Adaptations in placental nutrient transfer capacity to meet fetal growth demands depend on placental size in mice

Abstract

Experimental reduction in placental growth often leads to increased placental efficiency measured as grams of fetus produced per gram of placenta, although little is known about the mechanisms involved. This study tested the hypothesis that the smallest placenta within a litter is the most efficient at supporting fetal growth by examining the natural intra-litter variation in placental nutrient transfer capacity in normal pregnant mice. The morphology, nutrient transfer and expression of key growth and nutrient supply genes (Igf2P0, Grb10, Slc2a1, Slc2a3, Slc38a1, Slc38a2 and Slc38a4) were compared in the lightest and heaviest placentas of a litter at days 16 and 19 of pregnancy, when mouse fetuses are growing most rapidly in absolute terms. The data show that there are morphological and functional adaptations in the lightest placenta within a litter, which increase active transport of amino acids per gram of placenta and maintain normal fetal growth close to term, despite the reduced placental mass. The specific placental adaptations differ with age. At E16, they are primarily morphological with an increase in the volume fraction of the labyrinthine zone responsible for nutrient exchange, whereas at E19 they are more functional with up-regulated placental expression of the glucose transporter gene, Slc2a1/GLUT1 and one isoform the System A family of amino acid transporters, Slc38a2/SNAT2. Thus, this adaptability in placental phenotype provides a functional reserve capacity for maximizing fetal growth during late gestation when placental growth is compromised.

Figure 1

The relationship between individual placental and fetal weights at E16 (y = 0.98x + 0.29, r = 0.331, n = 283 fetuses from 36 litters, P < 0.0001) and E19 (y = −0.07x + 1.15, r =−0.009, n = 260 fetuses from 36 litters, P > 0.05).

Figure 2

Mean (± s.e.m.) transfer and mean difference in transfer in d.p.m. (g placenta)⁻¹ of [¹⁴C]inulin (A), [¹⁴C]methyl-d-glucose (B) and [¹⁴C]methyl aminoisobutyric acid (MeAIB) (C) across the lightest and heaviest placentas within a litter. H, heaviest placenta; L, lightest placenta. E16: inulin, n = 7 H and 7 L placentas from 7 litters; glucose, n = 9 H and 9 L placentas from 9 litters; MeAIB, n = 15 H and 15 L placentas from 15 litters. E19: inulin, n = 6 H and 6 L placentas from 6 litters; glucose, n = 10 H and 10 L placentas from 10 litters; MeAIB, n = 12 H and 12 L placentas from 12 litters. *Significantly different from zero (P < 0.05, significance of a single mean). #Significantly different from the corresponding weight category values at E16 (P < 0.001, t test).

Figure 3

Expression analysis of growth regulatory genes (Igf2P0 and Grb10) and of glucose and System A amino acid transporter genes (Slc2a1, Slc2a3, Slc38a1, Slc38a2 and Slc38a4) by Northern blotting in the lightest (filled columns) and heaviest (open columns) placenta within a litter at E16 (A; n = 7 litters) and E19 (B; n = 6 litters). Graphs of mean expression levels (± s.e.m.) are shown with the levels in the heaviest placenta in a litter normalized to 1 together with representative Northern blots of total RNA for each gene compared to Gapdh loading for 3 litters at each age. *Significantly different from the value in the heaviest placenta (P < 0.01, paired t test).