The pivotal role of insulin-like growth factors in pregnancy success.

Abstract

Appropriate placental development in early gestation is essential for subsequent placental function and hence optimal fetal growth and pregnancy outcome. Placental insufficiency has been implicated in common disorders of pregnancy, which result in fetal and maternal mortality or morbidity, and also increase the risk of poor health in adult offspring.

Prior to the onset of maternal blood flow to the placenta at ~10 weeks of gestation, placentation occurs in a relatively hypoxic environment, which is essential for healthy pregnancy. IGF-II is abundantly expressed by the invasive trophoblast and may interact with oxygen to regulate placentation. Additionally, maternally-derived IGFs may act on the placenta and the mother to regulate fetal growth. This thesis investigated the role and interaction of oxygen and IGF-II on human placental outgrowth during early pregnancy in vitro. Furthermore, the impact of maternal IGF treatment during early to mid pregnancy, on placental development and substrate transfer, nutrient partitioning between the mother and fetus, and fetal growth, were also determined in mid and late gestation in guinea pigs.

We have demonstrated, using human early first trimester placental villous explants, that IGF-II mediates the effect of hypoxia on placental outgrowth. Culture of placental explants in hypoxia, or with exogenous IGF-II, enhanced trophoblast outgrowth and inhibited TGF-β1 activation, a negative regulator of trophoblast function. In addition, culture of explants in hypoxia induced Igf2 gene expression in outgrowing trophoblast, without altering Upar, Igf1r, Igf2r or Tgfβ1 transcription. We propose that this novel interaction of oxygen, IGF-II and TGF-β1 during pregnancy is an important determinant of placental development. Furthermore, we showed that exogenous IGF-II stimulates villous explant trophoblast outgrowth in placenta from >10 weeks gestation, suggesting that IGF-II may be a potential therapeutic agent to enhance placental growth.

In guinea pigs, maternal treatment with IGF-I or IGF-II, in early to mid pregnancy, has sustained anabolic effects on fetal growth, enhanced fetal survival and increased placental delivery, and fetal and maternal utilization of, glucose and amino acids near term. These effects were also evident by mid gestation following earlier IGF-I treatment. Despite these similar pregnancy outcomes, there were IGF specific effects on the placenta and mother, suggesting that IGFs may mediate some of their effects via different pathways. IGF-I administration severely reduced maternal adiposity in late pregnancy, elicited its effects by substantially improving development of the placental exchange region, which correlated with placental function.

We have suggested that the discrete effects of IGF-I and IGF-II stem from distinct interactions of the IGFs with various receptors. Maternal administration of an analogue of IGF-II that selectively interacts with IGF2R (Leu ²⁷-IGF-II), revealed that many of the effects of IGF-II treatment, were mediated by IGF2R, while IGF-I presumably acts through IGF1R.

Together, this work has highlighted the major and somewhat complementary roles of maternal IGFs during the first half of pregnancy, in regulating placental development, fetal growth and pregnancy success. Importantly, it indicates the potential use of maternal IGFs in diagnostic and therapeutic approaches to pregnancy complications.