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Placenta 29, Supplement A, Trophoblast Research, Vol. 22 (2008) S42eS47

Distinct Actions of Insulin-Like Growth Factors (IGFs) on Placental

Development and Fetal Growth: Lessons from Mice and Guinea Pigs
C.T. Roberts*, J.A. Owens, A.N. Sferruzzi-Perri
Discipline of Obstetrics and Gynaecology, University of Adelaide, Adelaide, S.A. 5005, Australia
Accepted 3 December 2007

Abstract

Placental insufficiency is thought to be a key factor in many cases of intrauterine growth restriction which complicates about 6% of preg-
nancies in western countries. Understanding the molecular control of placental and fetal growth is essential to identifying diagnostic and ther-
apeutic 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. Con-
versely, 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.
Ó 2007 Published by IFPA and Elsevier Ltd.

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

1. Introduction supply for placental and hence fetal growth. This occurs pre-
dominantly in the first half of gestation and permits sufficient
Major complications of pregnancy occur in 19% of first blood flow into the placenta as well as its subsequent circum-
pregnancies in Australia and other affluent nations [1]. They ferential expansion. The second is terminal differentiation of
include pre-eclampsia (5e8%), pre-term birth (8%), and villous trophoblast and the accompanying fetal placental
placental insufficiency with intrauterine growth restriction vasculature to provide a maximal surface area for exchange
(IUGR, 6.4%). These complications are life-threatening to between the maternal and fetal circulations [3].
either the mother or her baby in more than 6% of pregnancies Impaired trophoblast invasion has been implicated in several
[1,2]. complications of pregnancy, such as unexplained miscarriage
The essential roles of the placenta in successful pregnancy [4], pre-eclampsia and IUGR [5]. In pre-eclampsia and some
place it as a major player in pregnancy complications. The miscarriages, for example, trophoblast invasion and colonisa-
human placenta has essentially two phases of development. tion of the spiral arterioles and the maternal decidual stroma
The first is placental extravillous cytotrophoblast invasion of is shallow, resulting in poor maternal blood flow to the placenta
the decidua and its vasculature to sequester an adequate blood [4,5]. In addition, impaired placental function is implicated in
a significant proportion of IUGR cases [5,6]. Furthermore, preg-
nancy complications, and IUGR in particular, have been associ-
* Corresponding author. Tel.: þ61 8 8303 3118; fax: þ61 8 8303 4099. ated with an increased risk for adult onset diseases including
E-mail address: [email protected] (C.T. Roberts). cardiovascular disease, hypertension and type 2 diabetes [7].

0143-4004/$ - see front matter Ó 2007 Published by IFPA and Elsevier Ltd.
doi:10.1016/j.placenta.2007.12.002
 C.T. Roberts et al. / Placenta 29, Supplement A, Trophoblast Research, Vol. 22 (2008) S42eS47 S43

