Abstract 104: Kisspeptin Signaling And Pregnancy Outcomes Are Ameliorated In The Preeclamptic-like BPH/5 Mouse After Synchronization Of Sex Steroid Hormones

Abstract

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.