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G. Byfield, M. E. Hartnett; Signaling Through gp130 and the JAK/STAT Pathway Play a Role in Intravitreous Neovascularization and VEGF Expression in the OIR Rat Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):532.
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© ARVO (1962-2015); The Authors (2016-present)
To assess pathways downstream of gp130 as a mechanism for VEGF expression and intravitreous neovascularization (IVNV) in a rat model of Retinopathy of Prematurity (ROP).
Upon four hours of birth, Sprague-Dawley rat pups and their mothers were exposed to 24 hours of 50% oxygen alternating with 24 hr of 10% oxygen until postnatal day (p) 14, at which time they were placed into room air (OIR Model). Starting at p3, pups were given daily intraperitoneal injections of either 5mg/kg AG490 (JAK2 inhibitor) or vehicle only control. Pups from similar litters were also given one time intravitreous injections in the right eye only of either leukemia inhibitory factor (LIF) in PBS (5ng/uL), Interleukin-6 in PBS (5ng/uL), 50ng VEGF antibody or appropriate vehicle only controls (PBS or IgG). Fellow eyes were used as non-injected controls. All animals were sacrificed at p14 or p18. Neurosensory retinas were dissected, made into flat-mounts, stained with TRITC conjugated Griffonia simplicifolia lectin, and imaged using a confocal microscope. Total retinal area, peripheral avascular area, and intravitreous neovascular areas were measured. Total protein from fresh retinal tissue was analyzed for VEGF by ELISA assay and gp130 phosphorylation by western blot.
At p14, the JAK2 inhibitor AG490 reduced IVNV but not avascular area. There was no effect on IVNV or VPAR at p18 and no significant difference in VEGF protein levels at p14 or p18. Animals that received LIF had significantly higher levels of VEGF protein compared to those treated with IL-6, despite no significance differences in avascular to total retinal area. At p18, 50ng VEGFab given at p12 reduced gp130 phosphorylation compared to control IgG.
Inhibiting JAK2 with AG490 in earlier stages of retinal development reduces IVNV without interfering with retinal vascularization. At p14, LIF and IL-6 which both signal through gp130 had opposing effects on VEGF protein levels in the OIR model. An understanding of the JAK/STAT pathway and signaling through gp130 as one of the mechanisms for VEGF expression and IVNV are key components in unraveling the complexity of ROP.
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