Insufficient invasion of conceptus-derived trophoblast cells in the maternal decidua is a key event in the development of early-onset preeclampsia (PE), a subtype of PE associated with high maternal and fetal morbidity and mortality. Kisspeptins, a family of peptides previously shown to inhibit trophoblast cell invasion, have been implicated in the pathogenesis of early-onset PE. However, a role of kisspeptin signaling during the genesis of this syndrome has not been elucidated. Herein, we used the preeclamptic-like BPH/5 mouse model to investigate kisspeptin expression and potential upstream regulatory mechanisms in a PE-like syndrome. Expression of the kisspeptin encoding gene, Kiss1, and the 10-amino-acid kisspeptide (Kp-10), are upregulated in the non-pregnant uterus of BPH/5 females during diestrus and in the maternal-fetal interface during embryonic implantation and decidualization. Correspondingly, the dysregulation of molecular pathways downstream to kisspeptins also occurs in this mouse model. BPH/5 females have abnormal sex steroid hormone profiles during early gestation. In this study, the normalization of circulating concentrations of 17β-estradiol (E2) and progesterone (P4) in pregnant BPH/5 females not only mitigated Kiss1 upregulation, but also rescued the expression of multiple molecules downstream to kisspeptin and ameliorated adverse fetoplacental outcomes. Those findings suggest that uterine Kiss1 upregulation occurs pre-pregnancy and persists during early gestation in a PE-like mouse model. Moreover, this study highlights the role of sex steroid hormones in uteroplacental Kiss1 dysregulation and the improvement of placentation by normalization of E2, P4 and Kiss1.
Preeclampsia (PE) is a devastating hypertensive disorder of pregnancy closely linked to obesity. Long-term adverse outcomes may occur in offspring from preeclamptic pregnancies. Accordingly, sex-specific changes in pubertal development have been described in children from preeclamptic women, but the underlying mechanisms remain vastly unexplored. Features of PE are spontaneously recapitulated by the blood pressure high subline 5 (BPH/5) mouse model, including obesity and dyslipidemia in females before and throughout pregnancy, superimposed hypertension from late gestation to parturition and fetal growth restriction. A sexually dimorphic cardiometabolic phenotype has been described in BPH/5 offspring: while females are hyperphagic, hyperleptinemic, and overweight, with increased reproductive white adipose tissue (rWAT), males have similar food intake, serum leptin concentration, body weight and rWAT mass as controls. Herein, pubertal development and adiposity were further investigated in BPH/5 progeny. Precocious onset of puberty occurs in BPH/5 females, but not in male offspring. When reaching adulthood, the obese BPH/5 females display hypoestrogenism and hyperandrogenism. Kisspeptins, a family of peptides closely linked to reproduction and metabolism, have been previously shown to induce lipolysis and inhibit adipogenesis. Interestingly, expression of kisspeptins (Kiss1) and their cognate receptor (Kiss1r) in the adipose tissue seem to be modulated by the sex steroid hormone milieu. To further understand the metabolic-reproductive crosstalk in the BPH/5 offspring, Kiss1/Kiss1r expression in male and female rWAT were investigated. Downregulation of Kiss1/Kiss1r occurs in BPH/5 females when compared to males. Interestingly, dietary weight loss attenuated circulating testosterone concentration and rWAT Kiss1 downregulation in BPH/5 females. Altogether, the studies demonstrate reproductive abnormalities in offspring gestated in a PE-like uterus, which appear to be closely associated to the sexually dimorphic metabolic phenotype of the BPH/5 mouse model.
Kisspeptins (KP), encoded by Kiss1 , are reported to play a role in early-onset preeclampsia (ePE), a life-threatening hypertensive disorder of pregnancy. KP is higher in term ePE placentae than in normal pregnancies. However, the role of KP in PE has not been confirmed. The Blood Pressure High Subline 5 (BPH/5) mouse model spontaneously develops the main features of ePE, including impaired placental expansion and maternal hypertension. We have shown that Kiss1 is higher at the BPH/5 maternal-fetal interface on embryonic days (e) 4.5 and 7.5. BPH/5 females have abnormal circulating sex steroid hormones (SSH) during early gestation (e2.5), with lower estradiol-17ß (E2) and higher progesterone (P4). Since E2 and P4 may modulate uterine Kiss1 , we aimed to investigate the effects of artificial synchronization of SSH (AS-SSH) in BPH/5 uteroplacental KP signaling and placental development. We hypothesized that AS-SSH would prevent BPH/5 uteroplacental Kiss1 upregulation and normalize KP downstream expression of tissue inhibitor of metalloproteinase (TIMP) 2 and placental defects. AS-SSH was performed after ovariectomy of pregnant BPH/5 and C57 females (n = 8/strain) at e2.5 with one dose of E2 (25 ng/mouse, subcutaneously), and daily subcutaneous injections of P4 (1ng/mouse) until embryonic implantation sites (eIS) were collected 3 days post-surgery (n = 8/group). Contrary to natural (Nat) BPH/5 pregnancies, eIS Kiss1 and TIMP2 expression was not different between AS-SSH BPH/5 and C57 (p > 0.05). Nat and AS-SSH pregnant mice were anesthetized at e12.5 to assess umbilical cord blood flow via ultrasound and uteroplacental units were harvested for placental morphometry (n = 4-6/group). Placental expansion into the maternal decidua was measured and expressed as the ratio of the placenta depth in relation to the placenta + decidua. Nat BPH/5 had lower placental expansion and umbilical blood flow than Nat C57, whereas AS-SSH BPH/5 had higher placental expansion and umbilical blood flow than Nat BPH/5 (p < 0.05). In conclusion, synchronization of the E2 and P4 profile in the BPH/5 mouse early gestation mitigated Kiss1 and TIMP2 upregulation at the maternal-fetal interface and ameliorated the placental defects previously reported in this model.
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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.