The influence of the intrauterine environment
on human placental development
GRAHAM J. BURTON*,1, ERIC JAUNIAUX2 and D. STEPHEN CHARNOCK-JONES1
1Centre for Trophoblast Research, University of Cambridge, Cambridge and
2Academic Department of Obstetrics and Gynaecology, Royal Free and University College, London, UK
ABSTRACT Development of the human placenta is modulated heavily by the intrauterine
environment. During the first trimester, development takes place in a low oxygen environment
supported by histiotrophic nutrition from the endometrial glands. Consequently, the rate of
growth of the chorionic sac is almost invariable across this period, and is remarkably uniform
between individuals. Towards the end of the first trimester the intrauterine environment under-
goes radical transformation in association with onset of the maternal arterial circulation and the
switch to haemotrophic nutrition. The accompanying rise in intraplacental oxygen concentration
poses a major challenge to placental tissues, and extensive villous remodelling takes place at this
time. Later in pregnancy a wide variety of stressors are capable of affecting placental growth, but
in the human, the most common are nutrient deprivation and vascular compromise. The latter is
usually secondary to deficient trophoblast invasion and can induce placental oxidative stress.
Closely linked to oxidative stress is endoplasmic reticulum stress, and we recently provided the
first evidence that the latter plays a major role in the pathophysiology of intrauterine growth
restriction. The endoplasmic reticulum is a key regulator of protein synthesis, exerting its effects
through the unfolded protein response. Consequently, we observed multiple blocks to translation
initiation and elongation in growth restricted placentas. Nutrient deprivation also modulates
protein synthesis through the mTOR pathway, and we demonstrated interactions between this
pathway and endoplasmic reticulum stress. Protein synthesis inhibition therefore appears to be
a common mechanism for regulating placental development under different adverse conditions.
KEY WORDS: placenta, oxidative stress, protein synthesis, growth restriction, endoplasmic reticulum stress
It is axiomatic that normal development of the placenta is an
essential prerequisite for growth of a healthy fetus. This has been
confirmed by both longitudinal studies in the human and experi-
mental manipulations in animals demonstrating that deficient
placental growth precedes growth restriction of the fetus. Classic
experiments, such as the Shire horse-Shetland pony crosses
conducted by Walton and Hammond (1938), have shown that the
intrauterine environment exerts a powerful influence over placen-
tal development. Recent research has shown that in the human
the intrauterine environment changes radically between the first
trimester and the remainder of pregnancy due to a switch from
histiotrophic to haemotrophic nutrition with onset of the maternal
arterial circulation to the placenta. Adapting to the new conditions
poses a major challenge to the placental tissues, and extensive
Int. J. Dev. Biol. 54: 303-311 (2010)
THE INTERNATIONAL JOURNAL OF
*Address correspondence to: Graham J. Burton. Physiological Laboratory, Downing Street, Cambridge CB2 3EG. UK. Fax: +44-1223-333-840.
Final author-corrected PDF published online: 4 September 2009.
ISSN: Online 1696-3547, Print 0214-6282
© 2009 UBC Press
Printed in Spain
Abbreviations used in this paper: IHC, immunohistochemistry; mTOR,
mammalian target of rapamycin.
remodelling takes place at that time. Later in pregnancy, vascular
or dietary compromise can limit placental growth through their
effects on protein synthesis. In this review, we consider the
molecular mechanisms by which these effects are mediated, and
identify common pathways.
