Placental glucose transport in growth-restricted pregnancies induced by overnourishing adolescent sheep

Abstract

Glucose clamp procedures were used to determine whether the slowing of fetal growth during the final third of gestation in overnourished adolescent ewes is due to a reduction in placental glucose transport capacity. Singleton pregnancies to a single sire were established by embryo transfer and thereafter adolescent dams were offered a high (n = 11) or moderate (n = 7) nutrient intake. Studies were conducted at 130 +/- 0.5 days gestation. Uterine and umbilical blood flows were studied by the steady-state transplacental diffusion technique and glucose fluxes quantified by the Fick principle. To determine the relationship between the transplacental glucose gradient and umbilical (fetal) glucose uptake, studies were conducted with maternal arterial glucose clamped at 5 micromol ml(-1) and fetal glucose at spontaneously occurring and two additional higher levels. Maternal body weight gain during gestation averaged 282 and 57 g day(-1) for high- and moderate-intake dams, respectively. Total placentome weight (209 +/- 23 vs. 386 +/- 34 g) and fetal weight (3072 +/- 266 vs. 4670 +/- 196 g) were lower (P < 0.001) in high- than in moderate-intake groups. The growth-restricted pregnancies in the high-intake dams were associated with reduced uterine (P < 0.05) and umbilical (P < 0.02) blood flows and, in the non-perturbed state, the fetuses were relatively hypoxic (2.1 vs. 3.0 micromol ml(-1), P < 0.05) and hypoglycaemic (0.90 vs. 1.31 micromol ml(-1), P < 0.002). Linear regression analysis of umbilical glucose uptake at three steady-state uterine-umbilical arterial transplacental plasma glucose concentration gradients revealed that absolute placental glucose transport capacity was lower in high- than in moderate-intake dams (mean slope, 0.8 vs. 1.5 dl min(-1), P < 0.05; and mean intercept, 1.84 vs. 3.40 micromol ml(-1)). However, glucose transfer capacity was not different between the two groups when expressed on a placental weight-specific basis. This confirms that the small size of the placenta per se is the major limitation to placental glucose transfer in the overnourished adolescent pregnant sheep.

Fetoplacental growth and vascular development in overnourished adolescent sheep at day 50, 90 and 130 of gestation

“…This approach was critical to determine the basis of the previously observed changes in placental development and function in late gestation. The study demonstrated that placental mass per se is not perturbed by maternal overfeeding until sometime during the final third of pregnancy and as such confirms previous studies in which the pregnancies were terminated at single points coincident with either mid (Wallace et al 2004b or late (Wallace et al 2000(Wallace et al , 2002a(Wallace et al , 2002b gestation. Moreover, the data revealed for the first time that the fetuses of overnourished dams may be initially on a higher growth trajectory than control fetuses between day 50 and 90 of gestation, with fetal weight being 11% greater by day 90 in the H group.…”

“…Although cellular proliferation within the fetal cotyledon was only marginally influenced by maternal diet at day 50 of gestation, we did observe a significant reduction in the vascular development within the fetal cotyledon at this early stage. The reductions in capillary area density and area per capillary (i.e., vessel size) in the overnourished dams may explain the previously reported reductions in uterine blood flow in mid-gestation (Wallace et al 2008a) and in uteroplacental blood flows and nutrient uptakes in late gestation (Wallace et al 2002a(Wallace et al , 2002b(Wallace et al , 2003a in this experimental paradigm. The mechanism underlying this nutritionally-mediated alteration in vascular development is unknown.…”

“…(Simmons et al 1979). In the present study, maternal glucose concentrations were elevated at all necropsy stages in the overnourished dams, and it was only during the last third of gestation, when the mass of the placenta was subsequently impaired, that the absolute nutrient transfer capacity of the placenta became limiting for further fetal growth (Wallace et al 2002b). Consequently, by day 130 of gestation, fetal growth had slowed and fetal body weight was reduced by 20% in fetuses from overnourished dams compared with those from controls, coincident with a 40% reduction in placental mass.…”

“…Inadequate placental development is central to these negative outcomes and by late gestation placental mass is typically reduced by 30-40% and is associated with a corresponding reduction in both uterine and umbilical blood flows (Wallace et al 2002a). This directly impacts transplacental transport of nutrients to the fetus, and hence absolute umbilical uptakes of glucose, oxygen and amino acids are attenuated, leading to a slowing of fetal growth in the final third of gestation (Wallace et al 2002a(Wallace et al , 2002b(Wallace et al , 2003b. We originally hypothesized that these late pregnancy events are preceded and mediated by alterations in placental angiogenesis and vascular development, and, indeed, we demonstrated attenuated expression of mRNA for a number of angiogenic factors and their receptors in whole placentomes collected at mid-gestation from overnourished dams .…”

Litter-size-dependent intrauterine growth restriction in sheep

“…In general, the size of the placenta is correlated with its glucose and amino acid transfer capacity, which is determined by transporter abundance (reviewed by Regnault et al (2005) and Fowden et al (2006c)). Interruptions in the normal placental growth trajectory caused by carunclectomy (Owens, et al, 1987), heat stress (Thureen et al, 1992), nutrition manipulation (Wallace et al, 2002), or prolonged hypoglycemia (Carver and Hay, 1995) may either increase or decrease glucose and amino acid transporter abundance and hence, the efficiency of placental nutrient-transfer capacity.…”