title: Vascular endothelial growth factor aggravates fibrosis and vasculopathy in experimental models of systemic sclerosis.
abstract: OBJECTIVE
  High levels of vascular endothelial growth factor (VEGF), a key angiogenic factor, are present in patients with systemic sclerosis (SSc), but its role in the pathogenesis of fibrosis and its contribution to the disturbed angiogenesis of SSc remains hypothetical.
  
  
  METHODS
  Mono (+/-) and double (+/+) VEGF transgenic (tg) mice and their wildtype (wt) controls were analysed. The bleomycin model was applied to VEGF tg mice to evaluate effects of VEGF under proinflammatory conditions. Additionally, tight skin (TSK) 1/VEGF+/+ mice were generated to mimic later non-inflammatory stages of SSc.
  
  
  RESULTS
  VEGF+/+, but not VEGF+/- tg mice, spontaneously developed significant skin fibrosis, indicating profibrotic effect of VEGF in a gene-dosing manner. In the proinflammatory bleomycin model, the profibrotic effect became more pronounced with induction of skin fibrosis in VEGF+/- tg mice and even more enhanced fibrosis in VEGF+/+ tg mice. Analysis in TSK1/VEGF+/+ mice showed similar profibrotic effects of VEGF also under non-inflammatory in vivo conditions. In vitro analysis revealed that VEGF is able to directly induce collagen synthesis in dermal fibroblasts. Additionally, there was an inverse gene-dosing effect on the efficacy of angiogenesis in that a higher number of microvessels was observed in VEGF+/- tg mice than in VEGF+/+ tg mice.
  
  
  CONCLUSIONS
  These data provide the first evidence for VEGF as a novel molecular link between fibrosis and vasculopathy in the pathogenesis of SSc. They suggest that high levels of VEGF potently induce fibrosis in inflammatory and non-inflammatory stages, and also contribute to the relatively insufficient angiogenesis characteristic for SSc.
authors.affiliation: Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Britta
authors.initials: B
authors.lastname: Maurer
authors.affiliation: Department of Internal Medicine 3, University of Erlangen, Erlangen, Germany.
authors.forename: Alfiya
authors.initials: A
authors.lastname: Distler
authors.affiliation: Department of Rheumatology and Rehabilitation, Faculty of Medicine, Assuit University Hospitals, Assuit, Egypt.
authors.forename: Yossra A
authors.initials: YA
authors.lastname: Suliman
authors.affiliation: Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Renate E
authors.initials: RE
authors.lastname: Gay
authors.affiliation: Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Beat A
authors.initials: BA
authors.lastname: Michel
authors.affiliation: Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Steffen
authors.initials: S
authors.lastname: Gay
authors.affiliation: Department of Internal Medicine 3, University of Erlangen, Erlangen, Germany.
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.affiliation: Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Distler
mesh_terms: D000818:Animals; D001761:Bleomycin; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis; D004195:Disease Models, Animal; D018450:Disease Progression; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D012867:Skin / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology / Q000502:physiology*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D001761:Bleomycin; D003094:Collagen
keywords: Fibroblasts; Inflammation; Systemic Sclerosis