Therefore, determination of the molecular interactions regulat- mouse, suggesting it plays a role in embryo differentiation, tro-
ing trophoblast invasion and placental function is essential to phoblast invasion and angiogenesis in the decidua [17]. After
understanding the defects inherent in pregnancy complications mid-gestation, IGF-II is most abundant in the spongiotropho-
and for the identification of potential targets for diagnostics and blast and glycogen cells with lower expression in the labyrinth
therapeutics. [18]. IGF-II is likely to promote TGC and glycogen cell inva-
sion in the mouse upon binding IGF2R since both proliferin
2. Insulin-like growth factors and placental [19] and hCG [20] exert a similar effect via this receptor.
and fetal growth
4. Endocrine actions of IGFS on the placenta
Insulin-like growth factors (IGFs), both IGF-I and IGF-II,
have been implicated in regulating fetal growth. Both in vivo Currently it is suggested that IGF-II acts in an autocrine/
and in vitro studies have revealed endocrine and autocrine/ paracrine fashion in the placenta. Although this is undoubtedly
paracrine actions of IGFs in regulating placental function the case in both the fetus and placenta, it has become apparent
and fetal growth. Studies of mice carrying null mutations of that endocrine IGF-II in the mother can significantly impact the
the IGF-I or IGF-II genes have shown that expression of these placenta. IGF-I expression in the placenta is absent or negligi-
growth factors is essential for normal fetal growth, since both ble, while IGF-II transcripts are abundant in most species
IGF null mice are born at about 60% of the weight of wild type examined, but particularly in those with an invasive placenta
[8,9]. IGF-I receptor gene ablation reduces fetal growth such [11]. Therefore, IGF-I is likely to exert its effects in autocrine/
that neonates weigh about 45% of wild type suggesting that paracrine and endocrine fashions in the mother to promote her
both ligands signal through IGF1R to promote growth in the adaptation to pregnancy and in the fetus to promote growth,
fetus [9]. IGF-II appears especially involved in the establish- while in the placenta IGF-I-induced uptake of glucose and
ment of placental function because placental weight is normal amino acids is likely to be a consequence of maternal endocrine
in mice that are deficient in IGF-I [9], whereas it is reduced by actions.
25% in IGF-II deficient mice [8]. Our previous studies of feed restriction during pregnancy in
Differences in IGF actions are likely to be due to their dif- the guinea pig, which induces IUGR, showed significant
ferential interactions with their receptors. IGF-II binds to the negative effects of undernutrition on maternal circulating
type 2 IGF (IGF2R), type 1 IGF (IGF1R) and insulin receptors IGF-I and -II and concomitant increases in circulating IGFBPs
(IR) with reducing affinity. IGF-I binds IGF1R with high affin- in both mid and late pregnancy [21]. These were associated
ity, but has negligible or low affinity for IGF2R and insulin re- with impaired fetal and placental growth in mid and late gesta-
ceptors, respectively [10]. Although it is well known that IGF tion [21]. Striking effects on placental differentiation indicated
actions are primarily mediated by IGF1R [11], emerging evi- more profound impacts on placental function than those im-
dence suggests control of fetal and placental growth by IGFs is posed by merely reduced placental size [22]. Structural corre-
more complex. This review will focus on IGFeIGFR interac- lates of placental function were associated with circulating
tions and fetal and placental growth and development. Atten- IGF-II and its ratio with IGFBP-2 in mid gestation [23] and
uation and potentiation of IGF actions by IGF binding proteins with IGF-I and IGF-I:IGFBP-1 in late gestation [24], suggest-
have been well described elsewhere [11,12] but are beyond the ing endocrine actions for both IGFs. Furthermore, placental
scope of this review. IGF-II mRNA expression in a similar cohort at day 40 was
reduced by maternal food restriction [25], so some of the
3. IGF-II and trophoblast invasion observed effects on placental and fetal growth may be due in
part to local effects within the placenta. Placental IGF-I
In women, evidence from in vitro studies and the localisa- mRNA was not detected at day 40 in agreement with in situ
tion of IGF-II to extravillous cytotrophoblasts in tissue ob- hybridisation studies [11]. These observations suggest specific
tained in vivo [12], indicate that IGF-II induces invasion of roles for each IGF and for those of endocrine origin, particu-
the maternal decidua by these cells via a mechanism that is larly in the mother, modulation of placental development.
not well understood, but is thought to be independent of
IGF1R [13]. The use of IGF-II analogues with specific receptor 5. Increasing IGF endocrine effects by IGF
binding has shown that IGF-II-induced invasion by a tropho- administration to the pregnant mother
blast cell line is mediated through the IGF2R [14]. In mice,
placentae from IGF-II nullizygotes exhibit reduced numbers We therefore proposed that increasing the abundance of
of glycogen cells, a highly invasive trophoblast cell type anal- IGFs in the pregnant guinea pig in early to mid gestation would
ogous to human extravillous cytotrophoblasts, and reduced in- promote fetal growth by specific actions in the placenta, since
vasive activity in the junctional zone [15]. In vitro, IGF-II also IGFs do not cross the placenta to the fetus. We selected guinea
stimulates differentiation of ectoplacental cone cells (EPCs, pigs for this investigation because their haemomonochorial
early post-implantation murine trophoblast stem cells) into placenta, although labyrinthine, is highly invasive and has sim-
the highly invasive trophoblast giant cells (TGCs), whereas ilar growth dynamics to that of women [26e28]. In addition,
IGF-I stimulates EPC migration [16]. IGF-II has been localised guinea pigs deliver precocial neonates [26] and their IGF
to the conceptus and decidua from days 5.5 to 10.5 in the axis is similar to that of humans [29,30]. A comparison of
S44 C.T. Roberts et al. / Placenta 29, Supplement A, Trophoblast Research, Vol. 22 (2008) S42eS47

