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Key Points: Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health. A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus. Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR. Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid-pregnancy, but this adaptation was insufficient in late pregnancy. Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR., Abstract: Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild-type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin-like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (K mf ) of 14 C-glutamine and 14 C-glutamate ( glutamine K mf and glutamate K mf ) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamine K mf and glutamate K mf were higher (P0 versus wild-type littermates, WTL) at E15.5. At E18.5, glutamine K mf remained elevated whereas glutamate K mf was similar between groups. In summary, we provide evidence that glutamine K mf and glutamate K mf adapt according to placental size in WT mice. The placenta of the growth-restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth., (© 2019 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

The role of parathyroid hormone-related protein (PTHrP) in fetal calcium homeostasis and placental calcium transport was examined in mice homozygous for the deletion of the PTHrP gene (PTHrP-/- null; NL) compared to PTHrP+/+ (wild-type; WT) and PTHrP+/- (heterozygous; HZ) littermates. Fetal blood ionized calcium was significantly reduced in NL fetuses compared to WT and HZ groups at 18 days of pregnancy (dp) with abolition of the fetomaternal calcium gradient. In situ placental perfusion of the umbilical circulation at 18 dp was used to measure unidirectional clearance of (45)Ca across the placenta in maternofetal ((Ca)K(mf)) and fetoplacental ((Ca)K(fp)) directions; (Ca)K(fp) was < 5% of (Ca)K(mf) for all genotypes. At 18 dp, (Ca)K(mf) across perfused placenta and intact placenta ((Ca)K(mf(intact))) were similar and concordant with net calcium accretion rates in vivo. (Ca)K(mf) was significantly raised in NL fetuses compared to WT and HZ littermates. Calcium accretion was significantly elevated in NL fetuses by 19 dp. Placental calbindin-D(9K) expression in NL fetuses was marginally enhanced (P < 0.07) but expression of TRPV6/ECaC2 and plasma membrane Ca2+-ATPase (PMCA) isoforms 1 and 4 were unaltered. We conclude that PTHrP is an important regulator of fetal calcium homeostasis with its predominant effect being on unidirectional maternofetal transfer, probably mediated by modifying placental calbindin-D(9K) expression. In situ perfusion of mouse placenta is a robust methodology for allowing detailed dissection of placental transfer mechanisms in genetically modified mice.