Animal Reproduction and Biotechnology Laboratory, Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado, United States.
Perinatal Research Center, University of Colorado School of Medicine, Aurora, Colorado, United States.
Am J Physiol Endocrinol Metab. 2024 May 1;326(5):E602-E615. doi: 10.1152/ajpendo.00331.2023. Epub 2024 Feb 14.
We previously demonstrated impaired placental nutrient transfer in chorionic somatomammotropin (CSH) RNA interference (RNAi) pregnancies, with glucose transfer being the most impacted. Thus, we hypothesized that despite experimentally elevating maternal glucose, diminished umbilical glucose uptake would persist in CSH RNAi pregnancies, demonstrating the necessity of CSH for adequate placental glucose transfer. Trophectoderm of sheep blastocysts (9 days of gestational age; dGA) were infected with a lentivirus expressing either nontargeting control (CON RNAi; = 5) or CSH-specific shRNA (CSH RNAi; = 7) before transfer into recipient sheep. At 126 dGA, pregnancies were fitted with vascular catheters and underwent steady-state metabolic studies (HO transplacental diffusion) at 137 ± 0 dGA, before and during a maternal hyperglycemic clamp. Umbilical glucose and oxygen uptakes, as well as insulin and IGF1 concentrations, were impaired ( ≤ 0.01) in CSH RNAi fetuses and were not rescued by elevated maternal glucose. This is partially due to impaired uterine and umbilical blood flow ( ≤ 0.01). However, uteroplacental oxygen utilization was greater ( ≤ 0.05) during the maternal hyperglycemic clamp, consistent with greater placental oxidation of substrates. The relationship between umbilical glucose uptake and the maternal-fetal glucose gradient was analyzed, and while the slope (CON RNAi, Y = 29.54X +74.15; CSH RNAi, Y = 19.05X + 52.40) was not different, the y-intercepts and elevation were ( = 0.003), indicating reduced maximal glucose transport during maternal hyperglycemia. Together, these data suggested that CSH plays a key role in modulating placental metabolism that ultimately promotes maximal placental glucose transfer. The current study demonstrated a novel, critical autocrine role for chorionic somatomammotropin in augmenting placental glucose transfer and maintaining placental oxidative metabolism. In pregnancies with CSH deficiency, excess glucose in maternal circulation is insufficient to overcome fetal hypoglycemia due to impaired placental glucose transfer and elevated placental metabolic demands. This suggests that perturbations in glucose transfer in CSH RNAi pregnancies are due to compromised metabolic efficiency along with reduced placental mass.
我们之前的研究表明，在绒毛膜生长激素（CSH）RNA 干扰（RNAi）妊娠中，胎盘营养物质的转移受损，其中葡萄糖的转移受到的影响最大。因此，我们假设尽管实验性地提高了母体的葡萄糖水平，但在 CSH RNAi 妊娠中，脐静脉葡萄糖摄取仍会持续减少，这表明 CSH 对于足够的胎盘葡萄糖转移是必要的。将表达非靶向对照（CON RNAi； = 5）或 CSH 特异性 shRNA（CSH RNAi； = 7）的慢病毒感染绵羊囊胚滋养层（妊娠 9 天；dGA），然后将其转移到受体绵羊中。在 126 dGA 时，给妊娠绵羊安置血管导管，并在 137 ± 0 dGA 时进行稳态代谢研究（HO 胎盘扩散），然后在母体高血糖钳夹期间进行该研究。CSH RNAi 胎儿的脐静脉葡萄糖和氧气摄取以及胰岛素和 IGF1 浓度均受损（≤0.01），并且母体高血糖不能使其恢复正常。这部分是由于子宫和脐血流受损（≤0.01）。然而，在母体高血糖钳夹期间，子宫胎盘氧利用率更高（≤0.05），这与底物的胎盘氧化增强一致。分析了脐静脉葡萄糖摄取与母体-胎儿葡萄糖梯度之间的关系，虽然斜率（CON RNAi，Y=29.54X+74.15；CSH RNAi，Y=19.05X+52.40）没有差异，但截距和升高有差异（=0.003），表明母体高血糖时最大葡萄糖转运减少。总的来说，这些数据表明 CSH 在调节胎盘代谢中发挥关键作用，最终促进最大的胎盘葡萄糖转移。本研究证明了绒毛膜生长激素在增强胎盘葡萄糖转运和维持胎盘氧化代谢方面具有新的、关键的自分泌作用。在 CSH 缺乏的妊娠中，由于胎盘葡萄糖转运受损和胎盘代谢需求增加，母体循环中过多的葡萄糖不足以克服胎儿低血糖。这表明 CSH RNAi 妊娠中葡萄糖转运的改变是由于代谢效率受损以及胎盘质量减少所致。
