Placenta (2006), Vol. 27, Supplement A, Trophoblast Research, Vol. 20
doi:10.1016/j.placenta.2005.11.010
IFPA 2005 AWARD IN PLACENTOLOGY LECTURE
Human Placental Transport in Altered Fetal Growth: Does
the Placenta Function as a Nutrient Sensor? – A Review
T. Janssona,b,* and T. L. Powella,b
a
Department of Obstetrics and Gynecology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way,
PO Box 670526, Cincinnati, OH 45267, USA; b Perinatal Center, Department of Physiology, Göteborg University, Sweden
Paper accepted 28 November 2005
Intrauterine growth restriction is associated with a range of alterations in placental transport functions: the activity of a number of
transporters is reduced (Systems A, L and Tau, transporters for cationic amino acids, the sodium-proton exchanger and the
sodium pump), placental glucose transporter activity and expression are unchanged whereas the activity of the calcium pump is
increased. In contrast, accelerated fetal growth in association to diabetes is characterized by increased activity of placental Systems
A and L and glucose transporters. Evidence suggests that these placental transport alterations are the result of specific regulation
and that they, at least in part, contribute to the development of pathological fetal growth rather than representing a consequence to
altered fetal growth. One interpretation of this data is that the placenta functions as a nutrient sensor, altering placental transport
functions according to the ability of the maternal supply line to provide nutrients. Placental transporters are subjected to
regulation by hormones. Insulin up-regulates several key placental transporters and maternal insulin may represent a ‘‘good
nutrition’’ signal to increase placental nutrient transfer and the growth of the fetus. Preliminary evidence suggests that placental
mammalian target of rapamycin, a protein kinase regulating protein translation and transcription in response to nutrient stimuli,
may be involved in placental nutrient sensing.
Placenta (2005), Vol. 27, Supplement A, Trophoblast Research, Vol. 20
Ó 2005 Published by IFPA and Elsevier Ltd.
Keywords: Maternalefetal exchange; Placenta/metabolism; Fetal growth restriction; Diabetes; Pregnancy
INTRODUCTION
Intrauterine growth restriction (IUGR) constitutes an important clinical problem associated with increased perinatal
morbidity [1], higher incidence of neuro-developmental
impairment [2] and increased risk of adult disease, such as
diabetes and cardiovascular disease [3,4]. Similarly fetal
overgrowth, resulting in the delivery of a large-for-gestational
age baby (LGA), represents a risk factor for operative delivery,
traumatic birth injury [5] and developing diabetes and obesity
later in life [6,7]. Thus, the adverse consequences of altered
fetal growth are not limited to the perinatal period and the
concept of an important developmental origin of adult disease
may have a profound impact on public health strategies for the
* Corresponding author. Department of Obstetrics and Gynecology,
University of Cincinnati, College of Medicine, 231 Albert Sabin Way,
PO Box 670526, Cincinnati, OH 45267, USA. Tel.: C1 513 558 7655;
fax: C1 513 558 6138.
E-mail address: Thomas.jansson@uc.edu (T. Jansson).
0143e4004/$esee front matter
prevention of major illnesses. Currently, no specific strategies
for treatment and intervention are available in cases of altered
fetal growth, and in order to make significant progress in this
area a better understanding of the underlying pathophysiological mechanisms is needed.
The growth restricted human fetus has reduced plasma
concentrations of certain key amino acids [8] and some are
hypoglycemic and hypoxic in utero [9]. Although generally
accepted that IUGR is associated with limitations in nutrient
and oxygen supply, the mechanisms involved remain to be fully
established. Similarly, the fetal overgrowth often observed in
pregnancies complicated by diabetes has been attributed to
an excess glucose delivery to the fetus due to maternal
hyperglycemia [10]. However, in modern clinical management
of the pregnant woman with diabetes, maternal glucose levels
are rigorously controlled throughout second and third trimesters suggesting that there are mechanisms other than maternal
hyperglycemia that contributes to fetal overgrowth in these
pregnancies. In this paper we will briefly review recent
advances in the study of human placental transport functions
Ó 2005 Published by IFPA and Elsevier Ltd.