pregnancy stages in women, guinea pigs and mice is shown in is consistent with observed increases in circulating IGF-I in
Fig. 1. Furthermore the figure indicates the timing of maternal pregnancy in several species [21] and may contribute to preg-
exposure to exogenous IGFs which is described below. nancy success.
Exogenous IGF-I or IGF-II administered to the mother with Increased maternal exposure to IGF-I or IGF-II in early to
mini osmotic pump infusion from days 20e37 (term w70 days) mid-pregnancy in the guinea pig also enhanced placental up-
increased maternal plasma IGFs by 340% and 240% respec- take and transfer of non-metabolisable radiolabelled ana-
tively at day 35 without altering total IGFBP levels and hence logues of glucose (MG) and amino acids (AIB) to the fetus
elevated free IGFs [31]. IGF infusion increased fetal and in late gestation, with IGF-I having particularly potent effects
placental weights at day 40 compared to vehicle [32] These [34]. Earlier in pregnancy just prior to the end of treatment
effects were already evident for IGF-I, but not IGF-II, at day (day 35), when only IGF-I had enhanced fetal and placental
35 just before the end of treatment [33]. IGF-I infusion also growth, IGF-I also increased placental MG and AIB uptake
reduced placental IGF-II mRNA levels at day 35 [33]. and content and their transfer to the fetus [34]. Although at
Near term (day 62) earlier administration of either IGF to day 35 placental mRNA expression of Slc2a1, the gene that
the mother increased fetal weight without altering placental encodes glucose transporter (GLUT)-1, was not affected by
weight. Exogenous IGF-II, but not IGF-I, increased the vol- IGF-I infusion, placental Slc38a2 mRNA, that encodes a Sys-
ume of the placental exchange region (placental labyrinth) tem A amino acid transporter (SNAT2), was increased nearly
[31]. Of particular interest was the observation that IGF-II, 8-fold by maternal IGF-I treatment [34]. So, despite the fact
but not IGF-I, treatment of the guinea pig in early to mid preg- that exogenous IGF-I did not alter placental weight at day
nancy improved the differentiation of the placental labyrinth in 62 nor its structural differentiation, it nevertheless altered
a manner predicted to improve placental exchange function at placental transporter expression and function to effect the
day 62 of gestation, just before term [31]. Interestingly, these sustained increase in fetal growth. Interestingly, in the mother,
effects on the placenta were present well after cessation of exposure in early to mid pregnancy to either IGF increased
IGF-II administration to the mother in early to mid pregnancy. AIB uptake by her visceral organs, while IGF-I also enhanced
Although IGF-I or IGF-II administration to the mother did uptake of AIB by muscle and MG uptake by visceral organs
not alter her weight gain during pregnancy, IGF-I at least al- and muscle in late gestation indicating endocrine roles on
tered maternal body composition at day 62, by reducing adi- maternal tissues [34].
posity by about 30% [31]. Only subtle effects of IGF-I on The identity of the receptors that mediate the common and
maternal adiposity were present at day 40, just following disparate actions of the IGFs on the placenta, fetus and mother
IGF-I treatment [32], suggesting that elevated maternal endo- are also becoming clearer. The IGF-II analogue, Leu27-IGF-II,
crine IGF-I in early to mid pregnancy alters maternal nutrient binds only the IGF2R and not to the IGF1R nor the IR.
partitioning and adaptation to pregnancy in a sustained fashion Treatment of the pregnant guinea pig with Leu27-IGF-II in early
reflected in reduced maternal adiposity in late pregnancy. This to mid pregnancy largely replicated and potentiated the

d1 d6 d 20+ d75-90 d280

Human

Implantation EVT invasion

Term
EPC Maternal Maternal
invasion blood flow blood flow

d1 d4 d7.5 d10.5 d12.5 d19

Mouse

Maternal Myometrial / Mesometrial

blood flow EVT invasion

d1 d7 d12 d20 d35 d37 d62 d70

Guinea IGF infusion
pig

Mating Surgery Post-mortem Post-mortem

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.
 C.T. Roberts et al. / Placenta 29, Supplement A, Trophoblast Research, Vol. 22 (2008) S42eS47 S45

mother Endocrine/local IGF-II Endocrine/local IGF-I

alterations in
body composition
↑ cardiovascular maternal metabolism
effectors adaptation nutrient partitioning

