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The Impact of a Human IGF-II Analogue ([Leu27]IGF-II) on Fetal Growth in a Mouse Model of Fetal Growth Restriction.

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AJP Endocrinology and Metabolism

Published online on

Abstract

Enhancing placental insulin-like growth factor(IGF) availability appears an attractive strategy for improving outcomes in fetal growth restriction(FGR). Our approach was the use of [Leu27]IGFII, a human IGF-II analogue that binds the IGF-II clearance receptor, IGF2R, in FGR mice. We hypothesised that the impact of [Leu27]IGFII infusion in C57BL/6J(wild-type,WT) and endothelial nitric oxide synthase knockout(eNOS-/-,FGR) mice would be to enhance fetal growth and investigated this from mid to late gestation. 1mg/kg/day [Leu27]IGFII was delivered via a subcutaneous mini-osmotic pump from E12.5-E18.5. Fetal and placental weights, recorded at E18.5, were used to generate frequency distribution curves; fetuses <5th centile were deemed growth-restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu27]IGFII treatment halved the number of FGR fetuses, reduced fetal(p=0.028) and placental weight variations(p=0.0032), and increased numbers of pups close to the mean fetal weight(131vs112 pups within 1 SD). Mixed-models analysis confirmed litter size to be negatively correlated with fetal and placental weight, and showed that Leu27[IGFII] preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional 14CMeAIB transfer per g placenta(System A amino acid transporter activity) was inversely correlated with fetal weight in Leu27IGFII-treated WT animals(p<0.01). In eNOS-/- mice, [Leu27]IGFII reduced the number of FGR fetuses(1vs5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS-/- litters suggests the use of this analogue as a means of standardising and rescuing fetal growth, preferentially in the smallest offspring.