Placenta
Volume 29, Supplement , Pages 42-47, March 2008

Distinct Actions of Insulin-Like Growth Factors (IGFs) on Placental Development and Fetal Growth: Lessons from Mice and Guinea Pigs

Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, S.A. 5005, Australia

Accepted 3 December 2007. published online 15 January 2008.

Article Outline

Abstract 

Placental insufficiency is thought to be a key factor in many cases of intrauterine growth restriction which complicates about 6% of pregnancies in western countries. Understanding the molecular control of placental and fetal growth is essential to identifying diagnostic and therapeutic targets to improve pregnancy success. Insulin-like growth factor (IGF)-I and IGF-II gene ablation or maternal food restriction reduce tissue and circulating IGF abundance in the fetus, placenta and mother and are associated with both placental and fetal growth restriction. Conversely, in vivo treatment of the pregnant guinea pig with IGF-I or IGF-II from early to mid pregnancy increases fetal weight and enhances placental transport near term. IGF-II, and an IGF2R specific analogue, enhanced placental structural differentiation, whereas IGF-I altered maternal body composition. These outcomes demonstrate endocrine roles within the mother for both IGFs, as well as autocrine/paracrine effects of IGF-II in enhancing placentation and pregnancy success. Therefore, factors that alter placental expression of IGF-II, or maternal circulating IGF-I or IGF-II in early pregnancy may affect placental exchange function late in gestation when the demands of the fetus escalate. IGF-II within the fetus may also signal its nutrient demands to the placenta to improve its function to suit. Therefore each IGF of endocrine and local origin has important, but distinct, roles in placental development and function.

Keywords: IGF-I, IGF-II, IGF2R, Trophoblast invasion, Placental transport, Fetal growth

 

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1. Introduction 

Major complications of pregnancy occur in 19% of first pregnancies in Australia and other affluent nations [1]. They include pre-eclampsia (5–8%), pre-term birth (8%), and placental insufficiency with intrauterine growth restriction (IUGR, 6.4%). These complications are life-threatening to either the mother or her baby in more than 6% of pregnancies [1], [2].

The essential roles of the placenta in successful pregnancy place it as a major player in pregnancy complications. The human placenta has essentially two phases of development. The first is placental extravillous cytotrophoblast invasion of the decidua and its vasculature to sequester an adequate blood supply for placental and hence fetal growth. This occurs predominantly in the first half of gestation and permits sufficient blood flow into the placenta as well as its subsequent circumferential expansion. The second is terminal differentiation of villous trophoblast and the accompanying fetal placental vasculature to provide a maximal surface area for exchange between the maternal and fetal circulations [3].

Impaired trophoblast invasion has been implicated in several complications of pregnancy, such as unexplained miscarriage [4], pre-eclampsia and IUGR [5]. In pre-eclampsia and some miscarriages, for example, trophoblast invasion and colonisation of the spiral arterioles and the maternal decidual stroma is shallow, resulting in poor maternal blood flow to the placenta [4], [5]. In addition, impaired placental function is implicated in a significant proportion of IUGR cases [5], [6]. Furthermore, pregnancy complications, and IUGR in particular, have been associated with an increased risk for adult onset diseases including cardiovascular disease, hypertension and type 2 diabetes [7]. Therefore, determination of the molecular interactions regulating trophoblast invasion and placental function is essential to understanding the defects inherent in pregnancy complications and for the identification of potential targets for diagnostics and therapeutics.

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2. Insulin-like growth factors and placental and fetal growth 

Insulin-like growth factors (IGFs), both IGF-I and IGF-II, have been implicated in regulating fetal growth. Both in vivo and in vitro studies have revealed endocrine and autocrine/paracrine actions of IGFs in regulating placental function and fetal growth. Studies of mice carrying null mutations of the IGF-I or IGF-II genes have shown that expression of these growth factors is essential for normal fetal growth, since both IGF null mice are born at about 60% of the weight of wild type [8], [9]. IGF-I receptor gene ablation reduces fetal growth such that neonates weigh about 45% of wild type suggesting that both ligands signal through IGF1R to promote growth in the fetus [9]. IGF-II appears especially involved in the establishment of placental function because placental weight is normal in mice that are deficient in IGF-I [9], whereas it is reduced by 25% in IGF-II deficient mice [8].

Differences in IGF actions are likely to be due to their differential interactions with their receptors. IGF-II binds to the type 2 IGF (IGF2R), type 1 IGF (IGF1R) and insulin receptors (IR) with reducing affinity. IGF-I binds IGF1R with high affinity, but has negligible or low affinity for IGF2R and insulin receptors, respectively [10]. Although it is well known that IGF actions are primarily mediated by IGF1R [11], emerging evidence suggests control of fetal and placental growth by IGFs is more complex. This review will focus on IGF–IGFR interactions and fetal and placental growth and development. Attenuation and potentiation of IGF actions by IGF binding proteins have been well described elsewhere [11], [12] but are beyond the scope of this review.

