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A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy
  1. Rob J Van Geest1,2,
  2. Sarit Y Lesnik-Oberstein1,
  3. H Stevie Tan1,
  4. Marco Mura1,
  5. Roel Goldschmeding3,
  6. Cornelis J F Van Noorden2,
  7. Ingeborg Klaassen1,
  8. Reinier O Schlingemann1,4
  1. 1Department of Ophthalmology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  2. 2Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  3. 3Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
  4. 4Netherlands Institute for Neurosciences, Amsterdam, The Netherlands
  1. Correspondence to Dr Reinier O Schlingemann, Medical Retina Unit and Ocular Angiogenesis Group, Department of Ophthalmology, Academic Medical Center, Room A2-122, PO Box 22660, 1100 DD Amsterdam, The Netherlands; r.schlingemann{at}


Introduction In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) may cause blindness by neovascularisation followed by fibrosis of the retina. It has previously been shown that a shift in the balance between levels of CTGF and VEGF in the eye is associated with this angiofibrotic switch. This study investigated whether anti-VEGF agents induce accelerated fibrosis in patients with PDR, as predicted by this model.

Methods CTGF and VEGF levels were measured by ELISA in 52 vitreous samples of PDR patients, of which 24 patients had received intravitreal bevacizumab 1 week to 3 months before vitrectomy, and were correlated with the degree of vitreoretinal fibrosis as determined clinically and intra-operatively.

Results CTGF correlated positively, and VEGF correlated negatively with the degree of fibrosis. The CTGF/VEGF ratio was the strongest predictor of fibrosis. Clinically, increased fibrosis was observed after intravitreal bevacizumab.

Conclusions These results confirm that the CTGF/VEGF ratio is a strong predictor of vitreoretinal fibrosis in PDR, and show that intravitreal anti-VEGF treatment causes increased fibrosis in PDR patients. These findings provide strong support for the model that the balance of CTGF and VEGF determines the angiofibrotic switch, and identify CTGF as a possible therapeutic target in the clinical management of PDR.

  • Angiogenesis
  • choroid
  • CTGF
  • diabetic retinopathy
  • drugs
  • fibrosis
  • imaging
  • macula
  • retina
  • VEGF
  • vitreous

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  • Funding This study was financially supported by grant 2005.00.042 from the Diabetes Fonds Nederland.

  • Competing interests Until 1 September 2009, RG received research grants and salary from FibroGen Inc., San Francisco, California, USA. The other authors have nothing to declare.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was obtained from the Institutional Review Board of the Academic Medical Center.

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

  • Data sharing statement Data available on request from the corresponding author Prof. dr. Reinier O. Schlingemann: r.o.schlingemann{at}

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