The first trimester
In normal human pregnancies the rate of growth of the embryo
and of the chorionic sac during the first trimester is remarkably
constant between individuals (Blaas et al., 1998), suggesting that
once started early growth is autonomous and that it occurs under
304 G.J. Burton et al.
stable conditions. During this period the conceptus is supported by
secretions from the endometrial glands delivered into the placenta
through the developing basal plate (Burton et al., 2002). This
relationship might be best described as ‘deciduochorial’ to distin-
guish it from the more familiar haemochorial state that exists during
the second and third trimesters. Hormonal manipulation of en-
dometrial gland morphogenesis in the sheep has confirmed the
importance of these secretions for normal development of the
conceptus (Gray et al., 2001). In this species, and in the pig and
rabbit, the conceptus influences the secretory activity of the glands
via a series of endocrine and paracrine signals (Spencer et al.,
2004). In contrast, little is known regarding the composition of the
secretions in the human, although it is clear from histochemical
staining that they are carbohydrate-rich and contain numerous lipid
droplets. In addition, a wide variety of cytokines and growth factors
are present, such as epidermal growth factor, vascular endothelial
growth factor and transforming growth factor beta, and receptors
for all these are present on the villous tissues. Hence, the secre-
tions have the potential to play an important role in regulating
placental cell proliferation and differentiation in the early stages of
pregnancy (Hempstock et al., 2004; Burton et al., 2007b).
The reliance on histiotrophic nutrition during the phase of
organogenesis is common to many mammalian species. The
principal benefit would appear to be that the oxygen concentration
within the chorionic sac is maintained at a relatively low value, and
this may protect from teratogenesis mediated by reactive oxygen
species (Burton et al., 2003; Jauniaux et al., 2003a). Free radicals,
molecules possessing unpaired electrons, are highly reactive and
may interfere with development by direct attack on genomic DNA
or by causing misfolding and inactivation of intermediate signalling
molecules. A rise in the prevailing oxygen concentration, or a
reduction in antioxidant defences, is associated with greater oxida-
tive damage to embryonic DNA, and an increased risk of both major
and minor congenital abnormalities (Eriksson, 1999; Nicol et al.,
2000; Ornoy, 2007). Maintaining metabolism at a low level during
blastocyst development improves pregnancy outcome (Leese,
2002), and it would appear that the same may apply during the
phase of organogenesis. Experimental data also suggest that a low
oxygen environment is necessary to maintain human embryonic
stem cells in a pluriopotent state (Ezashi et al., 2005), and for
promoting proliferation of cytotrophoblast cells, both in vitro and in
vivo (Fox, 1964; Genbacev et al., 1996; Ali, 1997). Daughter cells
may then feed through into either the villous or extravillous tropho-
Onset of the maternal arterial circulation to the placenta
Under these protective conditions the early placenta develops
rapidly, and so by the end of the third week post-conception villi
surround the whole of the chorionic sac. Initially, the villi are almost
uniform in length, but later those over the superficial pole begin to
regress (Fig. 1A). The cause for this has long been unknown, but
we recently speculated that it is driven by oxidative stress arising
from onset of the maternal arterial circulation to the placenta (Fig.
1B). During the first trimester the placental intervillous space is
filled with a clear fluid (Schaaps and Hustin 1988), for maternal
erythrocytes are prevented from entering by the presence of
endovascular trophoblast plugs that occlude the tips of the spiral
arteries (Hustin and Schaaps 1987; Burton et al., 1999). These
plugs are a component of the general phenomenon of extravillous
trophoblast invasion that occurs during the first and second trimes-
ters of human pregnancy (Pijnenborg et al., 2006). The extent of
this invasion varies across the placental bed, being greatest in the
central region and least in the periphery (Pijnenborg et al., 1981).
Intriguingly, when the maternal arterial circulation is first estab-
lished ultrasound evidence of significant flow is more often ob-
served in the peripheral regions of the placenta than in the centre
under the insertion of the umbilical cord (Jauniaux et al., 2003b).
This may reflect incomplete plugging of the arteries in the periphery
due to the less extensive trophoblast invasion (Pijnenborg et al.,
Onset of the maternal arterial circulation leads to a three-fold
rise in the intraplacental oxygen concentration (Rodesch et al.,
1992; Jauniaux et al., 2000). This poses a major challenge to the
placental tissues, as it will result in increased production of poten-
tially damaging reactive oxygen species from mitochondria and
other sources. The syncytiotrophoblast layer is particularly vulner-
able as it contains low concentrations of the principal antioxidant
enzymes during early pregnancy (Watson et al., 1997; Watson et
al., 1998). Consequently, exposure of first trimester villi to ambient
concentrations of oxygen in vitro results in rapid degeneration of
the syncytiotrophoblast (Palmer et al., 1997), although the cytotro-
phoblast and stromal cells survive in short-term culture. Morpho-
logically similar, but less severe, changes are observed in the
peripheral region of the placenta, where they are associated with
an increase in markers of oxidative stress such as nitrosylation of
tyrosine residues, expression of heat shock proteins and increased
lipid peroxidation (Fig. 2 A,B and Table 1) (Jauniaux et al., 2003b).