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3. IGF-II and trophoblast invasion 

In women, evidence from in vitro studies and the localisation of IGF-II to extravillous cytotrophoblasts in tissue obtained in vivo [12], indicate that IGF-II induces invasion of the maternal decidua by these cells via a mechanism that is not well understood, but is thought to be independent of IGF1R [13]. The use of IGF-II analogues with specific receptor binding has shown that IGF-II-induced invasion by a trophoblast cell line is mediated through the IGF2R [14]. In mice, placentae from IGF-II nullizygotes exhibit reduced numbers of glycogen cells, a highly invasive trophoblast cell type analogous to human extravillous cytotrophoblasts, and reduced invasive activity in the junctional zone [15]. In vitro, IGF-II also stimulates differentiation of ectoplacental cone cells (EPCs, early post-implantation murine trophoblast stem cells) into the highly invasive trophoblast giant cells (TGCs), whereas IGF-I stimulates EPC migration [16]. IGF-II has been localised to the conceptus and decidua from days 5.5 to 10.5 in the mouse, suggesting it plays a role in embryo differentiation, trophoblast invasion and angiogenesis in the decidua [17]. After mid-gestation, IGF-II is most abundant in the spongiotrophoblast and glycogen cells with lower expression in the labyrinth [18]. IGF-II is likely to promote TGC and glycogen cell invasion in the mouse upon binding IGF2R since both proliferin [19] and hCG [20] exert a similar effect via this receptor.

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4. Endocrine actions of IGFS on the placenta 

Currently it is suggested that IGF-II acts in an autocrine/paracrine fashion in the placenta. Although this is undoubtedly the case in both the fetus and placenta, it has become apparent that endocrine IGF-II in the mother can significantly impact the placenta. IGF-I expression in the placenta is absent or negligible, while IGF-II transcripts are abundant in most species examined, but particularly in those with an invasive placenta [11]. Therefore, IGF-I is likely to exert its effects in autocrine/paracrine and endocrine fashions in the mother to promote her adaptation to pregnancy and in the fetus to promote growth, while in the placenta IGF-I-induced uptake of glucose and amino acids is likely to be a consequence of maternal endocrine actions.

Our previous studies of feed restriction during pregnancy in the guinea pig, which induces IUGR, showed significant negative effects of undernutrition on maternal circulating IGF-I and -II and concomitant increases in circulating IGFBPs in both mid and late pregnancy [21]. These were associated with impaired fetal and placental growth in mid and late gestation [21]. Striking effects on placental differentiation indicated more profound impacts on placental function than those imposed by merely reduced placental size [22]. Structural correlates of placental function were associated with circulating IGF-II and its ratio with IGFBP-2 in mid gestation [23] and with IGF-I and IGF-I:IGFBP-1 in late gestation [24], suggesting endocrine actions for both IGFs. Furthermore, placental IGF-II mRNA expression in a similar cohort at day 40 was reduced by maternal food restriction [25], so some of the observed effects on placental and fetal growth may be due in part to local effects within the placenta. Placental IGF-I mRNA was not detected at day 40 in agreement with in situ hybridisation studies [11]. These observations suggest specific roles for each IGF and for those of endocrine origin, particularly in the mother, modulation of placental development.

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5. Increasing IGF endocrine effects by IGF administration to the pregnant mother 

We therefore proposed that increasing the abundance of IGFs in the pregnant guinea pig in early to mid gestation would promote fetal growth by specific actions in the placenta, since IGFs do not cross the placenta to the fetus. We selected guinea pigs for this investigation because their haemomonochorial placenta, although labyrinthine, is highly invasive and has similar growth dynamics to that of women [26], [27], [28]. In addition, guinea pigs deliver precocial neonates [26] and their IGF axis is similar to that of humans [29], [30]. A comparison of pregnancy stages in women, guinea pigs and mice is shown in Fig. 1. Furthermore the figure indicates the timing of maternal exposure to exogenous IGFs which is described below.

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  • Fig. 1 

    Timeline of gestation in human, mouse and guinea pig with particular reference to timing of common stages of the placenta. The timing of IGF infusion and post mortem in the guinea pig experiments described in the text is also shown.

Exogenous IGF-I or IGF-II administered to the mother with mini osmotic pump infusion from days 20–37 (term ∼70days) increased maternal plasma IGFs by 340% and 240% respectively at day 35 without altering total IGFBP levels and hence elevated free IGFs [31]. IGF infusion increased fetal and placental weights at day 40 compared to vehicle [32] These effects were already evident for IGF-I, but not IGF-II, at day 35 just before the end of treatment [33]. IGF-I infusion also reduced placental IGF-II mRNA levels at day 35 [33].

