Decreased placental amino acid transport and intrauterine growth restriction: which is the chicken and which is the egg?

Abstract

Intrauterine growth restriction (IUGR) is one of the major problems of pregnancy. IUGR is associated with a 5- to 20-fold increase in perinatal mortality (McIntire et al. 1999; Berstein et al. 2000). In addition, 40–50% of IUGR babies require neonatal intensive care (Lackman et al. 2001). While there are many causes of IUGR, the underlying pathology is a failure of adequate placental transfer of nutrients from mother to fetus. In this issue of The Journal of Physiology, Jansson et al. (2006) address a basic question relating to the mechanisms underlying poor fetal growth that has intrigued researchers and clinicians for many years, namely, is there evidence for a failure of placental nutrient transport prior to the start of growth restriction or are decreases in placental function, particularly nutrient transfer, secondary to the slowing of fetal growth? To answer this question, the authors have studied placental amino acid and glucose transport in a well established model of low protein, isocaloric nutritional restriction in the pregnant rat that impairs fetal growth. While previous researchers have shown that protein restriction down-regulates the activity of transporters for both the system A and cationic amino acids (Malandro et al. 1996), Jansson et al. (2006) provide the first data to show that a decrease in placental amino acid transport precedes IUGR and hence is likely to be a contributing cause rather then merely a secondary consequence of it. They demonstrate decreased amino acid, but not glucose, transfer to the fetus at day 19 of gestation, prior to the development of IUGR at day 21. There are three placental subtypes of the system A amino acid transporter, SNAT1, SNAT2 and SNAT4, which mediate the transport of neutral amino acids. This system is regulated by key growth factors such as insulin, leptin, cortisol and IGF1. The strength of the present study is that it provides firm data for total placental amino acid and glucose transport in awake, chronically catheterized animals as well as evaluating mRNA expression for SNATs 1, 2 and 4, and protein expression of SNAT2. Such in vivo data are indispensable to a determination of the full phenotype. At 19 days of gestation there was no significant difference between the control and low protein pregnancies in litter size, fetal weight or placental weight. However, fetal and placental weights were decreased by 21 days of gestation. The relative placental transport of the inert amino acid methylaminoisobutyric acid measured in the chronically instrumented non-anaesthetized pregnant rat was decreased by 25% (P < 0.05) in the low protein pregnancies at 19 days of gestation compared with controls. The data indicate the reduction in placental system A transport precedes the development of IUGR in this model. There was some discrepancy in the expressed changes in mRNA and protein for SNAT2; the former was decreased in a low protein group on the 15th day of gestation while protein expression did not change until day 21. These discrepancies show how important it is to measure overall function rather than rely entirely on measures of intermediate activities in the pathways such as mRNA transcription or protein translation. In contrast to the changes demonstrated in amino acid uptake, glucose uptake was not altered as a result of a low protein diet. The authors hypothesize that the placenta, in addition to responding to regulatory growth factors, acts as a nutrient sensing organ. Their hypothesis is supported by a decrease in placental mTOR protein expression at 18 days of gestation. However, this decrease only approached significance, as the authors point out (P < 0.09). The suggestion that mTOR acts as a nutrient sensor is provocative and should stimulate further and more definitive studies. Pursuing histological approaches to determine relative changes in distribution of both mRNA and protein, as well as the study of molecular and activity determinations of other factors in the mTOR signalling pathway, such as S6 kinase, in the various cellular components of the placenta will be fruitful ways of determining the value of this interesting hypothesis as it relates to the multiple signalling pathways within the placenta. In the light of the finding of functional changes in amino acid transport in the absence of changes in SNAT2 protein, it will be of interest to determine changes in the trafficking of transporter protein to the plasma membrane of the syncytiotrophoblast with subsequent increase in activity without a change in protein measured by western analysis. Some degree of caution must be exercised since although data show a time relationship between decreased amino acid transport and the appearance of IUGR, temporal relationships do not prove a causal relationship. Development is proceeding so fast at this stage of gestation that it is still possible that the events that eventually lead to fetal growth reduction are already in place prior to the observed reduction in amino acid transport. The mechanisms underlying IUGR are complex and likely to differ according to the underlying cause, e.g. placental insufficiency, maternal diet, multiple pregnancy. However, by investigating activity at several levels these studies provide a clear indication of a potential component role for alterations in amino acid transport that play a causal role in the production of IUGR. Finally, changes in transport of other factors such as oxygen, lipids and micronutrients need to be considered as they may also play causative roles in the induction of IUGR.