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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 (g plasma/g wet wt/min, mean SD) by sequential injection of125I- and131I-albumin (circulation times 10 and 2 min, respectively;131I -albumin served to correct for intravascular content of125I-albumin). Results. Infusion of 0.65 pmol VEGF/kg bwt/min for 20 min increased retinal125I-albumin permeation 2 fold from 8211 in controls to 16828 (p = 0.0013, N=4 each). Topical VEGF applied at concentrations of 2 to 4 pM increased125I -albumin permeation in chamber vessels to the same extent as 30 mM glucose (41257 (N=4) and 42042 (N=5), respectively vs. 15236 (N=5) for the vehicle, p < 0.0001 for both). The 30 mM glucose-induced increase in125I-albumin permeation was markedly attenuated by 100 g VEGF Ab/ml buffer (23432 (N=7), p < 0.0001), but not by nonspecific Ab (42614, 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.
Investigative Ophthalmology and Visual Science
author list (cited authors)
Williamson, J. R., Chang, K. C., LeJeune, W., Stephan, C. C., Brock, T. A., & Tilton, R. G.