Near term (day 62) earlier administration of either IGF to the mother increased fetal weight without altering placental weight. Exogenous IGF-II, but not IGF-I, increased the volume of the placental exchange region (placental labyrinth) [31]. Of particular interest was the observation that IGF-II, but not IGF-I, treatment of the guinea pig in early to mid pregnancy improved the differentiation of the placental labyrinth in a manner predicted to improve placental exchange function at day 62 of gestation, just before term [31]. Interestingly, these effects on the placenta were present well after cessation of IGF-II administration to the mother in early to mid pregnancy.

Although IGF-I or IGF-II administration to the mother did not alter her weight gain during pregnancy, IGF-I at least altered maternal body composition at day 62, by reducing adiposity by about 30% [31]. Only subtle effects of IGF-I on maternal adiposity were present at day 40, just following IGF-I treatment [32], suggesting that elevated maternal endocrine IGF-I in early to mid pregnancy alters maternal nutrient partitioning and adaptation to pregnancy in a sustained fashion reflected in reduced maternal adiposity in late pregnancy. This is consistent with observed increases in circulating IGF-I in pregnancy in several species [21] and may contribute to pregnancy success.

Increased maternal exposure to IGF-I or IGF-II in early to mid-pregnancy in the guinea pig also enhanced placental uptake and transfer of non-metabolisable radiolabelled analogues of glucose (MG) and amino acids (AIB) to the fetus in late gestation, with IGF-I having particularly potent effects [34]. Earlier in pregnancy just prior to the end of treatment (day 35), when only IGF-I had enhanced fetal and placental growth, IGF-I also increased placental MG and AIB uptake and content and their transfer to the fetus [34]. Although at day 35 placental mRNA expression of Slc2a1, the gene that encodes glucose transporter (GLUT)-1, was not affected by IGF-I infusion, placental Slc38a2 mRNA, that encodes a System A amino acid transporter (SNAT2), was increased nearly 8-fold by maternal IGF-I treatment [34]. So, despite the fact that exogenous IGF-I did not alter placental weight at day 62 nor its structural differentiation, it nevertheless altered placental transporter expression and function to effect the sustained increase in fetal growth. Interestingly, in the mother, exposure in early to mid pregnancy to either IGF increased AIB uptake by her visceral organs, while IGF-I also enhanced uptake of AIB by muscle and MG uptake by visceral organs and muscle in late gestation indicating endocrine roles on maternal tissues [34].

The identity of the receptors that mediate the common and disparate actions of the IGFs on the placenta, fetus and mother are also becoming clearer. The IGF-II analogue, Leu27-IGF-II, binds only the IGF2R and not to the IGF1R nor the IR. Treatment of the pregnant guinea pig with Leu27-IGF-II in early to mid pregnancy largely replicated and potentiated the consequences of IGF-II consistent with IGF-II actions occurring substantially via the IGF2R and its increased potency reflecting the lack of competition for the analogue by other receptors (Sferruzzi-Perri AN, Standen P, Owens JA, Roberts CT, submitted). If IGF-II promotes trophoblast invasion via the IGF2R in guinea pig, as it does in a human cytotrophoblast cell line [14], then it is possible that some of its observed effects on placental differentiation are facilitated by enhanced endovascular trophoblast invasion and vessel remodelling, a possibility we are currently examining.

The timing of maternal exposure to elevated IGFs may determine whether placental function is improved, since exogenous IGF-I infusion in late pregnancy in the rat had anabolic effects on the mother but did not improve fetal growth [35]. However, when maternal IGF-I treatment occurs throughout pregnancy in rats and mice, fetal growth is enhanced in late gestation [36]. Although IGF-I would not be expected to enhance trophoblast invasion in early pregnancy, we speculate that elevated endocrine IGF-I in early pregnancy may facilitate the maternal adaptation to pregnancy to indirectly enhance placental function and fetal growth in late gestation.

