ABSTRACT
Advanced maternal age is associated not only with a significant reduction in fertility but also with an additional risk of developing pregnancy-related disorders. Most of these disorders are now believed to be the clinical manifestation of an incorrect placentation, namely deficient transformation of maternal spiral arteries and ineffective trophoblast invasion through uterine stroma. In the present study it was hypothesized that an age-related loss in uterine redox homeostasis interferes with the function of extravillous trophoblasts (EVTs) and placentation. To test this hypothesis, relative levels of oxidatively modified proteins were evaluated in human samples from placenta and placental bed, and the role of specific oxidative modifications to proteins in placentation was studied using a cell culture model of EVTs. In the placental bed, the carbonylation level of a 66 kDa protein (identified as albumin) presented a strong, positive and significant correlation with maternal age. Albumin was immunodetected preferentially in endothelial cells and connective tissue between muscle fascicles. In vitro results showed that carbonylated albumin overload did not alter cell viability, but reduced EVTs motility and triggered cell stress response pathways. Moreover, EVTs presented decreased ability to adhere to and invade a collagen extracellular matrix pre-treated with carbonylated albumin. In conclusion, reproductive ageing is accompanied by an increase in maternal uterine carbonylated albumin, that may have a deleterious role in the modulation of EVTs function.
Subject(s)
Placenta , Trophoblasts , Albumins , Endothelial Cells , Female , Humans , Maternal Age , Oxidation-Reduction , Oxidative Stress , PregnancyABSTRACT
Blood flow assessment employing Doppler techniques is a useful procedure in pregnancy evaluation, as it may predict pregnancy disorders coursing with increased uterine vascular impedance, as pre-eclampsia. While the local causes are unknown, emphasis has been put on reactive oxygen species (ROS) excessive production. As NADPH oxidase (NOX) is a ROS generator, it is hypothesized that combining Doppler assessment with NOX activity might provide useful knowledge on placental bed disorders underlying mechanisms. A prospective longitudinal study was performed in 19 normal course, singleton pregnancies. Fetal aortic isthmus (AoI) and maternal uterine arteries (UtA) pulsatility index (PI) were recorded at two time points: 20-22 and 40-41 weeks, just before elective Cesarean section. In addition, placenta and placental bed biopsies were performed immediately after fetal extraction. NOX activity was evaluated using a dihydroethidium-based fluorescence method and associations to PI values were studied with Spearman correlations. A clustering of pregnancies coursing with higher and lower PI values was shown, which correlated strongly with placental bed NOX activity, but less consistently with placental tissue. The study provides evidence favoring that placental bed NOX activity parallels UtA PI enhancement and suggests that an excess in oxidation underlies the development of pregnancy disorders coursing with enhanced UtA impedance.
