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Ivan B Lobov, Eunice Cheung, Jingtai Cao, George D. Yancopoulos, Carl Romano, Stanley J Wiegand; Effects of combined inhibition of VEGF and Ang2 using aflibercept (VEGF Trap) and anti-Ang2 antibody on the developing retinal angiogenesis in mice.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2308.
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© ARVO (1962-2015); The Authors (2016-present)
VEGF is the key modulator of angiogenesis in normal and pathological angiogenesis. However, other growth factors are also involved in angiogenesis and are able to mediate blood vessel resistance to anti-VEGF therapies. Angiopoietin-2 (Ang2) was shown to be involved in blood vessel growth and regression in various circumstances in a context-dependent manner. In this study we tested the effects of VEGF blockade using aflibercept alone and in combination with anti-Ang2 antibody on blood vessel growth and regression in a normal retinal vascular development (RVD) model.
C57Bl/6 mouse pups were treated with aflibercept and anti-Ang2 antibody (REGN910) individually or in combination IntraViTreally (IVT) from postnatal day 4 (P4) to P6. Pups were injected with 5µg of a control protein (hFc), 5µg REGN910, or 1.25 µg aflibercept or mixture of aflibercept and REGN910. Pups were euthanized at P6, the eyes were removed and fixed in 4% paraformaldehyde. The retinas were then dissected and stained with FITC labeled GS Lectin I.
Administration of REGN910 or aflibercept reduced outgrowth of the superficial retinal vasculature. Specifically, REGN910 and aflibercept decreased the mean vascularized area of the retina by 17% and 36%, respectively, while combined treatment reduced vascular areas by 72%, representing complete arrest of retinal vascular development over the treatment period. REGN910 and aflibercept also decreased the mean vessel length by 23% and 22%. Combined treatment with REGN910 and aflibercept had a significant synergistic effect, leading to a dramatic 77% decrease in total vessel length. Total blood vessel length was even smaller by 25% in the combination treated samples compared to P4 retinas.
Combined pharmacological inhibition of Ang2 and VEGF-A had a greater effect on developmental retinal angiogenesis than administration of Ang2 or VEGF-A blocker alone, such that inhibition of both Ang2 and VEGF-A resulted in a near completed arrest of retinal vascular development and partial blood vessel regression compared to the initial treatment conditions at P4.
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