Gestational diabetes mellitus alters placental structure, efficiency, and plasticity

The hemochorial placenta provides a critical barrier at the maternal-fetal interface to modulate maternal immune tolerance and enable gas and nutrient exchange between mother and conceptus. Pregnancy outcomes are adversely affected by gestational diabetes mellitus (GDM); however, the effects of GDM on placental formation, and subsequently fetal development, are not fully understood. In this report, streptozotocin was used to induce hyperglycemia in pregnant rats for the purpose of investigating the impact of GDM on placental formation and fetal development. GDM caused placentomegaly and placenta malformation, decreasing placental efficiency and fetal size. Elevated glucose disrupted rat trophoblast stem (TS) cell differentiation in vitro. Evidence of altered trophoblast differentiation was also observed in vivo, as hyperglycemia affected the junctional zone transcriptome and interfered with intrauterine trophoblast invasion and uterine spiral artery remodeling. When exposed to hypoxia, rats with GDM showed decreased proliferation and ectoplacental cone development on gestation day (gd) 9.5 and complete pregnancy loss by gd 13.5. Furthermore, elevated glucose concentrations inhibited TS cell responses to hypoxia in vitro. Overall, these results indicate that alterations in placental development, efficiency, and plasticity could contribute to the suboptimal fetal outcomes in offspring from pregnancies complicated by GDM. Holtzman Sprague-Dawley rats were housed in an environmentally controlled facility at the University of Kansas Medical Center (KUMC) with lights on from 0600 to 2000 h and allowed free access to food and water. Female rats (8-10 weeks of age) were mated with adult male rats (>3 months of age). Mating was assessed by inspection of vaginal lavages. ­The presence of sperm in the vagina was designated gd 0.5. A single dose of either streptozotocin (STZ; 45 mg/kg of body weight) or vehicle control solution (0.1 M citrate buffer, pH 4.2) was administered via tail vein injection on gd 6.5. Placentation sites were dissected on gestation day 13.5 and junctional zones were isolated. Dissected junctional zone tissues were snap-frozen in liquid nitrogen and stored at -80 degrees celsius until processing for RNA isolation.