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Placenta (2006), Vol. 27, Supplement A, Trophoblast Research, Vol. 20
in association to altered fetal growth. These findings suggest
that alterations in the expression and activity of placental
nutrient and ion transporters may play a key role in regulating
fetal growth in normal and complicated pregnancies.
PLACENTAL BLOOD FLOW IS REDUCED
IN IUGR
Measurements of maternal placental blood flow and volume
blood flow in the umbilical circulation clearly suggest that
blood flows are reduced on both sides of the placental exchange
barrier in association with IUGR. However, it is unlikely that
the blood flow reduction is a sufficient explanation for the
reduced levels of various nutrients in the fetal circulation. In
general, the transfer of a molecule across a barrier may be
limited by the actual diffusion (diffusion-limitation) or by the
rate by which the molecule is supplied to and removed from
the barrier by blood flow (blood flow-limitation). An example
of a molecule subjected to blood flow-limited transport is
oxygen, which is a highly lipophilic and a relatively small
molecule that diffuses across the placental barrier without
difficulty. Thus, it is likely that the reduction in placental
blood flows contribute to fetal hypoxia in IUGR. In contrast,
transplacental transport of nutrients such as glucose and amino
acids will be less affected by changes in blood flow since the
transport across the barrier is the primary limiting factor for
the transfer of these molecules.
ARE PLACENTAL TRANSPORT FUNCTIONS
ALTERED IN IUGR?
Given the diffusion-limitation of nutrient transport across the
human placenta it was hypothesized that IUGR is associated
with alterations in the activity of placental transporters which
may contribute to the growth restriction. This hypothesis has
been tested in experimental systems from the human placenta,
primarily isolated syncytiotrophoblast plasma membranes. In
the human placenta there are two cell layers between the
maternal blood in the intervillous space and in the fetal
circulation: the syncytiotrophoblast transporting epithelium
and the fetal capillary endothelium (Figure 1). Human
placental capillaries closely resemble other non-brain continuous capillaries, having wide paracellular clefts [11] which
allow relatively unrestricted transfer of molecules like glucose
and amino acids across the capillary wall. Instead, it is the two
polarized plasma membranes of the syncytiotrophoblast that
represent the primary barrier for transplacental transfer of
nutrients and most ions. The plasma membrane directed
towards the maternal blood is the microvillous membrane
(MVM) whereas the basal plasma membrane (BM) faces the
fetal capillaries (Figure 1). Thus, studies of the transport
characteristics of isolated syncytiotrophoblast plasma membranes may provide important information on transplacental
transport in normal and complicated pregnancies.
Figure 1. A simplified representation of the placental barrier in the human.
The transplacental transport of nutrients and most ions is primarily
restricted by the transport characteristics of the two polarized plasma
membranes (MVM: microvillous membrane, BM: basal membrane) of the
syncytiotrophoblast (ST). (- - - - - - - -) represents the pathway for exchange
between the maternal circulation (intervillous space) and the fetal capillary.
REDUCED ACTIVITY OF PLACENTAL
AMINO ACID TRANSPORTERS IN IUGR
Glucose transporter isoform 1 (GLUT 1) is the primary
transporter mediating facilitated glucose transfer across the
human placental barrier in the second half of pregnancy and
glucose movement across BM appears to be the rate-limiting
step [12,13]. Fetal hypoglycemia in IUGR is unlikely to be due
to changes in placental glucose transporters since both GLUT
1 protein expression and glucose transport activity in
syncytiotrophoblast plasma membranes have been reported
to be unaltered in IUGR [12,13].
Transport of amino acids across the human placenta is an
active process resulting in amino acid concentrations in the
fetal circulation that are substantially higher than those in
maternal plasma. In IUGR, the activity of System A, a NaCdependent transporter mediating the uptake of non-essential
neutral amino acids, is markedly reduced in MVM [14,15],
especially in IUGR babies who are delivered prematurely [13].
