title: The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction.
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.
authors.affiliation: 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.
authors.forename: Jayne C
authors.initials: JC
authors.lastname: Charnock
authors.affiliation: 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.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Dilworth
authors.affiliation: 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.
authors.forename: John D
authors.initials: JD
authors.lastname: Aplin
authors.affiliation: 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.
authors.forename: Colin P
authors.initials: CP
authors.lastname: Sibley
authors.affiliation: 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.
authors.forename: Melissa
authors.initials: M
authors.lastname: Westwood
authors.affiliation: 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.
authors.forename: Ian P
authors.initials: IP
authors.lastname: Crocker
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D047109:Fetal Development / Q000187:drug effects*; D005317:Fetal Growth Retardation / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000235:genetics / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D011247:Pregnancy; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D011994:Recombinant Proteins; C067045:insulin-like growth factor II, Leu(27)-; D007335:Insulin-Like Growth Factor II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: [Leu27]insulin-like growth factor II; endothelial nitric oxide synthase knockout; fetal growth restriction; insulin-like growth factor