We also observe increased activation of the apoptotic cascade by
Western blotting in samples from the peripheral region of the
placenta, and immunohistochemistry localised this principally to
the cytotrophoblast cells (Fig. 2 C,D). Equally, proliferation, as
identified by immunostaining with antibodies directed against Ki67
is lower in the peripheral villi. It would seem reasonable to conclude
that this combination of increased cell death and decreased
renewal will ultimately lead to regression of the villi. Indeed, in
Fig. 1. Formation of the chorion laeve. (A) A placenta-in-situ specimen
at 8.5 weeks of gestational age illustrating regression of the villi over the
superficial pole of the chorionic sac (asterisk). (B) Diagrammatic repre-
sentation of how onset of the maternal arterial circulation in the periphery
of the placenta (arrows), where cytotrophoblast plugging of the spiral
arteries is minimal, causes a localised increase in oxidative stress
(depicted by the red shading) in the villi over the superficial pole. This is
believed to induce regression of the villi, giving rise to the chorion laeve.
Adapted from (Jauniaux et al., 2003b) with permission from the American
Society for Investigative Pathology and (Jauniaux et al., 2004) with
permission from The Endocrine Society respectively.
Intrauterine environment and placental development 305
placenta-in-situ specimens it appears that the villi over the super-
ficial pole of the chorionic sac are reduced to little more than
hypocellular cores of collagen and other extracellular fibres cov-
ered by a severely attenuated layer of trophoblast (Jauniaux et al.,
2003b) (Fig. 2 E,F). In this way the chorion frondosum is trans-
formed into the smooth chorion, the chorion laeve, and the defini-
This suggested mechanism of chorionic villous regression to
form the discoid placenta is supported by findings from cases of
missed miscarriage. In these onset of the maternal arterial circula-
tion is precocious, and occurs in a disorganised fashion throughout
the placenta. In two-thirds of cases this is secondary to shallow
trophoblast invasion (Khong et al., 1987; Hustin et al.,
1990), which will lead to incomplete plugging of the spiral
arteries. Villi that are maintained in this physiologically
hyperoxic environment show increased levels of oxida-
tive stress and equivalent morphological changes to
those in the periphery of the normal placenta (Jauniaux
et al., 1994a; Jauniaux et al., 2003b). As time progresses
after the onset of the blood flow the fetal capillaries
involute, leaving only avascular hypocellular villous
ghosts. On ultrasound the thickness of the placenta is
seen to gradually decrease until only a thin shell persists.
The regression of villi that occurs during formation of the
chorion laeve and in cases of missed miscarriage may
therefore be considered physiological and pathological
manifestations of the same oxygen-induced phenom-
mammalian species, being diffuse in the pig, cotyledonary in the
ruminants, zonary in many carnivores and discoid in the rodents
and primates (Mossman, 1987). In almost all cases this is due to
differential outgrowth of villi from the chorionic sac, often opposite
specialised areas of the endometrial surface. The situation de-
picted above where villi regress to leave a discoid placenta
appears to be unique to the human and the great apes, and is
presumably related to the phenomenon of interstitial implanta-
Although the human placenta is classified as being discoid, in
reality the margins are often irregular and do not conform to a
circular profile. In these cases the insertion of the umbilical cord
Fig. 2. Comparison of villi from the central and peripheral
regions of the first trimster placenta. (A-D) Villi removed
from the centre and periphery of a 10 week gestational age
placenta immunostained against hydroxynonenal (HNE) to de-
tect lipid peroxidation, and active (cleaved) caspase 3 to detect
apoptosis. Villi from the periphery react more strongly for both,
particularly in the synctyotrophoblast and cytotrophoblast lay-
ers. (E,F) Villi from the central and peripheral regions of the
placenta-in-situ specimen shown in Fig. 1 illustrating how the
regressing villi are hypocellular, avascular and have a very thin
Abnormal placental shapes
Placentas display a wide range of shapes across
Maternal blood flow
IHC reactivity for nitrotyrosine residues
IHC reactivity for lipidperoxidation
IHC reactivity for inducible heat shock protein 70
IHC for Ki67
Western blotting for active caspases 3 and 9
rare before 12-13 weeks
thick with profuse microvilli
parallel cristae with narrow intracristal spaces
numerous, rounded and undifferentiated
central and peripheral villous capillaries
scattered cytotrophoblast cells
common at 8-9 weeks
thin with few microvilli
distorted cristae with dilated intracristal spaces
fewer, elongated and more differerntiated
degenerating capillaries and many avascular villi
strong, especially in the syncytiotrophoblast
strong, especially in the syncytiotrophoblast
strong, especially before 11 weeks
reduced compared to centre
SUMMARY OF THE PRINCIPAL DIFFERENCES OBSERVED BETWEEN CENTRAL AND PERIPHERAL VILLI
IN PLACENTAS OF 8-12 WEEKS GESTATIONAL AGE*
*Data collated mainly from Jauniaux et al. (2003b)