In addition, the activity of a number of placental transport
systems for essential amino acids, such as lysine, leucine [16]
and taurine [17], is reduced in MVM and/or BM isolated
from IUGR placentas. These in vitro findings are compatible
with a recent study in pregnant women in which Paolini et al.
demonstrated, using stable isotope techniques, that placental
transfer of the essential amino acids leucine and phenylalanine
is reduced in IUGR [18]. The down-regulation of placental
amino acid transporters in IUGR results in a decreased
delivery of amino acids to the fetus and is likely to be an
important factor causing the low fetal plasma concentrations of
Jansson and Powell: Placental Transport in IUGR and LGA
certain amino acids in this pregnancy complication. Amino
acids are, together with glucose, the primary stimulus for
secretion of fetal insulin, probably the most important growthpromoting hormone in utero. Therefore, it appears that there
is a direct link between down-regulation of placental amino
acid transporters and restricted fetal growth in IUGR.
The IUGR fetus is typically characterized by having
markedly decreased subcutaneous fat depots, contributing to
the thin appearance of the IUGR newborn. This may be due to
decreased fetal fat synthesis and/or reduced placental transfer
of free fatty acids. Indeed, a recent report demonstrates that
the activity of MVM lipoprotein lipase, the first critical step in
transplacental transfer of free fatty acids, is reduced in IUGR
[19]. These data are in line with clinical studies showing lower
fetal/maternal ratios for long-chain polyunsaturated fatty acids
in IUGR [20]. However, the cellular mechanisms mediating
free fatty acid movement across the placenta remain to be fully
established and placental fatty acid transport has not been
studied in IUGR.
ALTERATIONS IN PLACENTAL ION
TRANSPORT IN IUGR
A subgroup of IUGR fetuses displays signs of chronic acidosis
in utero [21]. The activity and expression of the sodiumproton exchanger, the primary pH-regulating transporter in
the syncytiotrophoblast, are reduced in association with IUGR
[14,22] and we speculate that these alterations contribute to the
development of acidosis in these fetuses. Furthermore, MVM
NaCKC ATPase activity is decreased in IUGR, which may
result in an impaired driving force for a range of NaC
dependent transport processes in the placenta [23]. Postnatally
IUGR is associated with reduced bone mineralization both in
childhood [24] and in adult age [25] and there is a possible link
between restricted fetal growth and osteoporosis later in life. In
the third trimester there is a rapid mineralization of fetal bone,
a process crucially dependent on an efficient transport of
calcium across the placenta. Interestingly, the activity of BM
Ca2C ATPase is markedly increased in IUGR possibly due to
elevated fetal levels of an active fragment of parathyroid
hormone related peptide (PTHrp 38e94) [26]. The upregulation of a key component of the placental Ca2C
transporting system may represent a response to an increased
Ca2C demand in relation to placental size in IUGR due to the
asymmetric growth in this condition. In IUGR, fetal and
placental weights are often reduced to a similar degree whereas
fetal length, related to bone mass, is relatively preserved.
Thus, a smaller placenta has to supply Ca2C for a near-normal
bone mass, requiring up-regulation of placental Ca2C transport [26]. If this interpretation of data is correct, compensatory
changes in placental Ca2C transfer remain insufficient considering the link between IUGR and reduced bone mineralization. Reported alterations in the activity of nutrient and ion
transporters in the human placental barrier in association with
IUGR are summarized in Table 1.
S93
Table 1. Summary of reported alterations in the activity of nutrient
and ion transporters in the human placental barrier in association with
IUGR
IUGR
Transport system
System A
Taurine
Lysine
Leucine
Glucose
Ca2C ATPase
NaC/HC exchanger
NaCKC ATPase
Lipoprotein lipase
MVM
BM
References
Y
Y
4
Y
4
e
Y
Y
Y
4
4
Y
Y
4
[
e
4
e
[13e15]
[17,47]
[16,57]
[16]
[12,13]
[26]
[14,22]
[23]
[19]
Increased ([), unaltered (4) or reduced (Y) transporter activity in isolated
microvillous plasma membrane (MVM) and basal plasma membrane (BM)
vesicles.