↑ invasion ↑ transporter IGF1R

↑ differentiation expression/activity hormone IGF1R
placenta
synthesis IGF2R
IR
Autocrine/ ↑ placental capacity XR
paracrine and efficiency ↑ Substrate
IGF-II supply
↑ substrate delivery

fetus
Endocrine/local
IGF-I
↑ Fetal Growth
Endocrine/local
IGF-II

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.

consequences of IGF-II consistent with IGF-II actions occur- IGFBP-1 and -2, is positively correlated with birth weight
ring substantially via the IGF2R and its increased potency in human infants [37]. Cord blood soluble IGF2R concentra-
reflecting the lack of competition for the analogue by other tion also increases as birth weight decreases in human in-
receptors (Sferruzzi-Perri AN, Standen P, Owens JA, Roberts fants. While the molar ratio of IGF-II to soluble IGF2R in
CT, submitted). If IGF-II promotes trophoblast invasion via cord blood is positively correlated with birth weight, IGF-II
the IGF2R in guinea pig, as it does in a human cytotrophoblast alone is not related to birth weight [37]. Both IGFs and their
cell line [14], then it is possible that some of its observed effects specific receptors, as well as the IR, are ubiquitously ex-
on placental differentiation are facilitated by enhanced pressed in fetal tissues and the ligands are likely to promote
endovascular trophoblast invasion and vessel remodelling, growth in an autocrine/paracrine fashion. IGF-II is known to
a possibility we are currently examining. promote cell proliferation by binding IR [38] and this inter-
The timing of maternal exposure to elevated IGFs may de- action promotes fetal growth [39]. In fetal tissues the pre-
termine whether placental function is improved, since exog- dominant IR isoform is IR-A, which lacks the alternatively
enous IGF-I infusion in late pregnancy in the rat had spliced exon 11, and thereby has similar affinity for insulin
anabolic effects on the mother but did not improve fetal and IGF-II [40]. (IR-B is expressed more abundantly in post-
growth [35]. However, when maternal IGF-I treatment occurs natal tissues, has greater affinity for insulin and mediates its
throughout pregnancy in rats and mice, fetal growth is en- metabolic effects [40].) IR is most abundantly expressed on
hanced in late gestation [36]. Although IGF-I would not be human first trimester syncytiotrophoblasts and as gestation
expected to enhance trophoblast invasion in early pregnancy, proceeds it is increasingly expressed on fetal capillaries
we speculate that elevated endocrine IGF-I in early preg- and to a lesser extent in trophoblast [41]. However, to our
nancy may facilitate the maternal adaptation to pregnancy knowledge the identity of the IR isoform in placenta is not
to indirectly enhance placental function and fetal growth in known.
late gestation. In the fetus, IGF2R is also abundantly expressed. It is com-
monly thought that its primary role is to permit uptake and
6. The role of fetal IGFs degradation of IGF-II through the lysosomal pathway and
thereby inhibit growth [42]. In support of this view, IGF2R
Within the fetus, IGF-I, modulated by its binding proteins, gene ablation results in elevated circulating IGF-II and both
is thought to drive fetal growth. Thus cord blood IGF-I, but placental and fetal overgrowth [42] and simultaneous ablation
not IGF-II, concentration, particularly in association with of the igf2 gene rescues these fetuses [43]. However, IGF2R
S46 C.T. Roberts et al. / Placenta 29, Supplement A, Trophoblast Research, Vol. 22 (2008) S42eS47

