF in the ability of SSc fibroblasts to modulate angiogenesis. METHODS: PEDF and Cav-1 expression in fibroblasts and endothelial cells were evaluated by means of immunohistochemistry on human and mouse skin biopsies. PEDF and Cav-1 were silenced in cultured SSc and control fibroblasts using lentiviral short-hairpin RNAs. Organotypic fibroblast–endothelial cell co-cultures and matrigel assays were employed to assess angiogenesis. RESULTS: PEDF is highly expressed in myofibroblasts and reticular fibroblasts with low Cav-1 expression in SSc skin biopsies, and it is induced by TGF-β in vitro. SSc fibroblasts suppress angiogenesis in an organotypic model. This model is reproduced by silencing Cav-1 in normal dermal fibroblasts. Conversely, silencing PEDF in SSc fibroblasts rescues their antiangiogenic phenotype. Consistently, transgenic mice with TGF-β receptor hyperactivation show lower Cav-1 and higher PEDF expression levels in skin biopsies accompanied by reduced blood vessel density. CONCLUSIONS: Our data reveal a new pathway by which TGF-β suppresses angiogenesis in SSc, through decreased fibroblast Cav-1 expression and subsequent PEDF secretion. This pathway may present a promising target for new therapeutic interventions in SSc. BMJ Publishing Group 2018-03 2017-12-19 /pmc/articles/PMC5867407/ /pubmed/29259049 http://dx.doi.org/10.1136/annrheumdis-2017-212120 Text en © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ |
spellingShingle | Basic and Translational Research Liakouli, Vasiliki Elies, Jacobo El-Sherbiny, Yasser Mohamed Scarcia, Margherita Grant, Gary Abignano, Giuseppina Derrett-Smith, Emma C Esteves, Filomena Cipriani, Paola Emery, Paul Denton, Christopher P Giacomelli, Roberto Mavria, Georgia Del Galdo, Francesco Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor |
title | Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor |
title_full | Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor |
title_fullStr | Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor |
title_full_unstemmed | Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor |
title_short | Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor |
title_sort | scleroderma fibroblasts suppress angiogenesis via tgf-β/caveolin-1 dependent secretion of pigment epithelium-derived factor |
topic | Basic and Translational Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867407/ https://www.ncbi.nlm.nih.gov/pubmed/29259049 http://dx.doi.org/10.1136/annrheumdis-2017-212120 |
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