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1 From the Department of Surgical Research, Children’s Hospital, Harvard Medical School, Boston, Massachusetts; 2 Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston; 4 Department of Ophthalmology, Affiliated Hospital of Jining Medical College, Jining, Shandong, P.R. China; 5 Department of Vitreoretinal Surgery, Center for Ophthalmology, University of Cologne, Germany; 6 Pennsylvania State College of Medicine, Hershey, Pennsylvania; 7 Centre de recherche Guy-Bernier, Hopital Maisonneuve-Resemont, Montreal, Canada; 8 Department of Ophthalmology, Universite de Montreal, Canada; and 9 Regeneron Pharmaceuticals, Tarrytown, New York.
PURPOSE. The objectives of this study were to (1) determine whether endogenous vascular endothelial growth factor (VEGF) triggers diabetic blood–retinal 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 1-week diabetic rats using the RNase protection assay. VEGF bioactivity was blocked via the systemic administration of a highly specific VEGF-neutralizing soluble Flt/Fc construct (VEGF TrapA40). An inactive IL6 receptor/Fc construct (IL6R Trap) was used as an isotype control. Blood–retinal barrier breakdown was quantified using the Evans blue technique and was spatially localized with fluorescent 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 vascular permeability in 8-day diabetic animals was 1.8-fold higher than in normal nondiabetic controls (P < 0.05). Diabetes-induced blood–retinal barrier breakdown was dose-dependently inhibited with VEGF TrapA40, 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 alone or IL6R Trap did not differ significantly from untreated diabetic animals (P > 0.05). Spatially, early blood–retinal barrier breakdown 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 capillaries of the superficial inner retinal vasculature. VEGF inhibition should prove a useful therapeutic approach in the treatment of early diabetic blood–retinal barrier breakdown.
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