null mutation results in late gestation or perinatal death with 8. Conflict of interest
organomegaly and severe heart defects, polydactyly and kinky
tail, suggesting it is also likely to be involved in differentiation The authors do not have any potential or actual personal,
during development. This role is yet to be fully explored. political, or financial interest in the material, information, or
Evidence that fetal circulating IGF-II may also be an im- techniques described in this paper.
portant signalling molecule between the fetus and placenta
comes from studies in which placenta specific ablation of Acknowledgements
igf2 transcripts from the P0 promoter in mice has been under-
taken. These show placental growth restriction with transient We thank GroPep Pty Ltd for supply of recombinant IGFs.
compensatory up-regulation of placental System A amino This work was supported by grants from Channel 7 Children’s
acid transporters apparent before fetal growth restriction Research Foundation (J.A.O. and C.T.R.) and NHMRC (C.T.R.).
was manifest [44,45]. There is also evidence that fetal de-
mand for nutrients in part determines placental supply, with
References
products of imprinted genes, notably IGF-II, as key fetal
signals [46]. Thus the rapidly growing fetus signals to the [1] Laws PJ, Grayson N, Sullivan EA. Australia’s mothers and babies 2004.
placenta to maintain or increase supply, but when its growth Sydney: AIHW National Perinatal Statistics Unit; 2006.
is compromised, it may not be able to maintain the stimulus. [2] Heard AR, Dekker GA, Chan A, Jacobs DJ, Vreeburg SA, Priest KR.
In the case of IGF-II, this may be because igf2 expression in Hypertension during pregnancy in South Australia, Part 1: Pregnancy
a variety of tissues including placenta and maternal liver is outcomes. Aust N Z J Obstet Gynaecol 2004;44:404e9.
[3] Gude NM, Roberts CT, Kalionis B, King RG. Growth and function of the
also regulated by nutrition. Although IUGR induced by uter- normal human placenta. Thromb Res 2004;114:397e407.
ine artery ligation in guinea pigs results in reduced IGF [4] Khong TY, Liddell HS, Robertson WB. Defective haemochorial placen-
actions by increased expression of fetal IGFBPs [47], fetal tation as a cause of miscarriage: a preliminary study. Br J Obstet Gynae-
tissue expression of IGF-II in undernutrition is yet to be col 1987;94:649e55.
determined. [5] Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal
vascular response to placentation in pregnancies complicated by pre-
eclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol
7. Conclusion 1986;93:1049e59.
[6] Mayhew TM, Wijesekara J, Baker PN, Ong SS. Morphometric evidence
The fact that IGFs are not known to cross the placenta in- that villous development and fetoplacental angiogenesis are compromised
dicates that positive effects of IGF administration to the by intrauterine growth restriction but not by pre-eclampsia. Placenta
2004;25:829e33.
pregnant mother on fetal growth are mediated by effects [7] Barker DJP. Mothers, babies and health in later life. London: Churchill
on both the placenta and mother. A summary of proposed Livingstone; 1998.
actions for IGFs in mother, placenta and fetus is presented [8] DeChiara TM, Efstratiadis A, Robertson EJ. A growth-deficiency pheno-
in Fig. 2. type in heterozygous mice carrying an insulin-like growth factor II gene
IGF-II is an important regulator of growth and differentia- disrupted by targeting. Nature 1990;345:78e80.
[9] Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A. Mice carrying
tion in many tissues throughout life and is expressed at high null mutations of the genes encoding insulin- like growth factor-I (Igf-1)
levels in the placenta. It has long been proposed that factors and type-1 IGF receptor (Igf1r). Cell 1993;75:59e72.
that promote placental trophoblast invasion of the decidua [10] Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE. Molecular
would increase the numbers of spiral arterioles recruited to interactions of the IGF system. Cytokine Growth Factor Rev 2005;16:
421e39.
the placenta and hence increase the maternal blood flow that
[11] Han VK, Carter AM. Spatial and temporal patterns of expression of
is essential for placental and fetal growth and development. messenger RNA for insulin-like growth factors and their binding pro-
IGF-II is a prime candidate for controlling recruitment of teins in the placenta of man and laboratory animals. Placenta 2000;
the maternal blood supply to the placenta. In addition, mater- 21:289e305.
nal endocrine, placental and fetal IGF-II actions together may [12] Han VKM, Bassett N, Walton J, Challis JRG. The expression of insulin-
determine placental structural and functional differentiation like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the
human placenta and membranes: evidence for IGF-IGFBP interactions
and thereby fetal growth and development. Many of the effects at the feto-maternal interface. J Clin Endocrinol Metab 1996;81:2680e93.
of IGF-II in pregnancy may be mediated by IGF2R but IGF-II [13] Irving JA, Lala PK. Functional role of cell surface integrins on human
signalling via IGF1R in mother or placenta may also trophoblast cell migration - regulation by TGF beta, IGF-II and
contribute. IGFBP-1. Exp Cell Res 1995;217:419e27.
Since the placenta does not express significant amounts of [14] McKinnon T, Chakraborty C, Gleeson LM, Chidiac P, Lala PK.
Stimulation of human extravillous trophoblast migration by IGF-II is
IGF-I, maternal endocrine IGF-I, acting via IGF1R in the pla- mediated by IGF type 2 receptor involving inhibitory G protein(s) and
centa, may be the primary route by which it improves placental phosphorylation of MAPK. J Clin Endocrinol Metab 2001;86:3665e74.
functional capacity and efficiency. IGF-I effects on maternal [15] Lopez MF, Dikkes P, Zurakowski D, Villakomaroff L. Insulin-like
body composition may also affect nutrient partitioning between growth factor II affects the appearance and glycogen content of glycogen
mother and fetus and her adaptation to pregnancy. Thus, both cells in the murine placenta. Endocrinology 1996;137:2100e8.
[16] Kanai-Azuma M, Kanai Y, Kurohmaru M, Sakai S, Hayashi Y. Insulin-
IGF-I and IGF-II are likely to contribute by common and dispa- like growth factor (IGF)-I stimulates proliferation and migration of
rate routes to facilitate optimal placentation and pregnancy mouse ectoplacental cone cells, while IGF-II transforms them into tro-
success. phoblastic giant cells in vitro. Biol Reprod 1993;48:252e61.
 C.T. Roberts et al. / Placenta 29, Supplement A, Trophoblast Research, Vol. 22 (2008) S42eS47 S47