306 G.J. Burton et al.
can be highly eccentric. Such placentas are found more com-
monly in pregnancies resulting from in-vitro-fertilization and em-
bryo transfer, and in multiple pregnancies (Jauniaux et al., 1990;
Gavriil et al., 1993). Overall, they are often associated with a
poorer obstetric outcome (Salafia et al., 2005; Toal et al., 2007).
The realisation that regression is associated with oxidative stress
and onset of the maternal arterial blood flow to the placenta
enables us to link these findings through abnormal trophoblast
invasion and incomplete physiological conversion of the spiral
arteries. Physiological conversion is essential for ensuring an
adequate blood flow to the placenta in later gestation, and
complications such as intrauterine growth restriction and preec-
lampsia are associated with defects in this process (Brosens et
al., 1977; Gerretsen et al., 1981). Conversion leads to dilation of
the distal segments of the arteries, reducing the rate and the
pressure with which the maternal blood enters the intervillous
space. It also removes the highly contractile segment of the artery
lying at the endometrial-myometrial boundary, and we have
suggested that this ensures greater constancy of placental perfu-
sion (Burton et al., 2009). Although the molecular mechanisms
are still unknown, conversion is dependent in the human on the
presence of both interstitial and endovascular extravillous tropho-
blast (Kam et al., 1999; Pijnenborg et al., 2006). There is quanti-
tative evidence that the number of these cells is reduced in
complicated pregnancies (Naicker et al., 2003). Because it is the
endovascular trophoblast migrating down the lumen that plugs
the arteries during the first trimester it is not unreasonable to
assume that incomplete conversion of the arteries may also be
associated with poor plugging of the vessels, and so early onset
of the maternal blood flow.
The factors regulating trophoblast invasion are not fully under-
stood, but it is highly likely that the local endometrial environment,
including cells of the maternal immune system, plays a key role.
Thus, the extent of spiral arterial conversion is variable across the
normal placental bed, and even between different segments of
the same vessel (Pijnenborg et al., 1981; Meekins et al., 1994). In
pregnancies where trophoblast invasion is compromised, particu-
larly shallow invasion in areas of the placental bed could lead to
the early onset of the circulation normally seen in the periphery
extending into the central region. As a result excessive villous
regression will occur, the placental shape will be abnormal, and
the cord insertion eccentric (Fig. 3). The remaining spiral arteries
in the placental bed may not be fully converted, and as a result
maternal blood enters the intervillous space at excessive velocity.
The haemodynamics of the maternal circulation to the placenta
play an important role in shaping the topography of the villous
trees. Villi in the early placenta initially form a uniform dense
meshwork, but once the spiral arteries open towards the end of
the first trimester they become organised into the lobular arrange-
ment, with villus-free central cavities forming over the arterial
openings in the basal plate (Reynolds et al., 1968). In an equiva-
lent fashion, villus-free placental lakes are formed by the jet-like
inflow of blood from non-converted arteries. The force of this
inflow may also rupture the cell columns of the anchoring villi,
resulting in the placenta becoming thicker or more globular than
normal. This combination of changes affects the placental tex-
ture, rendering it ‘jelly-like’ and more ‘wobbly’ (Jauniaux et al.,
1994b, Jauniaux and Nicolaides, 1996, Toal et al., 2007) (Fig. 4).
