The Relationship of Retinal VEGF and Retinal IGF-1 mRNA with Neovascularization in an Acidosis-Induced Model of Retinopathy of Prematurity

Abstract

Purpose: Acidosis-induced retinopathy (AIR) in the neonatal rat provides an alternative model for retinopathy of prematurity (ROP). We studied the relationship of vascular endothelial growth factor (VEGF) retinal mRNA and insulin-like growth factor-1 (IGF-1) retinal mRNA expression with the emergence of neovascularization (NV) in AIR. Methods: Two hundred seventy-five newborn Sprague-Dawley rats were raised in 11 expanded litters of 25. Using our established AIR model, acidosis was induced by twice-daily gavage with NH4Cl from day 2 to day 8 of life (n = 175). Rats were sacrificed at days 5, 8, and 10. Nongavaged rats were used as age-matched controls (n = 100). Retinae from left eyes were dissected, flatmounts were ADPase-stained, and the presence and severity of NV was scored in a masked manner. Individual right retinae were processed for analysis of retinal VEGF and IGF-1 mRNA using quantitative real-time reverse-transcriptase PCR (qRT-PCR). Results: Retinal VEGF mRNA was increased 1.4-fold at day 10 in AIR, when compared with age-matched controls (p = 0.03). This correlated with maximal NV at day 10 in AIR. Retinal IGF-1 mRNA was decreased to 82% of its normal expression on day 8 (p = 0.006), prior to maximal NV, before returning to normal expression at day 10, when compared with nonacidotic controls. Conclusions: In AIR, preretinal neovascularization is associated with decreased retinal IGF-1 mRNA prior to maximal NV and increased retinal VEGF mRNA at the time of maximal NV. These growth factor changes in AIR are similar to those seen with hypercarbic oxygen-induced retinopathy. The retinal IGF-1 pathway may provide an alternative target for therapeutic intervention in abnormal retinal angiogenesis.