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Abstract Number: 768

Transforming Growth Factor Beta Induces anti  Angio and Vasculo-Genesis Phenotype in Dermal Fibroblasts through Secretion of Pigment Epithelium Derived Factor

Vasiliki Liakouli1, Margherita Scarcia2, Giuseppina Abignano3, Emma C. Derrett-Smith4, Justin Gillespie5, Paola Cipriani6, Paul Emery7, Christopher P. Denton8, R Giacomelli9, Georgia Mavria2 and Francesco Del Galdo10, 1Leeds Institute of Rheumatic and Musculoskeletal Medicine and Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L’Aquila, Leeds, United Kingdom, 2Signal Transduction and Angiogenesis group, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK, Leeds, United Kingdom, 3Leeds Institute of Rheumatic and Musculoskeletal Medicine and Department of Biotechnological and LTHT Leeds Musculoskeletal Biomedical Research Unit, leeds, United Kingdom, 4Centre for Rheumatology and Connective Tissue Diseases,, UCL Medical School Royal Free Campus, London, United Kingdom, 5University of Leeds, Leeds Institue of Rheumatic and Musculoskeletal Medicine, Leeds, United Kingdom, 6Department of Biotechnological and Applied Clinical Science, Rheumatology Unit, School of Medicine, University of L’Aquila, L'Aquila, Italy, 7NIHR-Leeds Musculoskeletal Biomedical Research Unit and Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom, 8Centre for Rheumatology and Connective Tissue Diseases, UCL Medical School Royal Free Campus, London, United Kingdom, 9Università degli Studi dell'Aquila, L'Aquila, Italy, 10Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: Angiogenesis, systemic sclerosis and transforming growth factor

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Session Information

Session Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: Systemic Sclerosis (SSc) is an autoimmune disorder characterized by tissue fibrosis and vasculopathy. A proteomic analysis of the secretome of SSc dermal fibroblasts (SSc-FBs) identified increased protein levels of Pigment Epithelium Derived Factor (PEDF), which is the major endogenous inhibitor of intraocular angiogenesis. Here we aimed to validate the findings in vitro and in vivo and determine whether PEDF could be involved in SSc vasculopathy. 

Methods: PEDF expression was investigated in the skin and FBs of 4 early diffuse SSc patients and 4 healthy controls (HC) by immunohistochemistry (IHC), qRT-PCR and flowcytometry. Functional effects of PEDF on angio/vasculogenesis were examined by Matrigel assays and CD31 IHC on organotypic co-culture assays of endothelial cells and either HC-FBs or SSc-FBs. Vascular tubule number, length and junctions were analyzed by Angiosys software. Caveolin expression was silenced by lentiviral induced shRNA expression. PEDF expression was also investigated by IHC on skin biopsies from wild-type (WT) and TβRIIΔk mice, which have fibroblast-specific constitutive activation of transforming growth factor-beta (TGF-β) signaling.

Results: In SSc skin 52% of FBs showed a strong expression of PEDF vs. 13% in HC skin (p<0.0006). Double IHC studies indicated that FBs positive for PEDF showed a decreased expression of cav-1. SSc-FBs in vitro showed on average a 5-fold PEDF expression compared to HC-FBs (p<0.05) . Increased PEDF expression was inducible by either TGF-β stimulation or silencing of cav-1 expression in vitro. Concordantly, TβRIIΔk-fib mice showed an increased PEDF expression and decreased CAV-1 expression in vivo. Recombinant human PEDF inhibited vasculogenesis in vitro by suppressing >50% of tubule length, number and junctions ( P<0.01). Consistently, organotypic co-culture assays indicated that SSc- FBs inhibited tubulogenesis in vitro.  shCAV-1 FBS displayed a similar phenotype to SSc fibroblasts, which was abrogated by immunodepletion of PEDF from shCAV supernatants.

 Conclusion: PEDF expression is increased in SSc biopsies and SSc-FBs and in TβRIIΔk-fib mice . PEDF expression is associated with decreased cav-1 expression in vivo and it is induced by silencing cav-1 in vitro. Functionally, PEDF can suppress vasculogenesis both in Matrigel and organotypic co-culture assays. This suggest that the decreased expression of cav-1 observed in SSc-FBs may contribute to the SSc vasculopathy through PEDF as well as other factors. Further studies unraveling the mechanisms of the antiangiogenic effect of PEDF may shed light in understanding the molecular events linking the profibrotic phenotype and SSc vasculopathy.


Disclosure:

V. Liakouli,
None;

M. Scarcia,
None;

G. Abignano,
None;

E. C. Derrett-Smith,
None;

J. Gillespie,
None;

P. Cipriani,
None;

P. Emery,
None;

C. P. Denton,

Actelion Pharmaceuticals US,

5;

R. Giacomelli,
None;

G. Mavria,
None;

F. Del Galdo,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/transforming-growth-factor-beta-induces-anti-angio-and-vasculo-genesis-phenotype-in-dermal-fibroblasts-through-secretion-of-pigment-epithelium-derived-factor/

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