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1From the Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts; the 2Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan; the 4Department of Ophthalmology, Faculty of Medicine, University of Tokyo, Tokyo, Japan; the 5Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan; 6Eyetech Research Center, Woburn, Massachusetts; and the 7Kyorin Eye Center, Mitaka, Japan.
PURPOSE. The objectives of this study were to characterize the differential potency of two major VEGF isoforms, VEGF120 and VEGF164, for inducing leukocyte stasis (leukostasis) within the retinal vasculature and blood–retinal barrier (BRB) breakdown and to determine whether endogenous VEGF164 mediates retinal leukostasis and BRB breakdown in early and established diabetes.
METHODS. Retinal leukostasis and BRB breakdown were simultaneously quantified by combining concanavalin A lectin (ConA) perfusion labeling with a fluorophotometric dextran leakage assay. CD45 immunohistochemistry was performed to confirm that ConA-stained cells within the vasculature were leukocytes. Retinal leukostasis and BRB breakdown were compared in nondiabetic rats receiving intravitreous injections of VEGF120 or VEGF164. Retinal intercellular adhesion molecule (ICAM)-1 and VEGF protein levels were studied by Western blot and ELISA, respectively. An anti-VEGF164(165) aptamer (EYE001) was administered by intravitreous injection to 2-week and 3-month diabetic rats, and the effect on retinal leukostasis and BRB breakdown was quantified.
RESULTS. Compared with VEGF120, VEGF164 more potently increased retinal ICAM-1 levels (2.2-fold), leukostasis (1.9-fold), and BRB breakdown (2.1-fold, P < 0.01 for all), despite negligible differences in vitreoretinal VEGF levels at the time of evaluation (P > 0.05). Retinal leukostasis and leakage increased with the duration of diabetes (P < 0.01) and correlated closely (P < 0.01, r = 0.889). The isoform-specific blockade of endogenous VEGF164 with EYE001 resulted in a significant suppression of retinal leukostasis and BRB breakdown in both early (72.4% and 82.6%, respectively) and established (48.5% and 55.0%, respectively) diabetes (P < 0.01).
CONCLUSIONS. On an equimolar basis, VEGF164 is at least twice as potent as VEGF120 at inducing ICAM-1–mediated retinal leukostasis and BRB breakdown in vivo. The inhibition of diabetic retinal leukostasis and BRB breakdown with EYE001 in early and established diabetes indicates that VEGF164 is an important isoform in the pathogenesis of early diabetic retinopathy.
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