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Am J Physiol Endocrinol Metab. 2016 Jan 1;310(1):E24-31. doi: 10.1152/ajpendo.00379.2015. Epub 2015 Nov 3.

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

Author information

1
Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester, United Kingdom; and Maternal and Fetal Health Research Centre, St. Mary's Hospital, Central Manchester Universities National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom.
2
Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester, United Kingdom; and Maternal and Fetal Health Research Centre, St. Mary's Hospital, Central Manchester Universities National Health Service Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, United Kingdom Ian.Crocker@manchester.ac.uk.

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 curves; 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 (14C)MeAIB 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.

KEYWORDS:

[Leu27]insulin-like growth factor II; endothelial nitric oxide synthase knockout; fetal growth restriction; insulin-like growth factor

PMID:
26530156
PMCID:
PMC4675800
DOI:
10.1152/ajpendo.00379.2015
[Indexed for MEDLINE]
Free PMC Article

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