Adaptive responses to maternal nutrient restriction alter placental transport in ewes

Introduction: Maternal nutrient partitioning, uteroplacental blood flow, transporter activity, and fetoplacental metabolism mediate nutrient delivery to the fetus. Inadequate availability or delivery of nutrients results in intrauterine growth restriction (IUGR), a leading cause of neonatal morbidity and mortality. Maternal nutrient restriction can result in IUGR, but only in an unforeseeable subset of individuals. Methods: To elucidate potential mechanisms regulating fetal nutrient availability, singleton sheep pregnancies were generated by embryo transfer. Pregnant ewes received either a 50% NRC (NR; n = 24) or 100% NRC (n = 7) diet from gestational Day 35 until necropsy on Day 125. Maternal weight did not correlate with fetal weight; therefore, the six heaviest (NR Non-IUGR) and five lightest (NR IUGR) fetuses from nutrient-restricted ewes, and seven 100% NRC fetuses, were compared to investigate differences in nutrient availability. Results: Insulin, multiple amino acids, and their metabolites, were reduced in fetal circulation of NR IUGR compared to NR Non-IUGR and 100% NRC pregnancies. In contrast, glucose in fetal fluids was not different between groups. There was a nearly two-fold reduction in placentome volume and fetal/maternal interface length in NR IUGR compared to NR Non-IUGR and 100% NRC pregnancies. Changes in amino acid concentrations were associated with altered expression of cationic (SLC7A2, SLC7A6, and SLC7A7) and large neutral (SLC38A2) amino acid transporters in placentomes. Discussion: Results establish a novel approach to study placental adaptation to maternal undernutrition in sheep and support the hypothesis that amino acids and polyamines are critical mediators of placental and fetal growth in sheep.