Advanced glycation end-products increase monocyte adhesion to retinal endothelial cells through vascular endothelial growth factor-induced ICAM-1 expression: inhibitory effect of antioxidants

J Leukoc Biol. 2004 Jun;75(6):1062-9. doi: 10.1189/jlb.0603265. Epub 2004 Mar 12.


Accumulating evidence indicates a role for advanced glycation end-products (AGEs) in the development of diabetic retinopathy. In the present study, we examined the in vitro effect of AGEs on human monocyte adhesion to bovine retinal endothelial cells (BRECs) and the molecular mechanisms involved in this effect. Treatment of cultured BRECs with AGEs led to a significant increase in monocyte adhesion and intercellular cell adhesion molecule-1 (ICAM-1) expression. These effects were inhibited by antioxidants including gliclazide and vitamins C and E. On the basis of the stimulatory effect of AGEs on vascular endothelial growth factor (VEGF) secretion by retinal endothelial cells, the role of this growth factor as mediator of AGE-induced monocyte adhesion to BRECs was next investigated. Incubation of BRECs with VEGF increased monocyte adhesion to these cells and enhanced ICAM-1 expression. Treatment of BRECs with an anti-VEGF antibody abrogated AGE-induced monocyte adhesion and ICAM-1 expression. Finally, incubation of BRECs with protein kinase C (PKC) and nuclear factor (NF)-kappaB inhibitors suppressed monocyte adhesion and ICAM-1 expression elicited by AGEs and VEGF. Taken together, these data indicate that AGEs increase monocyte adhesion to BRECs and that this effect is mediated through VEGF-induced ICAM-1 expression. They also demonstrate that this effect is oxidative stress-sensitive and involves PKC and NF-kappaB-dependent signaling pathways.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / pharmacology*
  • Ascorbic Acid / pharmacology
  • Cattle
  • Cell Adhesion / drug effects
  • Cell Division
  • Cells, Cultured
  • Endothelium, Vascular / metabolism*
  • Female
  • Gliclazide / pharmacology
  • Glycation End Products, Advanced / pharmacology*
  • Humans
  • Intercellular Adhesion Molecule-1 / metabolism*
  • Male
  • Monocytes / metabolism*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Protein Kinase C / pharmacology
  • Retinal Vessels / cytology
  • Signal Transduction
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vitamin E / pharmacology


  • Antioxidants
  • Glycation End Products, Advanced
  • NF-kappa B
  • Vascular Endothelial Growth Factor A
  • Intercellular Adhesion Molecule-1
  • Vitamin E
  • Protein Kinase C
  • Gliclazide
  • Ascorbic Acid