Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor

Liakouli, V, Elies, J, El-Sherbiny, YM ORCID: https://orcid.org/0000-0003-4791-3475, Scarcia, M, Grant, G, Abignano, G, Derrett-Smith, EC, Esteves, F, Cipriani, P, Emery, P, Denton, CP, Giacomelli, R, Mavria, G and Del Galdo, F, 2018. Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor. Annals of the Rheumatic Diseases, 77 (3), pp. 431-440. ISSN 0003-4967

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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: 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.

Item Type:	Journal article
Publication Title:	Annals of the Rheumatic Diseases
Creators:	Liakouli, V., Elies, J., El-Sherbiny, Y.M., Scarcia, M., Grant, G., Abignano, G., Derrett-Smith, E.C., Esteves, F., Cipriani, P., Emery, P., Denton, C.P., Giacomelli, R., Mavria, G. and Del Galdo, F.
Publisher:	BMJ Group
Date:	2018
Volume:	77
Number:	3
ISSN:	0003-4967
Identifiers:	Number Type 10.1136/annrheumdis-2017-212120 DOI
Rights:	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/. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	06 Feb 2019 15:55
Last Modified:	06 Feb 2019 15:59
URI:	https://irep.ntu.ac.uk/id/eprint/35777

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