Maternal diabetes and retinopathy of prematurity : establishment of mouse model, impact on oxygen-induced retinopathy and effect of lutein

Abstract

Retinopathy of prematurity (ROP) is a leading cause of childhood blindness characterized by two phases of pathological retinal vascular changes: retinal avascularization in the first phase followed by abnormal neovascularization in the second phase. Recently, maternal diabetes has been defined as one of the risk factors of ROP but the mechanism was unclear. To investigate the association of maternal diabetes with ROP, heterozygous C57BL/6-Ins2Akita/J (Akita) mice, a model of type I diabetes, was established as a model of maternal diabetes. Subsequently, its neonates were challenged with oxygen-induced retinopathy (OIR), an animal model for human ROP in which neonatal mice were exposed to 75% oxygen from postnatal day (P) 7 to P12. The changes in retinal vasculature, retinal function and neuronal phenotypes were compared among the pups from WT and Akita mothers. Hyperglycemic Akita mothers displayed similar sugar content in breastmilk as C57BL/6J (WT) mothers but higher pregnancy risks with higher number of dead pups and dystocia, which was similar to the condition in human diabetic mothers. Their pups generated from mating with WT male mice were then characterized. WT pups from Akita mothers (AW) showed accelerated development in retinal function with higher amplitudes. However, AW pups had thinner nuclear layers on P12 and P17 and thicker plexiform layers on P21, which may indicate the presence of cell loss and retinal edema. Hence, maternal hyperglycemia may cause retinal damage in neonates. The impact of maternal hyperglycemia in ROP was then investigated using maternal hyperglycemia-associated OIR model. OIR-treated AW pups showed more neovascularization with no difference in avascularization when compared with WT pups from WT mothers (WW) pups. Moreover, OIR-treated AW pups had aggravated retinal damage with severe cell apoptosis on P17, retinal thinning in nuclear layers on P21 and prolonged reactive gliosis on P30. Interestingly, a faster revascularization and retinal function recovery was showed in AW pups after OIR. Hence, maternal hyperglycemia exacerbated retinal damage in retinal structure, glial and cell death responses after OIR. Since maternal diabetes and ROP generated oxidative stress in the offsprings, lutein may promote protective effects in maternal hyperglycemia-associated OIR by its antioxidative and anti-inflammatory characteristics. Lutein-in-DMSO or lutein-in-olive oil (OL) was administered to mouse pups from P12 to P30. After lutein-in-DMSO administration, more endothelial tip cell formation was observed in OIR-treated WW pups. However, mortality was also found in OIR-treated pups. Therefore, OL was investigated in the modified maternal hyperglycemia-associated OIR models with controlled body weight. Olive oil alone (OO) and OL promoted revascularization in AW pups. However, no difference in retinal function, vasculature and structure could be identified. Taken together, maternal hyperglycemia disrupted the normal retinal development and further exacerbated the damage after OIR. Besides, the effect of lutein or OL in maternal hyperglycemia-associated OIR model promoted revascularization. These findings suggest that maternal diabetes may promote retinal damage and increase ROP severity in neonates, but the effect of lutein in maternal diabetes-associated ROP awaits further under investigation.