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

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.