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Eunice Cheung, Ivan Lobov, George Yancopoulos, Stanley Wiegand; Pathological retinal neovascularization is exacerbated by selective pharmacological blockade of VEGFR2, but ameliorated by combination with Placental Growth Factor (PlGF) inhibition in the Oxygen induced Retinopathy (OIR) model in mice. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4654.
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Vascular endothelial growth factor A (VEGF-A) signaling through VEGF receptor 1 (VEGFR1) and VEGFR2 regulates both physiological and pathological angiogenesis [Luttun et al., Nature Med. 2002, 8:831-840]. We have reported that genetic deletion or inhibition of the VEGFR1 ligand, PlGF, reduced vasoobliteration and neovascularization in OIR [IOVS 2009; 50:E-Abstract 2943; IOVS 2010; 51:E-Abstract 4486]. We also demonstrated that inhibition of either PlGF or VEGFR1 could improve normal blood vessel regrowth and also lessen neovascularizations [IOVS 2011; 52:E-Abstract 6064]. In this study, we administered DC101, a VEGFR2 blocking antibody, alone or in combination with a PlGF blocking antibody after vessel loss was complete, to evaluate the effects of selective blockade of activity of VEGFR2 alone, or in combination with inhibition of the VEGFR1 ligand, PlGF, in the murine model of OIR.
Mice were place in a hyperoxic environment (75% O2) at postnatal day 6 (P6) and returned to room air at P11. Pups were injected systemically with 25mg/kg DC101 or a control protein (Fc) at P12. Left eyes of DC101 treated pups were injected intravitreally (IVT) with 5ug of a polyclonal Goat anti-Mouse PlGF-2 or a control IgG (Normal Goat IgG) at P13. Retinal flatmounts were collected at P16 and endothelial cells stained with FITC-labeled Griffornia simplicifolia lectin I and anti-NG2, a pericyte marker.
At P16, pathological neovascularizations worsened in mice treated with DC101 relative to controls. In contrast, IVT administration of PlGF antibody in mice treated with DC101 produced significant improvement of pathological neovascularization relative to animals treated with DC101 and control IgG. No appreciable differences were noted among groups in the extent of the residual avascular area on P16.
This study demonstrates that selective pharmacological neutralization of VEGFR2 is ineffective in ameliorating pathological neovascularization in OIR, while co-incident neutralization of the VEGFR1 ligand, PlGF results in significant amelioration of pathological neovascularization.Thus, this study further supports the hypothesis that inhibition of VEGFR1 ligand, such as PlGF, can play an important role in the inhibition of pathological angiogenesis.
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