PLACENTAL NUTRIENT TRANSFER IS
INCREASED IN FETAL OVERGROWTH
Transplacental transport of glucose is a facilitated process and
net transfer is therefore strongly dependent on the concentration
gradient of glucose between maternal and fetal blood. Pedersen
proposed some 50 years ago that fetal overgrowth (‘‘macrosomia’’) in association with diabetes is caused by maternal
hyperglycemia that increases net transfer of glucose to the fetus,
resulting in increased fetal insulin secretion and growth [10].
However, despite marked improvements in the clinical
management of these patients with strict maternal blood glucose
control the incidence of LGA babies in pregnancies complicated
by diabetes remains surprisingly high. In fact, the correlation
between various indices of maternal glucose control and fetal
growth is poor, suggesting that other factors than maternal
hyperglycemia may contribute to accelerated fetal growth. One
possibility is that diabetes affects placental transport functions.
Indeed, placental glucose transport capacity [27,28] and the
activity of placental LPL [19] have been reported to be increased
in insulin-dependent diabetes (IDDM) associated with accelerated fetal growth, but not in gestational diabetes (GD) [19,29].
Thus, up-regulation of placental glucose transporters in IDDM
may contribute to increased placental glucose transfer and
stimulate fetal growth even if the mother is normoglycemic. The
activity of the placental amino acid transporter System A is
increased in diabetes, independent of accelerated fetal growth
and placental transport of leucine is increased in GD
pregnancies [30]. In contrast to these findings, a previous study
indicated that System A activity is reduced and the activity of
System L is unaltered in microvillous plasma membrane vesicles
isolated from IDDM pregnancies with LGA babies [31]. These
two studies were carried out in different populations and,
notably, placental weight was increased in parallel to fetal weight
in one study [30] whereas placental weight was largely
unaffected in the other [31]. Thus, the placental response to
Placenta (2006), Vol. 27, Supplement A, Trophoblast Research, Vol. 20
S94
metabolic disease may differ between study populations
although outcome with regard to fetal weight is the same.
Reported alterations in the activity of nutrient and ion
transporters in the human placental barrier in association with
fetal overgrowth in diabetes are summarized in Table 2. Collectively, these findings suggest that diabetes in pregnancy is
associated with enhanced placental capacity for nutrient transfer.
ARE THE ALTERATIONS IN PLACENTAL
TRANSPORT SPECIFIC?
One possible explanation to the observed changes in placental
transporter expression and/or activity is that they are the
result of a generalized pathological effect on, e.g., the
properties of the plasma membranes in which the transporters
are embedded. However, no marked differences in cholesterol
content, FFA composition, membrane fluidity, or passive
permeability in IUGR as compared to AGA syncytiotrophoblast plasma membranes have been reported [32]. In addition,
the findings that various transporter activities may be either
decreased, unchanged or increased in the one and same
pregnancy complication (IUGR) strongly argues against this
possibility. Furthermore, alterations in transporter function
are commonly observed in only one of the two polarized
plasma membranes of the syncytiotrophoblast. Thus, we argue
that reported changes in transport activities in syncytiotrophoblast plasma membranes in IUGR and fetal overgrowth in
association with diabetes are the result of specific regulation.
