The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction.

Jayne Charnock, MR Dilworth, JD Aplin, CP Sibley, M Westwood, IP Crocker

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Abstract

Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu 27]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu 27]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS -/-; FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mg·kg -1·day -1 [Leu 27]IGF-II was delivered via a subcutaneous miniosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curv es;fetuses <5th centile were deemed growth restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum was collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu 27]IGF-II treatment halved the number of FGR fetuses, reduced fetal(P = 0.028) and placental weight variations (P = 0.0032), and increased the numbers of pups close to the mean fetal weight (131 vs. 112 pups within 1 SD). Mixed-model analysis confirmed litter size to be negatively correlated with fetal and placental weight and showed that [Leu 27]IGF-II preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional 14CMeAIB transfer per gram placenta (System A amino acid transporter activity) was inversely correlated with fetal weight in [Leu 27]IGF-II-treated WT animals (P < 0.01). In eNOS -/- mice, [Leu 27]IGF-II reduced the number of FGR fetuses(1 vs. 5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS -/- litters suggests the use of this analog as a means of standardizing and rescuing fetal growth, preferentially in the smallest offspring.

Original languageEnglish
Pages (from-to)E24-E31
JournalAJP - Endocrinology and Metabolism
Volume310
Issue number1
Early online date9 Dec 2015
DOIs
Publication statusPublished - 1 Jan 2016

Keywords

  • Endothelial nitric oxide synthase knockout
  • Fetal growth restriction
  • Insulin-like growth factor
  • [Leu ]insulin-like growth factor II

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