Inhibition of platelet-derived growth factor promotes pericyte loss and angiogenesis in ischemic retinopathy

Am J Pathol. 2004 Apr;164(4):1263-73. doi: 10.1016/S0002-9440(10)63214-2.


We investigated whether inhibition of platelet-derived growth factor (PDGF) receptor tyrosine kinase activity would affect pericyte viability, vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR-2) expression and angiogenesis in a model of retinopathy of prematurity (ROP). ROP was induced in Sprague Dawley rats by exposure to 80% oxygen from postnatal (P) days 0 to 11 (with 3 hours/day in room air), and then room air from P12-18 (angiogenesis period). Shams were neonatal rats in room air from P0-18. STI571, a potent inhibitor of PDGF receptor tyrosine kinase, was administered from P12-18 at 50 or 100 mg/kg/day intraperitoneal (i.p.). Electron microscopy revealed that pericytes in the inner retina of both sham and ROP rats appeared normal; however STI571 induced a selective pericyte and vascular smooth muscle degeneration. Immunolabeling for caspase-3 and alpha-smooth muscle cell actin in consecutive paraffin sections of retinas confirmed that these degenerating cells were apoptotic pericytes. In all groups, VEGF and VEGFR-2 gene expression was located in ganglion cells, the inner nuclear layer, and retinal pigment epithelium. ROP was associated with an increase in both VEGF and VEGFR-2 gene expression and blood vessel profiles in the inner retina compared to sham rats. STI571 at both doses increased VEGF and VEGFR-2 mRNA and exacerbated angiogenesis in ROP rats, and in sham rats at 100 mg/kg/day. In conclusion, PDGF is required for pericyte viability and the subsequent prevention of VEGF/VEGFR-2 overexpression and angiogenesis in ROP.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Apoptosis / physiology
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Regulation
  • Humans
  • Immunohistochemistry
  • In Situ Hybridization
  • Infant, Newborn
  • Microscopy, Electron
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / pathology
  • Muscle, Smooth, Vascular / ultrastructure
  • Neovascularization, Pathologic / pathology*
  • Pericytes / drug effects
  • Pericytes / pathology*
  • Pericytes / ultrastructure
  • Platelet-Derived Growth Factor / drug effects
  • Platelet-Derived Growth Factor / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Retina / drug effects
  • Retina / pathology
  • Retina / ultrastructure
  • Retinal Vessels / physiology
  • Retinopathy of Prematurity / pathology*
  • Vascular Endothelial Growth Factor A / drug effects
  • Vascular Endothelial Growth Factor A / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / drug effects
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism


  • Enzyme Inhibitors
  • Platelet-Derived Growth Factor
  • Vascular Endothelial Growth Factor A
  • Receptor Protein-Tyrosine Kinases
  • Vascular Endothelial Growth Factor Receptor-2