VEGF-initiated blood-retinal barrier breakdown in early diabetes

PURPOSE. The objectives of this study were to (1) determine whether endogen ous vascular endothelial growth factor (VEGF) triggers diabetic blood-retin al barrier breakdown, and (2) identify the site as well as phenotype of the hyperpermeable diabetic retinal vessels. METHODS. Retinal VEGF mRNA levels were quantified in I-week diabetic rats u sing the RNase protection assay. VEGF bioactivity was blocked via the syste mic administration of a highly specific VEGF-neutralizing soluble Flt/F-c c onstruct (VEGF TrapA.(10)). An inactive IL6 receptor/F-c construct (IL6R Tr ap) was used as an isotype control. Blood-retinal barrier breakdown was qua ntified using the Evans blue technique and was spatially localized with flu orescent microspheres. RESULTS. Retinal VEGF mRNA levels in 1-week diabetic animals were 3.2-fold higher than in nondiabetic controls (P < 0.0001). Similarly, retinal vascul ar permeability in 8-day diabetic animals was 1.8-fold higher than in norma l nondiabetic controls (P < 0.05). Diabetes-induced blood-retinal barrier b reakdown was dose-dependently inhibited with VEGF TrapA(40), with 25 mg/kg producing complete inhibition of the diabetes-induced increases (P < 0.05). Blood-retinal barrier breakdown in diabetic animals treated with solvent a lone or IL6R Trap did not differ significantly from untreated diabetic anim als (P <greater than> 0.05). Spatially, early blood-retinal barrier break-d own was localized to the retinal venules and capillaries of the superficial retinal vasculature. CONCLUSIONS. Early blood-retinal barrier breakdown in experimental diabetes is VEGF dependent and is restricted, in part, to the venules and capillari es of the superficial inner retinal vasculature. VEGF inhibition should pro ve a useful therapeutic approach in the treatment of early diabetic blood-r etinal barrier breakdown.