These placentas are often associated with intrauterine growth
restriction. This may reflect excessive loss of villous tissue at the
time of onset of the circulation, but may also be due to impover-
ished growth during the second and third trimesters due to chronic
oxidative and other stresses induced through malperfusion of the
Placental growth during the second and third trimes-
The application of ultrasound imaging to obstetric practice in
the 1950s enabled the placenta to be visualised in vivo for the first
time in a safe and reproducible fashion. Longitudinal studies have
Fig. 3. Diagrammatic representation of villous regression associated
with onset of the maternal arterial circulation (small red circles) to
the placenta in normal and abnormal pregnancies. In normal pregnan-
cies flow starts in the periphery of the placenta and local oxidative stress,
depicted by red shading, leads to villous regression and formation of the
chorion laeve, shown in white. In cases of miscarriage onset of the
circulation occurs precociously and throughout the placental disc, leading
to overwhelming oxidative stress and pregnancy loss. An intermediate
state may occur if trophoblast invasion is particularly shallow in an area
of the placental bed. Early onset of flow in that region will cause excessive
villous regression, leading to abnormal placental shape and eccentric
Fig. 4. Diagrammatic representation of trophoblast invasion in
normal (A) and abnormal (B) pregnancies. In abnormal pregnancies
shallow invasion results in deficient plugging of the spiral arteries and
early onset of the maternal intraplacental circulation. The force of the jet-
like spurts of maternal blood damages the developing villi, rupturing the
cytotrophoblast cell columns of the anchoring villi. As a result the
placenta may be thicker than normal, and have an abnormal texture with
the presence of villus-free placental lakes. Reproduced from Johns et al.,
2006) with permission.
Intrauterine environment and placental development 307
revealed that placental development follows different trajectories
in normal and complicated pregnancies, and that these differ-
ences are established at the end of the first trimester. Thus in
cases of intrauterine growth restriction the placenta is smaller
than normal at 12 weeks but grows at the same rate thereafter. If
there is accompanying preeclampsia, however, the subsequent
rate of growth is slowed (Hafner et al., 2003). In cases of late-
onset preeclampsia placental size is often increased at 12 weeks,
but then the rate of growth slows between 16 and 20 weeks. The
importance of these trajectories in the causation of fetal growth
restriction is highlighted by the finding that fetal anthropometric
measurements are positively correlated with placental volume at
14 weeks and with the rate of placental growth between 17 and 20
weeks (Thame et al., 2004).
There are many potential non-genetic causes of intrauterine
growth restriction. On a world-wide basis maternal malnutrition is
still one of the principal reasons, but in developed countries it is
more usually the result of utero-placental malperfusion secondary
to incomplete spiral artery conversion (Brosens et al., 1977;
Gerretsen et al., 1981). Infection, metabolic disorders and endo-
crine disturbances can also be causative, and in experimental
animals growth restriction can be induced by heat stress, uterine
artery ligation or surgical reduction of the placental area (see
Fowden et al., 2008 for recent review). Recent advances are now
shedding light on the common molecular mechanisms by which a
variety of stressors can influence the rate of growth of cells and
tissues (Patel et al., 2002; Proud, 2007). Regulation of the cellular
protein synthetic machinery lies at the centre of this complex
network (Fig. 5), for without an adequate rate of protein synthesis
cells cannot enlarge sufficiently to be able to divide.
