Timothy R.H. Regnault

The relationship between transplacental O2 diffusion and placental expression of PlGF, VEGF and their receptors in a placental insufficiency model of fetal growth restriction

Placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) are involved in placental angiogenesis through interactions with the VEGFR‐1 and VEGFR‐2 receptors. The placenta of pregnancies whose outcome is fetal growth restriction (FGR) are characterized by abnormal angiogenic development, classically associated with hypoxia. The present study evaluated the near‐term expression of this growth factor family in an ovine model of placental insufficiency–FGR, in relationship to uteroplacental oxygenation. Compared to controls, FGR pregnancies demonstrated a 37 % increase in uterine blood flow (FGR vs. control, 610.86 ± 48.48 vs. 443.17 ± 37.39 ml min−1 (kg fetus)−1; P < 0.04), which was associated with an increased maternal uterine venous PO2 (58.13 ± 1.00 vs. 52.89 ± 1.26 mmHg; P < 0.02), increased umbilical artery systolic/diastolic ratio (3.90 ± 0.33 vs. 2.12 ± 0.26, P < 0.05), and fetal hypoxia (arterial PO2; 12.79 ± 0.97 vs. 18.65 ± 1.6 mmHg, P < 0.005). Maternal caruncle PlGF mRNA was increased in FGR (P < 0.02), while fetal cotyledon VEGF mRNA was reduced (P < 0.02). VEGFR‐1 mRNA was also reduced in FGR fetal cotyledon (P < 0.001) but was not altered in caruncle tissue. Immunoblot analysis of PlGF and VEGF demonstrated single bands at 19 000 and 18 600 Mr, respectively. Caruncle PlGF concentration was increased (P < 0.04), while cotyledon VEGF was decreased (P < 0.05) in FGR placentae. The data establish that uterine blood flow is not reduced in relationship to metabolic demands in this FGR model and that the transplacental PO2 gradient is increased, maintaining umbilical oxygen uptake per unit of tissue. Furthermore, these data suggest that an increased transplacental gradient of oxygen generates changes in angiogenic growth factors, which may underline the pathophysiology of the post‐placental hypoxic FGR.

Investigating the causes of low birth weight in contrasting ovine paradigms

Intrauterine growth restriction (IUGR) still accounts for a large incidence of infant mortality and morbity worldwide. Many of the circulatory and transport properties of the sheep placenta are similar to those of the human placenta and as such, the pregnant sheep offers an excellent model in which to study the development of IUGR. Two natural models of ovine IUGR are those of hyperthermic exposure during pregnancy, and adolescent overfeeding, also during pregnancy. Both models yield significantly reduced placental weights and an asymmetrically growth‐restricted fetus, and display altered maternal hormone concentrations, indicative of an impaired trophoblast capacity. Additionally, impaired placental angiogenesis and uteroplacental blood flow appears to be an early defect in both the hyperthermic and adolescent paradigms. The effects of these alterations in placental functional development appear to be irreversible. IUGR fetuses are both hypoxic and hypoglycaemic, and have reduced insulin and insulin‐like growth factor‐1 (IGF‐1), and elevated concentrations of lactate. However, fetal utilization of oxygen and glucose, on a weight basis, remain constant compared with control pregnancies. Maintained utilization of these substrates, in a substrate‐deficient environment, suggests increased sensitivities to metabolic signals, which may play a role in the development of metabolic diseases in later adult life.

Transport and metabolism of amino acids in placenta

In all mammalian species, the 20 amino acids of the genetic code are required for net protein accretion. The nutritional supply of amino acids for growth is defined as the net umbilical uptake of amino acids, representing the net transfer from maternal circulation, through the placenta and then to the fetus, of essential and non-essential amino acids. In considering the primary role of the placenta in the delivery of amino acids to the fetus for metabolism, it is important to consider the multiplicity of factors that may affect these overall delivery rates, including the activity and location of amino acid transporter systems, changes in these systems as gestation advances, effects of changes in placental surface area, uteroplacental blood flows, and maternal concentrations of amino acids. In this review, we discuss placental amino acid transport, the systems and their associated proteins, umbilical uptake data in animal and human studies, and amino acid transport in fetal growth restriction. Additionally, we discuss the current pool of thought concerning the mechanisms of placental amino acid transport as generated through in vitro vesicle studies and how they relate to the in vivo fluxes of animal studies. Finally, we discuss fetoplacental amino acid metabolism and specifically interorgan exchange.

