Kisspeptin and Sex Steroid Hormone Receptors Are Upregulated at the Maternal‐Fetal Interface of the Preeclamptic‐like BPH/5 Mouse

Abstract

The main features of preeclampsia (PE), a devastating syndrome that affects 5‐8% of pregnancies worldwide, are spontaneously recapitulated by the Blood Pressure High Subline 5 (BPH/5) mouse model. Comparable to women with early‐onset PE, BPH/5 females develop poor placentation with decreased trophoblast cell invasion, shallower placental discs and reduced placental endothelial remodelling than control C57 mice. Kisspeptins (KP), encoded by Kiss1, have been implicated in the etiology of PE: KP upregulation at the human maternal‐fetal interface is suggested to inhibit trophoblast cell invasion and angiogenesis. However, uterine KP expression pre‐pregnancy in women that later develop PE and the upstream signaling mechanisms leading to uterine/placental KP upregulation remain vastly unexplored. Interestingly, administration of estradiol‐17ß (E2) and/or progesterone (P4) to non‐pregnant ovariectomized CD‐1 mice resulted in uterine Kiss1upregulation. We have previously shown that BPH/5 females present abnormal circulating E2 and P4 throughout the estrous cycle and early pregnancy. Furthermore, KP and KP receptor (Kiss1r) are upregulated at the BPH/5 maternal‐fetal interface during the peak of decidualization, at embryonic day (e) 7.5. Therefore, the goal of this study was to investigate mRNA expression of Kiss1/Kiss1r,and the receptors for Progesterone (PR‐a/b/c)and Estrogen (ER‐αand GPER‐1)in BPH/5 non‐pregnant uterus during the first day of diestrus (NP‐D) and embryonic implantation sites (eIS) at e4.5. We hypothesized that the sex steroid hormone receptors would be upregulated in the uterus/eIS of BPH/5 during NP‐D and e4.5, respectively, potentially contributing with Kiss1/Kiss1rupregulation. Daily vaginal cytology samples were collected from adult BPH/5 and C57 females to determine the stage of the estrous cycle, and uterine samples were collected on the first day of cytologic diestrus (NP‐D, n = 3‐6/strain). Moreover, adult BPH/5 and C57 females were bred, and eIS were collected at e4.5 (n = 7‐9/strain). Gene expression was investigated using quantitative RT‐PCR and comparisons were performed using unpaired T‐tests. Welch’s corrections were performed for unequal variances and the significance level was set at α ≤ 0.05. Kiss1expression was higher in BPH/5 NP‐D uterus (p = 0.04) and e4.5 eIS (p = 0.01) when compared with C57. Contrarily, Kiss1rwas not different between BPH and C57 in NP‐D or e4.5 (p > 0.05). Interestingly, PR‐a/b/cand ER‐αwere also higher in the uterus/eIS of BPH/5 females both during NP‐D (p = 0.05 and 0.02, respectively) and e4.5 (p = 0.003 and 0.02, respectively). The trans‐membrane G‐protein‐coupled estrogen receptor 1 (GPER‐1), largely associated with rapid, non‐genomic cellular responses to estrogens, was also higher in BPH/5 eIS at e4.5 when compared with controls C57 (p < 0.001), but not different between groups in NP‐D (p > 0.05). In conclusion, uterine Kiss1upregulation precedes pregnancy in the BPH/5 mouse model. Furthermore, PR‐a/b/cand ER‐α expression in the NP‐D uterus and early maternal fetal interface parallels the expression levels of Kiss1in the PE‐like BPH/5 mouse.