Estrogen and Progesterone Receptors Are Dysregulated at the BPH/5 Mouse Preeclamptic-Like Maternal-Fetal Interface

Simple Summary Preexisting reproductive disorders and perturbed placentation are proposed to play a role in the development of preeclampsia, a leading hypertensive disorder of pregnancy. However, underlying mechanisms remain incompletely understood. Pregnancy establishment and maintenance are tightly regulated by estrogen and progesterone signaling in the uterus and developing placenta. Accordingly, placental estrogen and progesterone receptor dysregulations have been speculated to contribute to preeclampsia. Using a spontaneous model of superimposed preeclampsia, the Blood Pressure High Subline 5 (BPH/5) mouse, we tested the hypothesis that uteroplacental estrogen and progesterone receptor misexpression occur prior to pregnancy and during the peri-implantation period of preeclamptic-like pregnancies. BPH/5 females display estrogen deficiency, delayed embryonic development, and delayed decidualization. Herein, we describe for the first time estrogen and progesterone receptor dysregulation in the BPH/5 non-pregnant uterus and developing maternal-fetal interface. This study provides evidence of disrupted sex hormone signaling in the peri-conception phase of preeclamptic-like BPH/5 pregnancies, offering potential insights on estrogen and progesterone signaling at unexplored timepoints of human preeclampsia.Abstract The etiopathogenesis of preeclampsia, a leading hypertensive disorder of pregnancy, has been proposed to involve an abnormal circulating sex hormone profile and misexpression of placental estrogen and progesterone receptors (ER and PR, respectively). However, existing research is vastly confined to third trimester preeclamptic placentas. Consequently, the placental-uterine molecular crosstalk and the dynamic ER and PR expression pattern in the peri-conception period remain overlooked. Herein, our goal was to use the BPH/5 mouse to elucidate pre-pregnancy and early gestation Er and Pr dynamics in a preeclamptic-like uterus. BPH/5 females display low circulating estrogen concentration during proestrus, followed by early gestation hypoestrogenemia, hyperprogesteronemia, and a spontaneous preeclamptic-like phenotype. Preceding pregnancy, the gene encoding Er alpha (Er alpha, Esr1) is upregulated in the diestrual BPH/5 uterus. At the peak of decidualization, Esr1, Er beta (Er beta, Esr2), and Pr isoform B (Pr-B) were upregulated in the BPH/5 maternal-fetal interface. At the protein level, BPH/5 females display higher percentage of decidual cells with nuclear Er alpha expression, as well as Pr downregulation in the decidua, luminal and glandular epithelium. In conclusion, we provide evidence of disrupted sex hormone signaling in the peri-conception period of preeclamptic-like pregnancies, potentially shedding some light onto the intricate role of sex hormone signaling at unexplored timepoints of human preeclampsia.