The tissue and plasma concentration of polyols and sugars in sheep intrauterine growth retardation.

In an ovine model of placental insufficiency-induced intrauterine growth retardation (PI-IUGR), characterized by hypoxia, hypoglycemia and a significant reduction in fetal weight, we assessed alterations in fetal and placental polyols. Arterial maternal–fetal concentration differences of glucose and mannose were greater in the PI-IUGR fetus; glucose: C (n = 7), 2.68 ± 0.14 mmol/L versus PI-IUGR (n = 9), 3.18 ± 0.16 mmol/L (P < 0.02) and mannose: C, 42.9 ± 8.1 μmol/L versus PI-IUGR, 68.5 ± 19.1 μmol/L (P < 0.001). For PI-IUGR fetuses, fetal arterial plasma myo-inositol concentrations were significantly increased (P < 0.001). The concentrations of sorbitol, glucose and fructose were significantly reduced (P < 0.03, 0.01, 0.02, respectively). The cotyledons of IUGR placentas had a significantly increased concentration of myo-inositol (P < 0.003) and decreased concentrations of sorbitol, fructose and glycerol (P < 0.01, 0.02, 0.01, respectively). Fetal hepatic concentrations of sorbitol (P < 0.001) and fructose (P < 0.03) were also significantly reduced. These profound changes in both placental and fetal concentrations of polyols and sugars in sheep PI-IUGR pregnancies support the conclusion that within the PI-IUGR placenta there is an increased flux through the glucose 6-P:inositol 1-P cyclase system and decreased flux through the polyol dehydrogenase system, leading to increased placental myo-inositol production and decreased sorbitol production. The decreased placental supply of sorbitol to the fetal liver may lead to decreased fetal hepatic fructose production. These observations highlight that, in association with hypoxic and hypoglycemic PI-IUGR fetuses, there are major placental and fetal alterations in polyol production. The manner in which these alterations in fetoplacental carbohydrate metabolism contribute to the pathophysiology of PI-IUGR is currently unknown.

Effects of early gestation GH administration on placental and fetal development in sheep

Ovine GH (oGH) is synthesized in placental tissue during maximal placental growth and development. Our objectives were to localize oGH mRNA in the placenta, and study the impact of exogenous GH on twin pregnancies during the normal window (35-55 days of gestational age; dGA) of placental expression. In situ hybridization localized oGH mRNA in uterine luminal epithelium but not in tissues of fetal origin. While maternal GH and IGF-I concentrations were increased (P<0.001) approximately tenfold, uterine, uterine fluid, placental, and fetal weights were unaffected by treatment at either 55 or 135 dGA. Fetal length, liver weight, and liver weight per kg of body weight were unaffected by maternal GH treatment. However, in the cotyledon, IGF-binding protein (BP)-1 and IGFBP-4 mRNA concentrations were increased (P<0.05), while IGFBP-2 mRNA was decreased (P<0.05). The concentration of mRNA for IGFBP-3 was unaffected by treatment. Within the caruncle, IGFBP-1 mRNA was decreased (P<0.05), while IGFBP-3 and IGFBP-4 mRNA were increased (P<0.05), and IGFBP-2 mRNA was unchanged due to GH treatment. While our data indicate that elevated maternal GH and IGF-I concentrations during early and mid-gestation do not enhance placental and fetal growth in twin pregnancies, localization of GH mRNA in uterine luminal epithelium could explain GHs transitory expression from 35 to 55 dGA, since by the end of this period the majority of the uterine luminal epithelium has fused with chorionic binucleate cells forming the placental syncytium.

The IGF-II-deficient placenta: aspects of its function.

Abstract Gene ablation in mice has provided compelling evidence of the role that insulin-like growth factors (IGFs) and their receptors play in fetal and placental development. The recent deletion of the P0 transcript encoding IGF-II specifically within the labyrinthine trophoblast, resulted in placental and fetal growth restriction. This restriction was associated with reduced placental permeability and increased system A amino acid transporter activity. Whilst this report provides important new data on the role of placental IGF-II, they might not recapitulate the changes that occur in human placental insufficiency leading to intrauterine growth restriction.