[17] Pringle KG, Roberts CT. New light on early post-implantation pregnancy [34] Sferruzzi-Perri AN, Owens JA, Standen P, Taylor RL, Heinemann GK,
in the mouse: roles for insulin-like growth factor-II (IGF-II)? Placenta Robinson JS, et al. Early treatment of the pregnant guinea pig with
2007;28:286e97. IGFs promotes placental transport and nutrient partitioning near term.
[18] Redline RW, Chernicky CL, Tan HQ, Ilan J. Differential expression of Am J Physiol Endocrinol Metab 2007;292:E668e76.
insulin-like growth factor-II in specific regions of the late (post day [35] Gargosky SE, Owens JA, Walton PE, Owens PC, Wallace JC, Ballard FJ.
9.5) murine placenta. Mol Reprod Dev 1993;36:121e9. Insulin-like growth factor-I, but not growth hormone, increases maternal
[19] Volpert O, Jackson D, Bouck N, Linzer DI. The insulin-like growth factor weight gain in late pregnancy without affecting fetal or placental growth.
II/mannose 6-phosphate receptor is required for proliferin-induced angio- J Endocrinol 1991;130:395e400.
genesis. Endocrinology 1996;137:3871e6. [36] Gluckman PD, Morel PCH, Ambler BH, Breier HT, McCutcheon SN.
[20] Zygmunt M, McKinnon T, Herr F, Lala PK, Han VKM. HCG increases Elevating maternal insulin-like growth factor-1 in mice and rats alters
trophoblast migration in vitro via the insulin-like growth factor-II/man- the pattern of fetal growth by removing maternal constraint. J Endocrinol
nose-6 phosphate receptor. Mol Hum Reprod 2005;11:261e7. 1992;134:R1e3.
[21] Sohlstrom A, Katsman A, Kind KL, Roberts CT, Owens PC, [37] Ong K, Kratzsch J, Kiess W, Costello M, Scott C, Dunger D. Size at birth
Robinson JS, et al. Food restriction alters pregnancy-associated changes and cord blood levels of insulin, insulin-like growth factor I (IGF-I), IGF-
in IGF and IGFBP in the guinea pig. Am J Physiol 1998;274:E410e6. II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and the soluble IGF-II/
[22] Roberts CT, Sohlstrom A, Kind KL, Earl RA, Khong TY, Robinson JS, mannose-6-phosphate receptor in term human infants. The ALSPAC
et al. Maternal food restriction reduces the exchange surface area and in- Study Team. Avon Longitudinal Study of Pregnancy and Childhood.
creases the barrier thickness of the placenta in the guinea-pig. Placenta J Clin Endocrinol Metab 2000;85:4266e9.
2001;22:177e85. [38] Morrione A, Valentinis B, Xu SQ, Yumet G, Louvi A, Efstratiadis A,
[23] Roberts CT, Sohlstrom A, Kind KL, Grant PA, Earl RA, Robinson JS, et al. Insulin-like growth factor II stimulates cell proliferation through
et al. Altered placental structure induced by maternal food restriction the insulin receptor. Proc Natl Acad Sci USA 1997;94:3777e82.
in guinea pigs: a role for circulating IGF-II and IGFBP-2 in the mother? [39] Louvi A, Accili D, Efstratiadis A. Growth-promoting interaction of IGF-
Placenta 2001;22:S77e82. II with the insulin receptor during mouse embryonic development. Dev
[24] Roberts CT, Kind KL, Earl RA, Grant PA, Robinson JS, Sohlstrom A, Biol 1997;189:33e48.
et al. Circulating insulin-like growth factor (IGF)-I and IGF binding pro- [40] Denley A, Bonython ER, Booker GW, Cosgrove LJ, Forbes BE,
teins -1 and -3 and placental development in the guinea-pig. Placenta Ward CW, et al. Structural determinants for high-affinity binding of