Regulation of the protein synthetic machinery
Protein synthesis demands a high energy supply, and esti-
mates suggest it accounts for approximately 30% of human
placental oxygen consumption (Carter, 2000). Indeed, placental
oxygen consumption is high compared to other tissues, reflecting
its considerable secretory and active transport functions. Thus,
when the supply of oxygen is reduced, either through vascular
compromise or exposure to hypobaric hypoxia at altitude, one
might expect the placenta to conserve energy by shutting down its
protein synthetic machinery. Equally, preventing protein transla-
tion in an infected cell is an effective host defence against the
establishment and spread of disease. Protein synthesis com-
prises three main stages; initiation, elongation and termination or
release. Each step is subject to a number of regulatory mecha-
nisms that are controlled by families of factors referred to in
eukaryotes as eIFs, eEFs and eRFs respectively. Of the three
stages, translation initiation is subject to the greatest degree of
control and can respond rapidly to changes in the cellular environ-
Regulatory phosphorylation of a member of the eIF family,
eIF2α, plays a key role in these responses. Translation is initiated
by the binding of eIF4E to the 5' cap of the mRNA, which in turn
leads to binding of other regulatory subunits and the recruitment
of the 40S subunit of the ribosome. This complex scans along the
5' UTR to locate the start codon. The methionyl initiator tRNA is
brought to the ribosome by another factor, eIF2, which is a GTP-
binding protein. During translation initiation the GTP is hydroly-
sed, and eIF2-GTP needs to be regenerated for the process to
continue. This requires eIF2B, a guanine-nucleotide-exchange-
factor, which is competitively inhibited by P-eIF2α. Hence, phos-
phorylation of eIF2α blocks recycling and protein translation (Fig.
Four serine/threonine protein kinases have been identified that
can phosphorylate eIF2α; GCN2 which is activated by uncharged
tRNAs and so is sensitive to amino acid depletion, the haem-
regulated inhibitor HRI which is responsive to hypoxia, the double-
stranded RNA-activated kinase PKR which is responsive to viral
infections, and PERK which is localised to the lumen of endoplas-
mic reticulum and activated by the accumulation of misfolded
proteins (Wek et al., 2006). In this way cells are able to modulate
the rate of protein synthesis rapidly to accommodate to a variety
of unfavourable stresses.
We have recently identified increased levels of phosphoryla-
tion of eIF2α in non-laboured placentas from cases of intrauterine
growth restriction with a uterine vascular aetiology compared to
normal controls, and to an even greater degree in cases associ-
ated with early-onset preeclampsia (Yung et al., 2008). We also
observed activation of PERK and both morphological and mo-
lecular evidence of endoplasmic reticulum stress, suggesting a
causal link. In support of that linkage, we have demonstrated that
the induction of endoplasmic reticulum stress in trophoblast-like
cell lines by ischaemia-reperfusion or tunicamycin results in a
major suppression of protein synthesis (Yung et al., 2007),
including translation of kinases such as AKT that play a central
role in cell proliferation. As a result the cells proliferate at a slower
rate, which in vivo would lead to the growth restricted placental
phenotype. In other cell systems it has been shown that levels of
cyclin D1 are reduced through translation inhibition secondary to
induction of endoplasmic reticulum stress (Brewer et al., 1999).
We observed a similar reduction in cyclin D1 in our growth
restricted placentas (Yung et al., 2008).
Placental endoplasmic reticulum and oxidative stress
The cause of the endoplasmic reticulum stress in these placen-
tas is not proven, but it is highly likely to be secondary to maternal
Fig. 5. Overview diagram of how various stressors can reduce the
rate of cell proliferation through inhibition of protein synthesis.
Several feed-forward systems can operate to make the situation worse.
For example, levels of autocrine growth factors and kinases of the AKT/
mTOR pathway may be reduced due to the blocks to translation, further
inhibiting protein synthesis.
308 G.J. Burton et al.
malperfusion. There is no doubt that the preeclamptic placenta
displays considerable evidence of oxidative stress (Hubel,
1999; Myatt and Cui, 2004), and it is generally assumed that the
same holds in cases of intrauterine growth restriction alone. We
recently proposed that the retention of smooth muscle within
the walls of the incompletely converted spiral arteries renders
them liable to spontaneous vasoconstriction, leading to fluctua-
tions in intraplacental oxygen concentrations. Experiments in
vitro have confirmed that hypoxia-reoxygenation is a powerful
inducer of oxidative stress, and that the pattern of stress
markers, such as nitrosylation of tyrosine residues, closely
matches that seen in preeclamptic placentas (Myatt et al.,
1996; Hung et al., 2001). Further support is provided by the
observation that placentas subjected to labour, when perfusion
is interrupted intermittently by the uterine contractions, display
higher levels of oxidative stress than non-laboured controls.
