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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Ann+Rheum+Dis 2018 ; 77 (3): 431-40 Nephropedia Template TP
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Scleroderma fibroblasts suppress angiogenesis via TGF-?/caveolin-1 dependent secretion of pigment epithelium-derived factor #MMPMID29259049
Liakouli V; Elies J; El-Sherbiny YM; Scarcia M; Grant G; Abignano G; Derrett-Smith EC; Esteves F; Cipriani P; Emery P; Denton CP; Giacomelli R; Mavria G; Del Galdo F
Ann Rheum Dis 2018[Mar]; 77 (3): 431-40 PMID29259049show ga
Objectives: Systemic sclerosis (SSc) is characterised by tissue fibrosis and vasculopathy with defective angiogenesis. Transforming growth factor beta (TGF-?) 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-? 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-? 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-? 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-? 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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Ann+Rheum+Dis 2018 ; 77 (3): 431-40