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6. The role of fetal IGFs 

Within the fetus, IGF-I, modulated by its binding proteins, is thought to drive fetal growth. Thus cord blood IGF-I, but not IGF-II, concentration, particularly in association with IGFBP-1 and -2, is positively correlated with birth weight in human infants [37]. Cord blood soluble IGF2R concentration also increases as birth weight decreases in human infants. While the molar ratio of IGF-II to soluble IGF2R in cord blood is positively correlated with birth weight, IGF-II alone is not related to birth weight [37]. Both IGFs and their specific receptors, as well as the IR, are ubiquitously expressed in fetal tissues and the ligands are likely to promote growth in an autocrine/paracrine fashion. IGF-II is known to promote cell proliferation by binding IR [38] and this interaction promotes fetal growth [39]. In fetal tissues the predominant IR isoform is IR-A, which lacks the alternatively spliced exon 11, and thereby has similar affinity for insulin and IGF-II [40]. (IR-B is expressed more abundantly in postnatal tissues, has greater affinity for insulin and mediates its metabolic effects [40].) IR is most abundantly expressed on human first trimester syncytiotrophoblasts and as gestation proceeds it is increasingly expressed on fetal capillaries and to a lesser extent in trophoblast [41]. However, to our knowledge the identity of the IR isoform in placenta is not known.

In the fetus, IGF2R is also abundantly expressed. It is commonly thought that its primary role is to permit uptake and degradation of IGF-II through the lysosomal pathway and thereby inhibit growth [42]. In support of this view, IGF2R gene ablation results in elevated circulating IGF-II and both placental and fetal overgrowth [42] and simultaneous ablation of the igf2 gene rescues these fetuses [43]. However, IGF2R null mutation results in late gestation or perinatal death with organomegaly and severe heart defects, polydactyly and kinky tail, suggesting it is also likely to be involved in differentiation during development. This role is yet to be fully explored.

Evidence that fetal circulating IGF-II may also be an important signalling molecule between the fetus and placenta comes from studies in which placenta specific ablation of igf2 transcripts from the P0 promoter in mice has been undertaken. These show placental growth restriction with transient compensatory up-regulation of placental System A amino acid transporters apparent before fetal growth restriction was manifest [44], [45]. There is also evidence that fetal demand for nutrients in part determines placental supply, with products of imprinted genes, notably IGF-II, as key fetal signals [46]. Thus the rapidly growing fetus signals to the placenta to maintain or increase supply, but when its growth is compromised, it may not be able to maintain the stimulus. In the case of IGF-II, this may be because igf2 expression in a variety of tissues including placenta and maternal liver is also regulated by nutrition. Although IUGR induced by uterine artery ligation in guinea pigs results in reduced IGF actions by increased expression of fetal IGFBPs [47], fetal tissue expression of IGF-II in undernutrition is yet to be determined.

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7. Conclusion 

The fact that IGFs are not known to cross the placenta indicates that positive effects of IGF administration to the pregnant mother on fetal growth are mediated by effects on both the placenta and mother. A summary of proposed actions for IGFs in mother, placenta and fetus is presented in Fig. 2.

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  • Fig. 2 

    Schematic diagram representing IGF actions in the mother, placenta and fetus to enhance maternal adaptation to pregnancy and fetal and placental growth. IGF-I acts as an endocrine and autocrine/paracrine factor in the mother and fetus and as an endocrine factor in the placenta since its expression there is low in many species. It acts through the IGF1R. IGF-II acts as an endocrine and autocrine/paracrine factor in all three compartments. IGF-II exerts its effects through IGF1R, IGF2R, IR and a fourth as yet unidentified receptor XR.

IGF-II is an important regulator of growth and differentiation in many tissues throughout life and is expressed at high levels in the placenta. It has long been proposed that factors that promote placental trophoblast invasion of the decidua would increase the numbers of spiral arterioles recruited to the placenta and hence increase the maternal blood flow that is essential for placental and fetal growth and development. IGF-II is a prime candidate for controlling recruitment of the maternal blood supply to the placenta. In addition, maternal endocrine, placental and fetal IGF-II actions together may determine placental structural and functional differentiation and thereby fetal growth and development. Many of the effects of IGF-II in pregnancy may be mediated by IGF2R but IGF-II signalling via IGF1R in mother or placenta may also contribute.

Since the placenta does not express significant amounts of IGF-I, maternal endocrine IGF-I, acting via IGF1R in the placenta, may be the primary route by which it improves placental functional capacity and efficiency. IGF-I effects on maternal body composition may also affect nutrient partitioning between mother and fetus and her adaptation to pregnancy. Thus, both IGF-I and IGF-II are likely to contribute by common and disparate routes to facilitate optimal placentation and pregnancy success.

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8. Conflict of interest 

The authors do not have any potential or actual personal, political, or financial interest in the material, information, or techniques described in this paper.

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Acknowledgements 

We thank GroPep Pty Ltd for supply of recombinant IGFs. This work was supported by grants from Channel 7 Children's Research Foundation (J.A.O. and C.T.R.) and NHMRC (C.T.R.).

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PII: S0143-4004(07)00291-3

doi:10.1016/j.placenta.2007.12.002

Placenta
Volume 29, Supplement , Pages 42-47, March 2008

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