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L. J. Peterson, P. Geisen, Y. Saito, X. Lu, D. Martiniuk, G. Cui, M. E. Hartnett; Neutralizing Antibody to VEGF164 Reduces IVNV and Capillary Density in a Rat Model of Oxygen-Induced Retinopathy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3411.
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To investigate the effects of a neutralizing anti-VEGF antibody and a receptor tyrosine kinase inhibitor of VEGF-receptor 2 (VEGFR2), on intravitreous neovascularization (IVNV), percent avascular area (%AVA), capillary density, and intraretinal cell death in a rat model of oxygen-induced retinopathy (OIR).
We used the 50/10 OIR model that exposes Sprague-Dawley newborn rat pups to repeated cycles of 24 h of 50% oxygen alternating with 24 h of 10% oxygen until postnatal 14 days (p14), followed by exposure to room air until p18. At age p12, the right eyes of pups received 1 µL intravitreous injections of 25ng/ul or 50 ng/ul anti-VEGF neutralizing antibody, 500 ng/ml (3µM) SU5416 (VEGF-R2 inhibitor), or respective controls of nonimmune IgG or DMSO. In vivo doses were determined by assessing the effects of 1-10µM SU5416 on inhibiting receptor phosphorylation in HUVECs. All fellow eyes were noninjected. On p18 or p25, pups were sacrificed, and retinas were flat-mounted and lectin-stained for flat-mount assays (clock hours of IVNV, %AVA, capillary density, apoptosis) or processed to measure VEGF protein by ELISA.
VEGF protein was increased in OIR compared to room air pups at p12, p14 and p18 with the greatest spike at p14 (ANOVA, p=0.001). Injection of 25 µg anti-VEGF neutralizing antibody reduced mean clock hours of IVNV, 4 and 5 fold below IgG-injected and noninjected eyes respectively (ANOVA, p=0.001), and capillary density (ANOVA, p=0.008) at p18. However, there was no significant effect on IVNV, % AVA, or capillary density with several different doses of SU5416, which specifically and significantly inhibited R2 phosphorylation in HUVECs (ANOVA p<0.01).
Neutralizing antibody to VEGF reduced clock hours of IVNV significantly and at a level that if translated to the clinical situation in retinopathy of prematurity (ROP) would be clinically meaningful to reduce blindness. However, the concomitant reduction in capillary density may be an undesirable effect.
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