CSH RNA Interference Reduces Global Nutrient Uptake and Umbilical Blood Flow Resulting in Intrauterine Growth Restriction

Abstract

Deficiency of the placental hormone chorionic somatomammotropin (CSH) can lead to the development of intrauterine growth restriction (IUGR). To gain insight into the physiological consequences of CSH RNA interference (RNAi), the trophectoderm of hatched blastocysts (nine days of gestational age; dGA) was infected with a lentivirus expressing either a scrambled control or CSH-specific shRNA, prior to transfer into synchronized recipient sheep. At 90 dGA, umbilical hemodynamics and fetal measurements were assessed by Doppler ultrasonography. At 120 dGA, pregnancies were fitted with vascular catheters to undergo steady-state metabolic studies with the 3H2O transplacental diffusion technique at 130 dGA. Nutrient uptake rates were determined and tissues were subsequently harvested at necropsy. CSH RNAi reduced (p ≤ 0.05) both fetal and uterine weights as well as umbilical blood flow (mL/min). This ultimately resulted in reduced (p ≤ 0.01) umbilical IGF1 concentrations, as well as reduced umbilical nutrient uptakes (p ≤ 0.05) in CSH RNAi pregnancies. CSH RNAi also reduced (p ≤ 0.05) uterine nutrient uptakes as well as uteroplacental glucose utilization. These data suggest that CSH is necessary to facilitate adequate blood flow for the uptake of oxygen, oxidative substrates, and hormones essential to support fetal and uterine growth.

Uptake of Phosphate, Calcium, and Vitamin D by the Pregnant Uterus of Sheep in Late Gestation: Regulation by Chorionic Somatomammotropin Hormone

“…The experimental design and sample collection methods have been published with regard to the impact of chorionic somatomammotropin RNA interference (CSH RNAi) on uterine and umbilical blood flows, and nutrient utilization for lentiviral scrambled control RNAi (control, n = 10), normal-weight (non-IUGR, n = 6) and growth restricted sheep fetuses (IUGR, n = 4) [ 24 , 25 ]. In brief, all ewes (Dorper breed composition) were group housed in pens at the Colorado State University Animal Reproduction and Biotechnology Laboratory, and were provided access to hay, trace minerals, and water in order to meet or slightly exceed their National Research Council requirements.…”

“…Recent studies utilizing lentiviral-mediated RNA interference (RNAi) in pregnant sheep have demonstrated an important role of CSH in the regulation of fetal growth. The knockdown of CSH protein led to the formation of two fetal phenotypes: non-intrauterine growth restricted and intrauterine growth restricted (IUGR) [ 24 , 25 ]. In non-IUGR pregnancies, CSH RNAi reduced uterine blood flow and the expression of endothelial nitric oxide synthase (NOS3) protein in caruncles, while increasing utero-placental glucose utilization [ 25 ].…”

“…In non-IUGR pregnancies, CSH RNAi reduced uterine blood flow and the expression of endothelial nitric oxide synthase (NOS3) protein in caruncles, while increasing utero-placental glucose utilization [ 25 ]. In contrast, in CSH RNAi IUGR pregnancies, reduced uterine and umbilical blood flow, utero-placental glucose utilization, and uterine uptake of amino acids was accompanied by lighter uterine and fetal weights [ 24 ]. These findings highlight the potential role of CSH in the regulation of nutrient transport in the pregnant sheep.…”

Trophectoderm Transcriptome Analysis in LIN28 Knockdown Ovine Conceptuses Suggests Diverse Roles of the LIN28-let-7 Axis in Placental and Fetal Development

“…Interferon-tau produced by the trophoblast cells plays an essential role in the pregnancy recognition in ruminants [ 16 ], and its peak production in sheep is at day 16 of gestation [ 17 ]. The BNCs in sheep TE secrete ovine placental lactogen (OPL) or chorionic somatomammotropin (CSH) in both fetal and maternal circulation [ 18 ], an important hormone that has been associated with fetal growth and metabolism in sheep [ 19 , 20 ].…”

Placental Related Disorders of Pregnancy

“…Finally, a very topical and informative overview highlighting the role of the placenta and the use of low-dose aspirin in the prevention of pre-eclampsia [ 4 , 5 ]. In addition to the reviews, our collection also contains several novel studies covering pre-eclampsia [ 6 , 7 , 8 ]; fetal growth restriction [ 7 , 9 , 10 , 11 ]; calcium signaling [ 12 ]; placental oxidative stress, nutrition, senescence and apoptosis [ 6 , 9 , 13 , 14 , 15 ]; sexual dimorphism [ 16 , 17 , 18 ], intrahepatic cholestasis [ 19 ]; placental vascular modelling [ 20 ]; and placental villous explant culture models [ 21 ].…”