Different effects of various anti-angiogenic treatments in an experimental mouse model of retinopathy of prematurity

Clin Exp Ophthalmol. 2019 Jan;47(1):79-87. doi: 10.1111/ceo.13368. Epub 2018 Aug 27.

Abstract

Background: Anti-vascular endothelial growth factor (VEGF) drugs are an option for the treatment of retinopathy of prematurity (ROP). Blocking of other angiogenic factors is also of interest. We therefore investigated in which effects would result blocking of placental growth factor (PlGF).

Methods: C57BL/6 mice were exposed to 75% oxygen from P7 to P12. Intravitreal injections were performed at P12. Mice of control groups remained untouched after oxygen treatment, or phosphate buffered saline or neutral IgG molecules were injected. In the treatment groups, antibodies against VEGF or PlGF, a mixture of anti-VEGF and anti-PlGF, aflibercept or sunitinib were injected. On P17, electroretinographic (ERG) measurements were performed. Avascular zones and neovascularization were evaluated in retinal flat-mounts. Results are expressed as percent of total retinal area (median with median absolute deviation, MAD).

Results: Eyes of control groups showed similar neovascularization (1.4-3.3%, MAD 0.4-0.9%). Neovascularization was significantly less (0.5-0.7%, MAD 0.1-0.3%) in all treatment groups. Avascular zones in the retinas of control groups showed similar values (18.3-25.7%, MAD 4.8-8.8%). Avascular zones were significantly reduced down to 3.6 ± 1.3% after anti-VEGF injection, but they were not reduced significantly in the other treatment groups (13.3-22%, MAD 3.6-6.1%). ERG measurements did not reveal significant differences between the controls and the treatment groups.

Conclusions: Blocking of PlGF or injection of sunitinib results in a similar inhibition of neovascularization as by anti-VEGF treatment in the mouse model of ROP. However, physiological angiogenesis that occurs after anti-VEGF treatment is blocked by anti-PlGF or sunitinib treatment, indicating that pathological neovascularization may follow different pathways than physiological angiogenesis.

Keywords: intraocular drugs; pharmacology; retinal pathology; retinopathy of prematurity; vascular development.

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage
  • Animals
  • Animals, Newborn
  • Disease Models, Animal
  • Electroretinography
  • Intravitreal Injections
  • Mice, Inbred C57BL
  • Microscopy, Fluorescence
  • Receptors, Vascular Endothelial Growth Factor / administration & dosage*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors
  • Recombinant Fusion Proteins / administration & dosage*
  • Retina / pathology*
  • Retinopathy of Prematurity / diagnosis
  • Retinopathy of Prematurity / drug therapy*
  • Sunitinib / administration & dosage*
  • Treatment Outcome

Substances

  • Angiogenesis Inhibitors
  • Recombinant Fusion Proteins
  • aflibercept
  • Receptors, Vascular Endothelial Growth Factor
  • Sunitinib