Elsevier

Placenta

Volume 27, Supplement, April 2006, Pages 91-97
Placenta

IFPA 2005 Award in Placentology Lecture
Human Placental Transport in Altered Fetal Growth: Does the Placenta Function as a Nutrient Sensor? – A Review

https://doi.org/10.1016/j.placenta.2005.11.010Get rights and content

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.

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 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 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.

Section snippets

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

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:

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

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 sodium-proton 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 Na+K+ ATPase activity is decreased in IUGR, which may result in an impaired driving force for a range of Na+ dependent transport

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

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

Regulation of placental nutrient and ion transporters

The findings of altered activity and expression of placental transporters in pregnancies complicated by abnormal fetal 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

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 (Table 1, Table 2) indicate the opposite. We have recently developed a working hypothesis that we believe

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

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 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

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