Furthermore, changes in the gene transcript profile closely
resemble those seen in preeclampsia (Cindrova-Davies et al.,
In other situations there is a close link between oxidative
stress, endoplasmic reticulum stress and ischaemia-reperfusion
injury (DeGracia and Montie, 2004; Cullinan and Diehl, 2006).
Both depletion of ATP and increased generation of reactive
oxygen species can cause the release of calcium from the
endoplasmic reticulum through the inhibition of ATP-depen-
dent ion pumps. Depletion of calcium within the lumen results
in loss of function of Ca2+-dependent chaperone proteins, such
as GRP78, resulting in protein misfolding and activation of the
unfolded protein response. One arm of that response aims to
inhibit the introduction of new proteins into the lumen of the
endoplasmic reticulum, and this is achieved through the action
of PERK on eIF2α.
The mTOR pathway as a central regulator of translational
Phosphorylation of eIF2α by PERK, or one of the other three
kinases, provides for rapid control of translation initiation, but
other stages of protein synthesis can also be regulated through
mTOR (mammalian target of rapamycin), a multidomain protein
that displays protein kinase activity (Proud, 2007). mTOR
functions to integrate extracellular signals from growth factors
and hormones with amino acid availability, intracellular energy
status and protein synthesis (Fingar and Blenis, 2004; Hay and
Sonenberg, 2004; Jansson and Powell, 2006). For example, it
is capable of regulating cap-dependent translation initiation by
controlling the binding of eIF4E to the mRNA. This control is
exerted through phosphorylation of a binding protein, 4E-BP1,
that in its unphosphorylated state associates with eIF4E and
prevents its interaction with the mRNA. We observed reduced
phosphorylation of 4E-BP1 in our growth restricted placentas
(Yung et al., 2008), indicating a second block to protein trans-
lation and suggesting activity of the mTOR pathway is reduced
in these cases (Fig. 6).
mTOR is regulated through the intermediate Rheb by the
dimeric TSC1/2 (tuberous sclerosis) complex, which in turn is
subject to regulatory phosphorylation by both AKT and AMPK.
AKT is activated by a variety of cytokines and growth factors
through the PI 3-kinase pathway, and stimulates mTOR through
its actions on TSC1/2 (Yang et al., 2004). AKT can also
phosphorylate mTOR directly, although the importance of this
is contentious (Sekulic et al., 2000). AMPK on the other hand is
activated by the accumulation of AMP and hence detects
energy depletion. Its actions are inhibitory to mTOR, suppress-
ing protein synthesis (Fig. 6).
There are three isoforms of AKT, each encoded by a sepa-
rate gene; AKT1, AKT2 and AKT3. We observed that the protein
level of each isoform was dramatically reduced in the growth
restricted placentas (Yung et al., 2008). The mRNA levels were
unchanged, however, indicating that these kinases were them-
selves affected by the general protein synthesis inhibition
observed in these placentas. A feed-forward cycle may there-
fore be established, possibly initiated by phosphorylation of
eIF2α but leading to reduced activity in the AKT/mTOR pathway
(Fig. 5). Genetic knockout of Akt1 in the mouse results in
placental and fetal growth retardation (Yang et al., 2003), and
we observed a strong correlation between levels of P-Akt and
placental weight in both mutant and wild type mice.
Other adverse feed-forward cycles affecting the mTOR path-
way may also occur as a result of the translation inhibition
observed. Thus, IGF2 protein level was reduced by approxi-
mately 70%, suggesting that autocrine signalling is severely
compromised, and this was reflected by a reduction in phospho-
rylation of PDK1, accompanied by a fall in total PDK1 in the
growth restricted placentas (Yung H-W, unpublished data).
