Senescent Changes and Endoplasmic Reticulum Stress May Be Involved in the Pathogenesis of Missed Miscarriage.

Background: Senescence is involved in many complications of pregnancy. However, whether senescent changes are also associated with missed miscarriage has not been fully investigated. Methods: The levels of p16, p21, and gamaH2AX, markers of senescence were measured in placentae collected from women with missed miscarriage by immunohistochemistry and western blotting. Levels of misfolded proteins in missed miscarriage placentae or normal first-trimester placenta that had been treated with H2O2 (100µM) or extracellular vesicles (EVs) collected from missed miscarriage placental explant culture were measured by fluorescent compound, Thioflavin-T. The production of reactive oxygen species (ROS) by missed miscarriage placentae was measured by CellROX® Deep Red. Results: Increased levels of p16, p21, and gamaH2AX were presented in missed miscarriage placentae, compared to controls. Increased levels of misfolded proteins were shown in missed miscarriage placentae, but not in EVs that were collected from missed miscarriage placentae. The ROS production was significantly increased in missed miscarriage placental explant cultures. Increased levels of misfolded proteins were seen in the normal first-trimester placenta that had been treated with H2O2, compared to untreated. Conclusion: Our data demonstrate that there are increases in senescence and endoplasmic reticulum stress, and ROS production in missed miscarriage placenta. Oxidative stress and an accumulation of misfolded proteins in missed miscarriage placentae may contribute to the changes of senescence and endoplasmic reticulum stress seen in missed miscarriage placentae.