REGULATION OF PLACENTAL NUTRIENT
AND ION TRANSPORTERS
The findings of altered activity and expression of placental
transporters in pregnancies complicated by abnormal fetal
Table 2. Summary of reported alterations in the activity of nutrient
and ion transporters in the human placental barrier in association with
fetal overgrowth in diabetes
Fetal overgrowth
Transport system
System A
Taurine
Lysine
Leucine
Glucose
Ca2C ATPase
NaC/HC exchanger
NaCKC ATPase
Lipoprotein lipase
MVM
BM
References
[
4
4
[a
4
e
4
4
[
4
4
4
4
[b
[
e
4
e
[30],c
[30]
[30]
[30],c
[27e29]
[26]
[31]
[58]
[19]
Increased ([), unaltered (4) or reduced (Y) transporter activity in isolated
microvillous plasma membrane (MVM) and basal plasma membrane (BM)
vesicles.
a
Only GD.
b
Only IDDM.
c
Different results have been reported by others [31], see text.
growth have stimulated interest in regulation studies.
Although our understanding of the regulation of placental
transporters remains incomplete and warrants further studies,
some pieces of information are available. Glucocorticoids
decrease the expression of placental glucose transporters [33].
Most of the previous studies [34], but not all [35], show that
insulin does not affect placental glucose transporters at term.
In a first trimester trophoblast cell line glucose transport
activity was increased after 1 h of incubation with insulin,
IGF-I or IGF-II [36,37]. We recently demonstrated that
human placental glucose transporter activity was not affected
by hormones such as leptin, GH, IGF-I, insulin and cortisol,
at term [38]. However, in first trimester, insulin stimulated
mediated glucose uptake at 6e8 weeks of gestation [39]. We
have shown the presence of the insulin-sensitive glucose
transporter GLUT 4 in the cytosol and microvillous plasma
membranes of the syncytiotrophoblast in first trimester [39].
This is the first report of localization of GLUT 4 to the
transporting epithelium of the human placenta.
IGF-I has been shown to stimulate System A uptake in
cultured trophoblast cells [37,40,41]. Similarly, insulin
increases transport of neutral amino acids in the perfused
human lobule [42] and in cultured trophoblast cells [37,43]. In
addition, System A transporter activity and expression are
down-regulated by hypoxia [44]. We reported that a 1-h
incubation with leptin and insulin stimulated System A
activity uptake by 50e60% in primary villous fragments at
term [45]. Furthermore, nitric oxide and oxygen radicals have
been shown to reduce the activity of several placental amino
acid transporters [46,47]. The mechanisms of regulation of
placental ion transporters are largely unknown, however, the
basal plasma membrane Ca2C ATPase is stimulated by the
fetal hormone PTHrp 38e94 [48].
DOES THE PLACENTA FUNCTION
AS A NUTRIENT SENSOR?
In a situation, such as IUGR, where fetal plasma concentrations
of amino acids are decreased it might be expected that placental
transporters will be up-regulated in an attempt to increase
transport. Similarly, in situations with maternal (and fetal)
hyperglycemia (diabetes) a down-regulation of placental glucose
transporters may seem appropriate. However, the data reviewed
in this paper (Tables 1 and 2) indicate the opposite. We have
recently developed a working hypothesis that we believe takes
into account the data that we, and others, have obtained and
provides a testable model for further study. We have suggested
that the placenta may act as a nutrient sensor, coordinating
nutrient transport functions with maternal nutrient availability
[49]. According to this hypothesis the ability of the maternal
supply line to deliver nutrients (i.e., placental blood flow,
maternal nutrition, substrate and oxygen levels in maternal
blood etc.) regulates key placental nutrient transporters
(Figure 2). With this perspective placental transport alterations
represent a mechanism to match fetal growth rate to a level
which is compatible with the amount of nutrients that can be
Jansson and Powell: Placental Transport in IUGR and LGA
S95
Figure 2. Does the placenta function as a nutrient sensor? The figure illustrates the hypothesis that placental nutrient and ion transporters are regulated in
response to a primary event, such as a lack of increase in placental blood flow, maternal malnutrition or hyperglycemia. Alterations in placental transport activity
result in changes in nutrient delivery to the fetus which, in turn, affects fetal growth. Hormones produced by the placenta or the mother, hypoxia and nutrient
sensing mechanisms ‘‘intrinsic’’ to the placenta (such as mammalian target of rapamycin-mTOR) may be involved.
provided by the maternal supply line. In the case of IUGR the
placenta may register a lack of normal increase in placental blood
flow or maternal malnutrition and as a consequence some key
placental transporters are down-regulated in order to decrease
fetal growth. Similarly, hyperglycemia early in pregnancy
(which is common even in the well-regulated IDDM patient)
may convey a ‘‘good nutrition’’ signal to the placenta resulting
in up-regulation of glucose and amino acid transporters.
