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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2018
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.
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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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