Links between retinal vascular dysfunction induced by elevated glucose levels and VEGF

J. R. Williamson, K. C. Chang, W. LeJeune, C. C. Stephan, T. A. Brock, R. G. Tilton

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Purpose. Diabetes and hyperglycemia per se induce "hypoxia-like" reductive stress (an increased ratio of NADH/NAD+). Since vascular endothelial growth factor (VEGF; vascular permeability factor) mRNA levels are increased by hypoxia which also causes reductive stress, these studies were undertaken to investigate a possible role for VEGF in mediating hyperglycemia-induced vascular dysfunction. Methods. Recombinant human VEGF was infused into the femoral vein or applied topically to skin chamber vessels in normal rats. Solutions containing 5 mM glucose ± VEGF and 30 mM glucose ± VEGF antibodies (Ab) were applied to skin chamber vessels 60 min prior to assessment of vascular albumin permeation (μg plasma/g wet wt/min, mean ± SD) by sequential injection of 125I- and 131I-albumin (circulation times 10 and 2 min, respectively; 131I -albumin served to correct for intravascular content of 125I-albumin). Results. Infusion of ∼0.65 pmol VEGF/kg bwt/min for 20 min increased retinal 125I-albumin permeation 2 fold from 82±11 in controls to 168±28 (p = 0.0013, N=4 each). Topical VEGF applied at concentrations of 2 to 4 pM increased 125I -albumin permeation in chamber vessels to the same extent as 30 mM glucose (412±57 (N=4) and 420±42 (N=5), respectively vs. 152±36 (N=5) for the vehicle, p < 0.0001 for both). The 30 mM glucose-induced increase in 125I-albumin permeation was markedly attenuated by 100 μg VEGF Ab/ml buffer (234±32 (N=7), p < 0.0001), but not by nonspecific Ab (426±14, N=4). Conclusions. These observations indicate that glucose-induced vascular dysfunction is mediated in part by VEGF, thus supporting the hypothesis that "hypoxia-like" reductive stress induced by hyperglycemia increases VEGF production resulting in vascular dysfunction.

Original languageEnglish (US)
Pages (from-to)S969
JournalInvestigative Ophthalmology and Visual Science
Volume37
Issue number3
StatePublished - Feb 15 1996

ASJC Scopus subject areas

  • Ophthalmology
  • Sensory Systems
  • Cellular and Molecular Neuroscience

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