Oxygen-Induced Retinopathy in Mice: Amplification by Neonatal IGF-I Deficit and Attenuation by IGF-I Administration

Abstract

ABSTRACT:In preterms, low serum levels of IGF (IGF-I) correlate with retinopathy of prematurity (ROP). In mice, IGF-I is a prerequisite for normal retinal development. We further explored the link between IGF-I and oxygen-induced retinopathy (OIR). To assess the role of endogenous IGF-I, pups were redistributed into smaller versus larger litters at birth; in one subgroup, we measured body weight and circulating IGF-I; in another, we applied hyperoxia and assessed retinal neovascularization (NV). To screen for the potential role of exogenous IGF-I, we administered a single bolus of rhIGF-I on postnatal day (P) 4 to pups in normal litters, and applied hyperoxia; body weight and IGF-I were measured; maturation and NV were assessed. Neonatal mice in larger litters had a lower body weight than mice in smaller litters; they had lower levels of circulating IGF-I, and developed more OIR (p ϭ 0.002). Mice who had received rhIGF-I, weighed more and had higher endogenous IGF-I levels; they matured faster and developed less OIR (p ϭ 0.00001). These findings in mice are the first to support the notion that higher availability of endogenous or exogenous IGF-I reduces OIR risk, and thus sharpen the perspective that ROP may be preventable by briefly up-regulating IGF-I after birth. (Pediatr Res 65: 307-310, 2009) R etinopathy of prematurity (ROP) is a blinding disease initiated by delayed retinal vessel growth and regression of existing vessels after premature birth (1,2). Major risk factors are low gestational age and oxygen; despite more controlled oxygen use, there is no decrease in the overall prevalence of ROP, possibly due to increased survival of very low birth weight infants (2,3).In humans, ROP risk has been linked to low circulating levels of IGF I (IGF-I) (4,5) and slow postnatal weight gain (6,7). In mice, IGF-I is a prerequisite for normal development of retinal vessels (8 -10). These findings have led to the concept that up-regulation of IGF-I shortly after birth may contribute to prevent ROP (11,12). In mice, we further explored the link between circulating IGF-I and oxygeninduced retinopathy (OIR). MATERIALS AND METHODSHyperoxia. The murine OIR model of Smith was applied (13). In brief, 7-d-old C57BL/6J WT mice with their dams were exposed to 75% oxygen for 5 d; on postnatal day (P), 12 the mice were returned to room air. Pups were nursed by their dams; food (standard mouse chow) and water were given ad libitum. Pups were killed on P17 after 5 d of room air recovery, when retinal neovascularization (NV) is known to peak.Endogenous IGF-I. Circulating IGF-I levels were measured in prenatal and neonatal mice from normal litters (median 7 pups per litter) from embryonic day (E) 17.5 till P14.Smaller versus larger litter. As depicted in Figure 1 (panel A), pups from concomitantly born litters were on P1 redistributed among dams, so that there were smaller litters (median, 6 pups; range 4 -9) and larger litters (median, 15 pups; range, 14 -16). On P7-12, the OIR model was applied. Body weight and circulating IGF-I wer...

Mechanisms and Management of Retinopathy of Prematurity

“…56 Administration of IGF-1 in growth-restricted mice reduced oxygeninduced retinopathy. 57 These findings support the possible role of IGF-1 in reducing severe retinopathy of prematurity.…”

Postnatal Weight Gain Modifies Severity and Functional Outcome of Oxygen-Induced Proliferative Retinopathy

“…27 Animal studies have shown that IGF-1 supplementation can reduce retinopathy. 20 The results from our study support the notion that poor postnatal nutrition is associated with low IGF-1 levels and a more prolonged duration of vaso-obliteration and proliferative retinopathy. Thus, good postnatal nutrition (along with additional IGF-1 supplementation in those infants unable to produce sufficient IGF-1) might be beneficial to improve functional retinal vascularization and subsequently reduce the duration of hypoxia-triggered VEGF overexpression and neovascularization in infants at risk of ROP.…”

“…19,20 However, a stringent analysis of the correlation between weight gain and severity of retinopathy in rodents during OIR remained to be performed. We therefore initiated our study by screening a cohort of 15 litters of C57BL/6 wild-type mice undergoing OIR for correlations between postnatal body weight and extent of NV at P17, the standard time point to investigate NV in the OIR mouse model.…”

Influence of Insulin-Like Growth Factor I and Nutrition During Phases of Postnatal Growth in Very Preterm Infants

“…Further IGF-I infusion to fetal sheep results in anabolic effects with increased transplacental amino acid and glucose uptake and decreased fetal protein breakdown (34,35). In a recent study in mice, administration of IGF-I was associated with higher weight gain and higher endogenous IGF-I levels (36). Thus, hypothetically an increase in IGF-concentrations during the early postnatal period when undernutrition is more or less present may be of benefit for a better utilization of nutrients and for neural protection.…”