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Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor
Liakouli, V. El-Sherbiny, Y.M. Scarcia, M. Grant, G. Abignano, G. Derrett-Smith, E.C. Esteves, F. Cipriani, P. Emery, P.
Liakouli, V.
El-Sherbiny, Y.M.
Scarcia, M.
Grant, G.
Abignano, G.
Derrett-Smith, E.C.
Esteves, F.
Cipriani, P.
Emery, P.
Publication Date
2018-03
End of Embargo
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© 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/
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Yes
Open Access status
openAccess
Accepted for publication
29/11/2017
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Abstract
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 P EDF 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 cocultures
and matrigel assays were employed to assess
angiogenesis.
Results P EDF 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 O ur 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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Citation
Liakouli V, Elies J, El-Sherbiny YM et al (2018) Scleroderma fibroblasts suppress angiogenesis via TGF- ß/caveolin-1 dependent secretion of pigment epithelium-derived factor. Annals of the Rheumatic Diseases. 77(3): 431-440.
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