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

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Basic and translational research
Extended report
Scleroderma fibroblasts suppress angiogenesis via TGF-β/caveolin-1 dependent secretion of pigment epithelium-derived factor
  1. Vasiliki Liakouli1,2,
  2. Jacobo Elies1,3,
  3. Yasser Mohamed El-Sherbiny1,4,5,
  4. Margherita Scarcia6,
  5. Gary Grant6,
  6. Giuseppina Abignano1,7,8,
  7. Emma C Derrett-Smith9,
  8. Filomena Esteves10,
  9. Paola Cipriani2,
  10. Paul Emery1,5,
  11. Christopher P Denton9,
  12. Roberto Giacomelli2,
  13. Georgia Mavria6,
  14. Francesco Del Galdo1,5
  1. 1 Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK
  2. 2 Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L’Aquila, L’Aquila, Italy
  3. 3 School of Pharmacy and Medical Sciences, University of Bradford, Bradford, UK
  4. 4 Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
  5. 5 NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospital NHS Trust, Leeds, UK
  6. 6 Signal Transduction and Tumour Microenvironment Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
  7. 7 Rheumatology Department of Lucania, Rheumatology Institute of Lucania (IReL), San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Potenza, Italy
  8. 8 Rheumatology Institute of Lucania (IReL), San Carlo Hospital of Potenza, Potenza, Italy
  9. 9 Centre for Rheumatology and Connective Tissue, UCL Medical School Royal Free Campus, London, UK
  10. 10 Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK
  1. Correspondence to Dr Georgia Mavria, Signal Transduction and Tumour Microenvironment Group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS2 9JT, UK; g.mavria{at}leeds.ac.uk and Dr Francesco Del Galdo, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospital NHS Trust, Leeds LS74SA, UK; f.delgaldo{at}leeds.ac.uk

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.

  • systemic sclerosis
  • fibroblasts
  • autoimmune diseases

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/

https://doi.org/10.1136/annrheumdis-2017-212120

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    Footnotes

    • VL and JE contributed equally.

    • Handling editor Tore K Kvien

    • Contributors VL, JEC, YME-S, MS, GG, ECD-S and FE contributed to the experimental data collection and analysis. GA and PC contributed to the identification and collection of patient clinical data and biosamples. PE, CPD, RG and GM contributed to data revision, manuscript revision and discussion. VL and JEC drafted the manuscript. FDG ideated the experimental plan and supervised all aspects of research. FDG and GM critically reviewed data and their analysis.

    • Funding This study was partially funded by NIHR CDF to FDG and EULAR ODP grant to FDG.

    • Competing interests None declared.

    • Ethics approval The study was approved by the NHS REC 10/H1306/88 and Institutional Review Board of University of L’Aquila.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement There are no additional or unpublished data that need to be shared as part of this study.