Complex, coordinated and highly regulated changes in placental signaling and nutrient transport capacity in IUGR

Abstract

The most common cause of intrauterine growth restriction (IUGR) in the developed world is placental insufficiency, a concept often used synonymously with reduced utero-placental and umbilical blood flows. However, placental insufficiency and IUGR are associated with complex, coordinated and highly regulated changes in placental signaling and nutrient transport including inhibition of insulin and mTOR signaling and down-regulation of specific amino acid transporters, Na⁺/K⁺-ATPase, the Na^+/H⁺-exchanger, folate and lactate transporters. In contrast, placental glucose transport capacity is unaltered and Ca²⁺-ATPase activity and the expression of proteins involved in placental lipid transport are increased in IUGR. These findings are not entirely consistent with the traditional view that the placenta is dysfunctional in IUGR, but rather suggest that the placenta adapts to reduce fetal growth in response to an inability of the mother to allocate resources to the fetus. This new model has implications for the understanding of the mechanisms underpinning IUGR and for the development of intervention strategies.

Keywords: Fetal development; Fetal growth restriction; Human; Maternal-fetal exchange; Placental transport; Syncytiotrophoblast.

Fig 1.. The placental barrier at term and a model for placental transport of neutral amino acids.

The syncytiotrophoblast cell layer (ST) and in particular its two polarized plasma membranes, the microvilllous (MVM) and basal plasma membranes (BM) constitute the primary barrier for the transfer of molecules such as glucose, amino acids and folate. The uptake of neutral amino acids from the maternal circulation across the MVM represents the active step of amino acid transport and is largely mediated by the System A and System L amino acid transporters. System A is predominantly expressed in the MVM and transports non-essential neutral amino acids (NEAA) against a concentration gradient energized by the inwardly directed Na⁺-gradient. System L is an exchanger, which uses the steep outwardly directed concentration gradient of some NEAAs to drive uptake of essential amino acids (EAA) against their concentration gradients. Amino acids are transferred across BM by facilitated diffusion driven by the outwardly directed concentration gradient mediated by System L and efflux transporters. N,nucleus; ET, endothelial cells of the fetal capillary.

Fig 2.. Changes in placental signaling in IUGR.

Placental insulin/IGF-1 and mTORC1 and mTORC2 signaling is inhibited and the ER stress pathway is activated in IUGR. For details, see text. Abbreviations: IGF-1: insulin-like growth factor I; IGF1-R: insulin-like growth factor 1 receptor; AKT: protein kinase B; mTORC1: mechanistic target of rapamycin complex 1; mTORC2: mechanistic target of rapamycin complex 2; eIF2α: eukaryotic initiation factor 2α.

Figure 3.. Alterations in Placental Transport in IUGR.

Increased (red), decreased (blue) and unchanged (grey) transporter activity in microvillous (MVM) and basal (BM) syncytiotrophoblast plasma membranes isolated from IUGR placentas, as compared to gestational age matched AGA controls. For details, see text.

Fig 4.. Placental nutrient sensing.

The placenta integrates signals conveying information on the ability of the maternal supply line to deliver nutrients and oxygen to the placenta (maternal supply) and on fetal demand through intrinsic nutrient sensors, such as mechanistic target of rapamycin (mTOR) signaling. These signals then regulate placental growth, mitochondrial respiration, nutrient transport and hormone secretion to balance fetal demand with the ability of the mother to support pregnancy. Thus, the placenta plays a critical role in modulating maternal-fetal resource allocation, thereby affecting fetal growth and the long-term health of the offspring. See text for detailed explanation. IGF-2, insulin-like growth factor 2; PTHrp, parathyroid hormone related peptide.