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

Vasiliki Liakouli1,2, Jacobo Elies1,3, Yasser Mohamed El-Sherbiny1,4,5

  • 1Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK.

Annals of the Rheumatic Diseases
|December 21, 2017
PubMed
Abstract

Insights

Transforming growth factor beta (TGF-β) reduces caveolin-1 (Cav-1) in systemic sclerosis (SSc), increasing pigment epithelium-derived factor (PEDF) and inhibiting blood vessel formation. Silencing PEDF restores normal angiogenesis in SSc.

Area of Science:

  • Cell Biology
  • Vascular Biology
  • Fibrosis Research

Background:

  • Systemic sclerosis (SSc) involves tissue fibrosis and impaired blood vessel formation (angiogenesis).
  • Transforming growth factor beta (TGF-β) is implicated in fibrosis and may affect angiogenesis by altering caveolin-1 (Cav-1) expression.
  • Pigment epithelium-derived factor (PEDF), a known antiangiogenic factor, is highly secreted by SSc fibroblasts, suggesting a role in defective angiogenesis.

Purpose of the Study:

  • To investigate the impact of TGF-β and Cav-1 on PEDF expression in SSc.
  • To determine the role of PEDF in the angiogenic capacity of SSc fibroblasts.
  • To elucidate the molecular mechanisms underlying TGF-β-mediated suppression of angiogenesis in SSc.

Main Methods:

  • Immunohistochemistry was used to assess PEDF and Cav-1 expression in human and mouse skin biopsies.
  • Short-hairpin RNAs were employed to silence PEDF and Cav-1 in cultured SSc and control fibroblasts.
  • Organotypic co-cultures and matrigel assays were utilized to evaluate angiogenesis in vitro and in vivo.

Main Results:

  • SSc fibroblasts exhibit high PEDF and low Cav-1 expression, a pattern induced by TGF-β in vitro.
  • SSc fibroblasts demonstrated suppressed angiogenesis, which was replicated by silencing Cav-1 in normal fibroblasts.
  • Silencing PEDF in SSc fibroblasts reversed their antiangiogenic phenotype, and TGF-β-overactivated mice showed reduced vascularity with altered Cav-1 and PEDF levels.

Conclusions:

  • TGF-β suppresses angiogenesis in SSc by decreasing fibroblast Cav-1 expression, leading to increased PEDF secretion.
  • This newly identified pathway represents a potential therapeutic target for treating SSc-related vascular complications.
  • Targeting the TGF-β/Cav-1/PEDF axis may offer novel treatment strategies for systemic sclerosis.
Keywords:
autoimmune diseasesfibroblastssystemic sclerosis

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