152 Impact of chorionic somatomammotropin RNA interference on uterine blood flow and placental glucose uptake in the absence of intrauterine growth restriction

Abstract

Abstract Chorionic somatomammotropin (CSH) is one of the most abundant hormones produced by the sheep placenta, yet the exact function of CSH has been elusive. Previously we reported the use of in vivo RNA interference (RNAi) to assess the impact of CSH deficiency on placental and fetal growth in sheep. Near-term (135 dGA), there are two distinct CSH RNAi phenotypes: 1) pregnancies with intrauterine growth restriction (IUGR), and 2) pregnancies with normal fetal and placental weights. This study describes physiological changes in the latter phenotype. To generate the CSH RNAi pregnancies, the trophectoderm of hatched blastocysts (9 dGA) were infected with lentiviral-constructs expressing either a scrambled control (NTS) or CSH-specific shRNA (CSH RNAi), prior to transfer into synchronized recipient ewes. At 120 dGA, 6 NTS and 6 CSH RNAi pregnancies were fitted with maternal and fetal catheters. Uterine and umbilical blood flows were measured utilizing the 3H2O transplacental diffusion technique at 132 dGA, and nutrient uptakes were calculated by the Fick principle. Resulting data were analyzed by Student’s t-test and significance was set at P ≤ 0.05. CSH RNAi tended (P ≤ 0.10) to reduce placentome weight with no effect on fetal weight. Absolute (ml/min) and relative (ml/min/kg fetus) uterine blood flows were reduced (P ≤ 0.05) in CSH RNAi pregnancies, but umbilical flows were not impacted. The uterine artery-to-vein glucose gradient (mmol/l) was significantly (P ≤ 0.05) increased, whereas the gradients for taurine and glycine were reduced (P ≤ 0.05). Uteroplacental glucose uptake (mmol/min/kg placenta) was increased 27% (P ≤ 0.05), whereas umbilical glucose uptake (mmol/min/kg fetus) was reduced 13%. This cohort demonstrates that even in the absence of IUGR, CSH deficiency has significant physiological ramifications, and the investigation of CSH RNAi pregnancies exhibiting both IUGR and non-IUGR phenotypes may help determine the direct effects of CSH and its potential impact on fetal programming. Supported by NIH R01 HD093701.