The placental nutrient sensor hypothesis discussed in this
review concerns interactions between the ability of the
maternal supply line to deliver nutrients to the placenta and
placental supply capacity. Fetal demand may also modify
placental nutrient transport capacity, interactions that may be
mediated by imprinted genes, such as the Igf2 gene, as recently
proposed by Reik et al. [50].
POSSIBLE MECHANISMS INVOLVED IN
PLACENTAL NUTRIENT SENSING
The mechanisms conveying information about the ability of
the maternal supply line to deliver nutrients and regulating
placental nutrient transporters remain speculative. However, it
is likely that the activity of key placental nutrient transporters
in a particular situation represents an integrated response
dependent on information from a number of signalling
pathways. For example, we propose that maternal nutrition
influences placental transporters and fetal growth by altering
the levels of metabolic hormones such as insulin, IGF-I and
leptin, which all have been shown to regulate placental
nutrient transporters [37,39e41,43,45]. In IUGR, a pregnancy
complication associated with reduced placental blood flow,
hypoxia may also down-regulate placental amino acid transporters [44]. In addition, we have recently pursued the
possibility that the mammalian target of rapamycin (mTOR)
signalling system represents an ‘‘intrinsic’’ placental nutrient
sensing mechanism. mTOR is a serine/threonine kinase and
represents an important nutrient sensing pathway in mammalian cells by controlling cell growth through regulation of
translation and transcription in response to nutrient availability, in particular branched chain amino acids [51], hypoxia [52]
and cellular energy status [53]. The down-stream effects of
mTOR are mediated by phosphorylation of 4E-BP1 (eukaryotic initiation factor 4E binding protein 1) and S6K (p70 S6
kinase) [54]. Our preliminary data indicate that mTOR protein
is highly expressed in the cytosol of the syncytiotrophoblast,
that mTOR regulates placental transport of the essential amino
acid leucine, and that placental mTOR expression is related to
fetal growth in pregnancy complications [55]. Thus, these initial
observations are compatible with the hypothesis that placental
mTOR is involved in nutrient sensing, regulating placental
transport according to resources available in the maternal
supply line. Future research will prove or reject this hypothesis.
POSSIBLE CLINICAL IMPLICATIONS
Recently it was proposed that the placental transporter
alterations in IUGR, summarized in Table 1, represent
a placental transport ‘‘phenotype’’ characteristic for intrauterine under-nutrition [56]. This phenotype could, for example,
be used to differentiate between an IUGR baby (pathological
Placenta (2006), Vol. 27, Supplement A, Trophoblast Research, Vol. 20
S96
transport phenotype) and a constitutionally small baby (normal
transport phenotype), thereby providing a diagnostic tool to
identify small-for-gestational age babies that have been
subjected to restricted growth in utero. Fetal under-nutrition
is a risk factor for adult disease such as diabetes and
cardiovascular disease. However, birth weight is a very crude
proxy for nutrition in fetal life and it is possible that the
placental transport phenotype may provide better information
with regard to postnatal prognosis and long-term consequences.
No specific treatment is currently available in cases of
altered fetal growth. In IUGR, a number of strategies for
intervention to alleviate placental insufficiency have been
proposed, including maternal IGF-I administration and
modulation of maternal diet. The detailed information on
placental transport alterations in IUGR and the increased
understanding of the mechanisms regulating placental nutrient
transporters will facilitate the development of efficient
interventions in the near future.
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