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Haibo Wang, Grace Byfield, Mary Elizabeth Hartnett; Vegf Mediated Stat3 Activation Contributes To Retinal Avascularity In Rat Model Of Rop. Invest. Ophthalmol. Vis. Sci. 2011;52(14):3126.
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To investigate 1) whether upregulated vascular endothelial growth factor (VEGF) following repeated fluctuations in oxygen in the 50/10 oxygen-induced retinopathy (50/10 OIR) rat model contributes to avascular retina through activation of signal transducer and activator of transcription (STAT3), and 2) the molecular mechanisms involved.
Newborn rat pups were exposed to repeated fluctuations in oxygen between 50% and 10% inspired oxygen every 24 hours for 14 days. Pups were given the STAT3 inhibitor, AG490 (10mg/kg/d), or equal volume of PBS as control by daily intraperitoneal injections from postnatal day (P)3 to P13 or a neutralizing antibody to VEGF or non-immune IgG as control as an intravitreous injection on P12. Avascular area (AVA), expressed as a percentage of the avascular/total retinal areas, was measured in isolectin-stained retinal flat mounts. Phosphorylated STAT3, caspase 3, and erythropoietin (EPO) were measured by western blots and the amount of retinal VEGF protein was quantified by ELISA.
Repeated fluctuations in oxygen in the 50/10 OIR model resulted in increased AVA (p<0.05) with upregulation of VEGF expression (p<0.01) and activation of STAT3 (p<0.01) compared to room air raised pups. In the 50/10 OIR model, inhibition of STAT3 with AG490 decreased retinal AVA (p<0.05) compared to PBS control and led to an increase in EPO expression without affecting the amount of cleaved caspase-3 or VEGF measured in whole retinas. Neutralizing VEGF activity significantly reduced phosphorylated STAT3 (p<0.001) and increased EPO protein expression (p<0.05) compared to control IgG.
The activation of STAT3 is associated with AVA at p14 in the 50/10 OIR model. In this signaling cascade, repeated oxygen fluctuations lead to increased VEGF, which induces downstream STAT3 phosphorylation that mediates retinal EPO expression. Further studies are needed to explore the molecular mechanisms by which STAT3 regulates EPO gene expression.
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