Chapter Eight - Regulation of Placental Amino Acid Transport and Fetal Growth

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Abstract

The fetus requires amino acids for the processes of protein synthesis, carbon accretion, oxidative metabolism, and biosynthesis, which ultimately determine growth rate in utero. The fetal supply of amino acids is critically dependent on the transport capacity of the placenta. System A amino acid transporters in the syncytiotrophoblast microvillous plasma membrane, directed toward maternal blood, actively accumulate amino acids, while system L exchangers mediate uptake of essential amino acids from the maternal circulation. The functional capacity and protein abundance of these transporters in the placenta are related to fetal growth in both humans and experimental animals. Maternal nutritional and endocrine signals including insulin, insulin-like growth factors, adipokines, and steroid hormones regulate placental amino acid transport, against the background of growth signals originating from the fetus. Anabolic signals of abundant maternal resource availability stimulate placental amino acid transport to optimize offspring fitness, whereas catabolic signals reduce placental amino acid transport in an attempt to ensure survival and long-term reproductive capacity of the mother when resources are scarce. These signals regulate placental amino acid transport by controlling transcription, translation, plasma membrane trafficking, and degradation of transporters. Adaptations in placental amino acid transport capacity may underlie either under- or overgrowth of the fetus when maternal nutrient and hormone levels are altered as a result of altered maternal nutrition or metabolic disease. Strategies to modulate placental amino acid transport may prove effective to normalize fetal growth in intrauterine growth restriction and fetal overgrowth.

Introduction

Fetal growth is a major determinant of pregnancy outcome and lifelong health. Both restricted and excessive growth in utero are associated with increased perinatal morbidity and mortality.1, 2 Moreover, birth weight predicts lifelong risk of cardiovascular and metabolic disease.3 Fetal growth requires accretion of a net quantity of protein, synthesized entirely from the umbilical supply of amino acids.4 To meet the needs of rapid fetal protein synthesis, particularly in skeletal muscle, liver, and gut, amino acids must be supplied at a rate estimated to be between 10 and 60 g/day per kg fetus.5, 6 Amino acids taken up by the fetus are also used for oxidative production of ATP, carbon accretion, interorgan nitrogen cycling and in the biosynthesis of other molecules including haem, porphyrins, nitric oxide, neurotransmitters, and nucleotides.7, 8 All of these requirements must be satisfied by placental transfer of amino acids from the mother to the fetus. Moreover, as in postnatal life, essential amino acids cannot be synthesized by the fetus and must therefore be derived directly from the maternal circulation. Hence, total placental amino acid delivery and fetal availability of specific amino acids are direct determinants of the rate of fetal growth. This is supported by studies showing plasma amino acid concentrations tend to be lower in human fetuses that are growth restricted,9, 10 and fetal uptake of essential amino acids has been reported to be reduced in growth-restricted fetuses both in humans and experimental animals.11, 12, 13, 14

Several biophysical factors determine the net fetal umbilical uptake of each individual amino acid. The fetal concentration of some amino acids is correlated with maternal concentrations.10 However, because uptake of amino acids from the uteroplacental circulation is carrier mediated, the rate of total amino acid uptake is influenced by the absolute size and surface area of the placenta, and the rate of uterine blood flow. Amino acids taken up by the syncytiotrophoblast from the maternal circulation may either be transferred directly to the fetus or utilized in oxidative or anabolic processes within the placenta. Therefore, the net umbilical uptake rate of each amino acid also depends upon its rate of metabolism within the placenta.12, 15 In some cases, placental amino acid metabolism may be an important mechanism by which the fetus obtains certain amino acids. For example, there is net placental uptake of glutamate from both the maternal and fetal circulations, and this glutamate is converted into glycine and released to the fetus.16, 17 The regulation of placental morphology and metabolism and their importance in determining fetal growth rates have been reviewed in detail recently.18, 19 This review will provide an overview of mechanisms of placental amino acid transport across the maternal blood/trophoblast interface and their importance for fetal growth. It will also examine the various endocrine and nutritional factors known to alter rates of placental amino acid transport and the molecular mechanisms that may underlie these processes, with particular emphasis on the haemochorial placentae of humans, nonhuman primates, and rodents.

Section snippets

Placental Amino Acid Transport and Fetal Growth

Concentrations of most amino acids are higher in fetal plasma than in maternal plasma, indicating that they are actively accumulated across the syncytiotrophoblast, the transporting and hormone-producing epithelium of the human placenta.9, 20 Such directional transfer requires the coordinated action of more than 20 different amino acid transporter proteins localized both to the maternal and fetal facing plasma membrane of the epithelium.8, 21, 22 These proteins may be broadly classified as

Physiological Regulators of Placental Amino Acid Transport

Growth in utero is regulated by several endocrine and metabolic signals, including insulin, insulin-like growth factor (IGF)-I and -II, adipose-derived cytokines (adipokines), and glucocorticoids.56, 57, 58, 59, 60 Abnormal fetal growth is often associated with perturbations in the levels of these signals in either the mother, the fetus, or both. Because fetal growth is ultimately dependent upon placental nutrient delivery and the placenta expresses receptors for the endocrine growth regulators,

Molecular Mechanisms Underlying Regulation of Placental Amino Acid Transport

Active transplacental transport of amino acids depends upon the abundance of amino acid transporters at the trophoblast apical plasma membrane. In turn, rates of uptake of nutrients depend on transcription, translation, membrane trafficking, and degradation of the transporter genes and proteins. There is evidence that these processes are regulated by nutritional and hormonal cues, but, in a number of studies, alterations in placental amino acid transporter activity are not associated with

Conclusions and Translational Perspectives

Amino acid transport across the syncytial epithelium of the placenta is a highly regulated process that is dependent on a number of nutritional and hormonal signals (Fig. 3). In general, anabolic signals indicating abundant maternal fuel reserves stimulate placental transport of amino acids, thereby increasing their availability for fetal growth and optimizing offspring fitness. When nutritional conditions are poor and resources are scarce, catabolic signals in the mother downregulate placental

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