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