Artificial Synchronization of Sex Steroid Hormones Normalizes Kisspeptin Expression and Placentation in the Preeclamptic‐Like BPH/5 Mouse

Abstract

Insufficient invasion of the maternal decidua by conceptus‐derived trophoblast cells is a key event in the pathogenesis of early‐onset preeclampsia (ePE), a subclass of PE associated with high maternal morbidity and fetal intrauterine growth restriction (IUGR). Kisspeptins (KP) are a family of small peptides previously shown to inhibit trophoblast cell invasion. Interestingly, KP expression is higher in the placentae of women with ePE than in those with uncomplicated pregnancies. Nonetheless, the mediators of placental KP upregulation remain largely unknown. The Blood Pressure High Subline 5 (BPH/5) is a mouse model that spontaneously develops the main features of PE, including decreased trophoblast cell invasion, lower decidual placental expansion, reduced placental labyrinth endothelial remodelling and IUGR. We have previously shown that Kiss1is higher at the BPH/5 maternal‐fetal interface during early gestation, at embryonic days (e) 4.5 and 7.5, when compared with control C57 mice. Moreover, BPH/5 females have abnormal sex steroid hormone profile during early gestation, including an earlier and depressed surge of estradiol‐17ß (E2) and higher blood progesterone (P4) at e2.5. Upregulation of uterine Kiss1expression has been previously demonstrated by administration of E2 and P4 to non‐pregnant ovariectomized CD‐1 mice. Therefore, we aimed to investigate the effects of artificial synchronization of sex steroid hormones (AS‐SSH) in BPH/5 uteroplacental Kiss1expression and placental morphology. It was hypothesized that AS‐SSH during early gestation would prevent the BPH/5 Kiss1upregulation at the embryonic implantation sites (eIS) and result in higher decidual placental expansion. AS‐SSH was performed via ovariectomy of pregnant BPH/5 and C57 females (n = 8/strain) at e2.5; administration of a single dose of E2 (25 ng/mouse, subcutaneously) to stimulate embryonic implantation and daily subcutaneous injections of P4 (1mg/mouse) until sample collection. The eIS were collected at e5.5 and Kiss1 expression was assessed via RT‐PCR. Additionally, e12.5 fetoplacental units from BPH/5 and C57 natural (Nat) and AS‐SSH pregnancies were stained with Isolectin, and the placental decidual expansion was assessed using Image J® (n = 4‐6/group). The placental expansion into the maternal decidua was calculated as the ratio of the labyrinth and junctional zone in relation to the entire placental disc (placenta + decidua). Comparisons were done using unpaired T‐tests and ANOVA with post‐hoc Newman‐Keuls tests. Contrary to Nat BPH/5 pregnancies, eIS Kiss1 expression was not different between AS‐SSH BPH/5 and C57 (p = 0.77). Nat BPH/5 had lower placental expansion (p < 0.05) than Nat C57, whereas AS‐SSH BPH/5 presented higher placental expansion than Nat BPH/5 (p < 0.05). In conclusion, normalization of the E2 and P4 profile in the PE‐like BPH/5 mouse early gestation not only mitigated the Kiss1upregulation at the maternal‐fetal interface, but also ameliorated the placental defects previously reported in this mouse model.