Ovarian stimulation induced reduction of uterine NK cells proliferation and production of cytokines by perturbing estrogen signaling in mice

Abstract

Abstract Background Ovarian stimulation is associated with an increased incidence of abnormal placentation. Uterine natural killer (uNK) cells are the major subpopulation of decidual immune cells, which are crucial for placentation. In a previous study, we found that ovarian stimulation impairs uNK cell density on gestation day (GD) 8.5 in mice. However, it is not clear how ovarian stimulation led to a reduction in the density of uNK cells. In this study, we transferred blastocysts that were obtained from natural mating and in vivo development into individual pseudopregnant recipients produced by either natural mating (control group) or mating following ovarian stimulation (SO group). Materials and Methods Results The fetal weights of the SO group were significantly lower than those of the control group on GD 18.5 (P < 0.001). In the SO placentas, PAS−positive area was significantly expanded (P < 0.05), and the micro vessel density values at the labyrinth zone were significantly reduced (P < 0.05). Notably, the density, maturity and cell proliferation activity of PAS+DBA+ uNK cells significantly declined in SO pregnant uteri compared with control, and the production of cytokines including IFN-γ, VEGF and PLGF of CD45+CD3−DBA+ uNK cells was also attenuated by ovarian stimulation. Additionally, we demonstrated that the production of chemokines and cytokines related to uNK recruitment, proliferation, and differentiation in the decidua is suppressed by ovarian stimulation. Conclusion we found that ovarian stimulation resulted in aberrant estrogen signaling and may contribute to the disorder of uNK cells caused by ovarian stimulation. Together, these results provided new insights on the mechanisms of aberrant maternal endocrine environments and abnormal placentation.