2002;23:763e70. insulin-like growth factor II to insulin receptor (IR)-A, the exon 11 minus
[25] Olausson H, Sohlstrom A. Effects of food restriction and pregnancy on isoform of the IR. Mol Endocrinol 2004;18:2502e12.
the expression of insulin-like growth factors-I and -II in tissues from [41] Desoye G, Hartmann M, Jones CJ, Wolf HJ, Kohnen G, Kosanke G, et al.
guinea pigs. J Endocrinol 2003;179:437e45. Location of insulin receptors in the placenta and its progenitor tissues.
[26] Carter AM. Animal models of human placentationda review. Placenta Microsc Res Tech 1997;38:63e75.
2007;28(Suppl. A):S41e7. [42] Lau MM, Stewart CE, Liu Z, Bhatt H, Rotwein P, Stewart CL. Loss of
[27] Mess A. The Guinea pig placenta: model of placental growth dynamics. the imprinted IGF2/cation-independent mannose 6-phosphate receptor
Placenta 2007;28:812e5. results in fetal overgrowth and perinatal lethality. Genes Dev 1994;
[28] Mess A, Zaki N, Kadyrov M, Korr H, Kaufmann P. Caviomorph placen- 8:2953e63.
tation as a model for trophoblast invasion. Placenta 2007;28:1234e8. [43] Ludwig T, Eggenschwiler J, Fisher P, D’Ercole AJ, Davenport ML,
[29] Gargosky SE, Owens PC, Walton PE, Owens JA, Robinson JS, Efstratiadis A. Mouse mutants lacking the type 2 IGF receptor
Wallace JC, et al. Most of the circulating insulin-like growth factors I (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null back-
and II are present in the 150kDa serum complex during human preg- grounds. Dev Biol 1996;177:517e35.
nancy. J Endocrinol 1991;131:491e7. [44] Constancia M, Hemberger M, Hughes J, Dean W, Ferguson-Smith A,
[30] Sohlstrom A, Katsman A, Kind KL, Grant PA, Owens PC, Robinson JS, Fundele R, et al. Placental-specific IGF-II is a major modulator of
et al. Effects of acute and chronic food restriction on the insulin-like placental and fetal growth. Nature 2002;417:945e8.
growth factor axis in the guinea pig. J Endocr 1998;157:107e14. [45] Sibley CP, Coan PM, Ferguson-Smith AC, Dean W, Hughes J, Smith P,
[31] Sferruzzi-Perri AN, Owens JA, Pringle KG, Robinson JS, Roberts CT. et al. Placental-specific insulin-like growth factor 2 (Igf2) regulates the
Maternal insulin-like growth factors-I and -II act via different pathways diffusional exchange characteristics of the mouse placenta. Proc Natl
to promote fetal growth. Endocrinology 2006;147:3344e55. Acad Sci USA 2004;101:8204e8.
[32] Sohlstrom A, Fernberg P, Owens JA, Owens PC. Maternal nutrition af- [46] Constancia M, Angiolini E, Sandovici I, Smith P, Smith R, Kelsey G,
fects the ability of treatment with IGF-I and IGF-II to increase growth et al. Adaptation of nutrient supply to fetal demand in the mouse involves
of the placenta and fetus, in guinea pigs. Growth Horm IGF Res interaction between the Igf2 gene and placental transporter systems. Proc
2001;11:392e8. Natl Acad Sci USA 2005;102:19219e24.
[33] Sferruzzi-Perri AN, Owens JA, Standen P, Taylor RL, Robinson JS, [47] Carter AM, Kingston MJ, Han KK, Mazzuca DM, Nygard K,
Roberts CT. Early pregnancy maternal endocrine insulin-like growth fac- Han VK. Altered expression of IGFs and IGF-binding proteins during
tor I programs the placenta for increased functional capacity throughout intrauterine growth restriction in guinea pigs. J Endocrinol 2005;
gestation. Endocrinology 2007;148:4362e70. 184:179e89.