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 [Leu27]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 [Leu27]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 [Leu27]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, [Leu27]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 [Leu27]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 [Leu27]IGF-II-treated WT animals (P < 0.01). In eNOS−/− mice, [Leu27]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.
Highlights
FETAL GROWTH RESTRICTION (FGR) affects 3–10% of babies worldwide and is associated with increased risk of stillbirth, postnatal disability, and impaired motor and cognitive functions
IGF-IIR displayed a similar localization to IGF-IR, including glycogen cells, trophoblast, labyrinthine trophoblast, and endothelium (Fig. 1, C and F). [Leu27]IGF-II treatment reduces fetal and placental weight variations in WT mice
The importance of IGF-II signaling in mouse fetal growth is well described, with both total and placental specific IGF-II knockout transgenic animals associated with impaired fetal and placental development [9, 10]
Summary
FETAL GROWTH RESTRICTION (FGR) affects 3–10% of babies worldwide and is associated with increased risk of stillbirth, postnatal disability, and impaired motor and cognitive functions. Evidence for signaling through this receptor is accumulating [14, 15], but classically IGF-IIR has been considered a clearance receptor, trafficking excess IGF-II to lysosomes for degradation. This concept is exemplified in IGF-IIR knockout mice, which exhibit fetal and placental overgrowth [45], as a presumed consequence of surplus IGF-II overactivating fetal IGF-IR. Recent work on gene knockout and transgenic mouse models of pregnancy disease suggests that these may be useful [12]
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