IGF2 is one of the principal autocrine growth factors secreted by
the placenta. The gene has several promoters, including one in
the mouse specific to the trophoblast, the P0 promoter. The
importance of IGF2 to normal placental development was
confirmed by the observation that genetic ablation of the P0
promoter alone results initially in growth restriction of the
Fig. 6. A diagrammatic representation of the principal molecular
mechanisms regulating protein translation initiation and elonga-
tion. Initiation may be regulated by blocking the activity of eIF4E by
preventing the recycling of eIF2-GDP (1), or preventing eIF4E from
binding to the 5´-cap region of the mRNA through the action of binding
proteins (2). The elongation phase can be regulated by the action of eEF2
kinase (3). We have observed blocks (1) and (2) to be operative in growth
restricted placentas (Yung et al., 2008).
Intrauterine environment and placental development 309
placenta, which is followed later in pregnancy by growth restric-
tion of the fetus (Constancia et al., 2002).
Other blocks to protein synthesis
Depletion of AKT can also inhibit translation initiation indepen-
dent of the mTOR pathway by preventing the recycling of eIF2. As
described earlier eIF2B is required to regenerate eIF2-GTP. One
of the subunits of eIF2B, epsilon, is subject to regulatory phospho-
rylation by GSK-3, which in turn is a substrate for AKT. Hence,
both P-eIF2α and reduced AKT activity can block initiation (Fig.
The elongation phase of protein synthesis involving the eEF2
family is one of the principal sites of regulation by the mTOR
pathway, acting through eEF2 kinase. This can also be directly
affected by AMPK (Fig. 6). We observed both reduced activation
and reduced total level of eEF2K in the growth restricted placen-
tas, suggesting that the elongation phase of protein synthesis
may remain active. This may explain why some placental pro-
teins, such as leptin and soluble fms-like tyrosine kinase (sFLT),
are markedly increased in preeclampsia and following acute
oxidative stress (Levine et al., 2004; Laivuori et al., 2006; Cindrova-
Davies et al., 2007a). The associated rise in their mRNAs sug-
gests a combination of both transcriptional and translational
activation (Tsatsaris et al., 2003; Laivuori et al., 2006). It has been
reported that mRNAs containing small upstream open reading
frames within their promoter regions or internal ribosome entry
sites are selectively translated independent of eIF-2α regulation
(Harding et al., 2000; Lu et al., 2004). To date, there are no
published reports of these sequences within the promoter regions
of the leptin and sFLT genes. However, we found three in-frame
upstream open reading frames in the 5’UTR of the leptin mRNA,
and consensus motifs for internal ribosome entry sites in the
5’UTR of sFLT1 mRNA (Yung H-W, unpublished data). These
observations suggest potential bypass mechanisms exist in both
the leptin and sFLT1 promoters that allow their mRNAs to be
translated even when initiation is inhibited by P-eIF2α. Further
promoter analysis is required to confirm these findings.
There is no doubt that placental development is influenced
heavily by the intrauterine environment. Previously, in the human
this has been considered relatively stable throughout pregnancy,
but the realisation that the maternal arterial circulation to the
placenta is not fully established until the end of the first trimester
has led to a radical revision of our understanding. The accompa-
nying rise in oxygenation poses a major challenge to the placental
tissues, and temporo-spatial differences in the opening of the
spiral arteries are now considered to be a key factor in promoting
villous regression and formation of the chorion laeve. Later in
pregnancy, a variety of insults, including oxygen and nutrient
deprivation, can result in growth restriction. Protein synthesis
inhibition provides a common mechanism by which these can act,
although there are many potential pathways involved with consid-
erable interconnections. We have recently identified placental
endoplasmic reticulum stress as a key step in the pathophysiol-
ogy of unexplained intrauterine growth restriction, and speculate
that this arises secondary to malperfusion. Poor trophoblast
invasion leading to deficient plugging and physiological conver-
sion of the spiral arteries provides a common link between
abnormal villous regression at the end of the first trimester and
impoverished growth of the placenta in the second and third
trimesters. Understanding the factors regulating trophoblast inva-
sion and the molecular mechanisms underlying physiological
conversion remains one of the major challenges for contemporary
The authors are most grateful to Drs Tereza Cindrova-Davies and
Hong-Wa Yung, and to all their collaborators for their input into these
studies. The work has been supported by the Wellcome Trust, the Medical
Research Council, WellBeing and Tommy’s, the baby charity.
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