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Ivan B. Lobov, Eunice Cheung, George Yancopoulos, Stanley J. Wiegand; Systemic Administration of VEGF Trap Prevents Pervasive Blood Vessel Regression in the Murine Model of Oxygen-Induced Retinopathy (OIR). Invest. Ophthalmol. Vis. Sci. 2012;53(14):2539.
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VEGF plays a critical role in both normal and pathological angiogenesis, but much less is known about its roles in vascular remodeling. In the retina, VEGF inhibition prevents pathological neovascularization and leads to regression of existing neovasculature. In the OIR model, it has been believed that the characteristic obliteration of capillaries in the central retina is caused by a decreased expression of VEGF. However, we have recently observed that administration of VEGF Trap (a potent VEGF-A and PlGF blocker) does not cause pervasive vasoobliteration, but rather induces a moderate, diffuse pruning of immature capillaries [Lobov et al, Blood 2011]. Here we tested the effect of VEGF Trap on oxygen-induced vasoobliteration.
Mouse pups received intraperitoneal injections of VEGF Trap (25 mg/kg) or a control hFc protein on postnatal day 8 (P8), 24 hours prior to exposure to 75% O2 on P9. Retinas were stained with FITC-labeled GS Lectin I (Vector Labs) to visualize the vasculature. Concanavalin A (Vector Labs) labeled with rhodamine was infused intracardially to assess blood vessel patency. To study the progression of blood vessel regression, retinas were collected 6, 16, 18, and 24 hours after the beginning of oxygen exposure and stained using an antibody against cleaved Caspase3 (Cell Signaling). Changes in retinal gene expression were evaluated by microarray.
Six hours after the beginning of high oxygen exposure, capillaries of control animals became occluded and at 16 hours showed a characteristic pattern of synchronous apoptosis. Administration of VEGF Trap prior to exposure to hyperoxia significantly reduced blood vessel loss. This was associated with maintenance of blood flow crucial for survival of newly-formed microvessels. VEGF Trap treatment significantly down-regulated the expression of Dll4. We recently showed that inhibition of Dll4/Notch signaling similarly improves blood flow and retinal blood vessel survival after high-oxygen exposure [Lobov, Blood 2011]. Moreover, administration of VEGF Trap upregulated the expression of adrenomedullin, a potent vasodilator critical for maintaining capillary perfusion.
It has been shown that pharmacological inhibition of VEGF ameliorates pathological neovascularization in diverse models of disease. Paradoxically, in this preclinical study, systemic administration of VEGF Trap reduced the loss of normal immature retinal capillaries in mice exposed to hyperoxia. This seemingly paradoxical response appears to be mediated, at least in part, by changes in the expression of genes involved in the oxygen-mediated regulation of retinal blood flow, such as Dll4 and adrenomedullin.
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