Scleroderma fibroblasts suppress angiogenesis via TGF-ß/caveolin-1 dependent secretion of pigment epithelium-derived factor.
Ann Rheum Dis
; 77(3): 431-440, 2018 03.
Article
in En
| MEDLINE
| ID: mdl-29259049
ABSTRACT
OBJECTIVES:
Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-ß) 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-ß 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-ß 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-ß 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-ß 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Scleroderma, Systemic
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Serpins
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Transforming Growth Factor beta
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Caveolin 1
/
Eye Proteins
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Fibroblasts
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Neovascularization, Pathologic
/
Nerve Growth Factors
Type of study:
Prognostic_studies
Limits:
Animals
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Female
/
Humans
/
Male
Language:
En
Journal:
Ann Rheum Dis
Year:
2018
Document type:
Article
Affiliation country:
United kingdom