Artificial Synchronization of Ovarian Hormones in Early Pregnancy Improves Adverse Pregnancy Outcomes Associated with Preeclampsia in the BPH/5 Mouse Model
Authors: Sones Jenny L , Woods Ashley K , Cha Jeeyeon , Dey Sudhansu K , Davisson Robin L 
Published: November 2023

Preeclampsia (PE) is a pregnancy‐specific disorder characterized by maternal hypertension and proteinuria during the second half of pregnancy. It is a leading cause of fetal and maternal morbidity/mortality and the only treatment is delivery of the fetus and placenta. Adverse pregnancy outcomes associated with PE include fetal demise and growth restriction due to uteroplacental ischemia. The pathophysiology of these adverse pregnancy outcomes in the context of PE is not clearly defined. The inbred mouse strain BPH/5 spontaneously develops the maternal syndrome as well as the placental defects observed in PE, shallow trophoblast invasion and reduced fetoplacental perfusion. Since proper placental development begins with synchronous implantation of a blastocyst into a hormonally‐primed receptive uterus, we hypothesized that defects in the implantation process would characterize the BPH/5 model of PE. BPH/5 females have an aberrant pre‐implantation estrogen (E2) profile characterized by a depressed E2 surge at e2.5pm (5.85±1.1pg/mL, n=9) when C57 control females have peak circulating E2 (16.97±2pg/mL, n=7, p<0.05). Expression of the E2‐sensitive implantation signaling molecule, Lif, is decreased in BPH/5 e4.5am implantation sites by qRT‐PCR (2‐fold v C57, n=3–4, p<0.05). Downstream Ptgs2 also shows dysregulated expression in BPH/5 implantation sites at e4.5am (4‐fold v C57, n=7–9, p<0.05) and e5.5am (.44±.07 vs C57:.25±.06, n=7, p<0.05). Expression patterns of Lif and Ptgs2 mRNA were confirmed by in situ hybridization. BPH/5 females also show embryo clustering (abnormal spacing along the uterus) at e5.5am (43±8%, n=5 vs. C57: 4±4%, n=6, p<0.05), a sign of dysregulated implantation in mice. Together, this points towards asynchronous embryo‐uterine interactions. To test if ovarian hormone signaling is central to the observed implantation defects, we utilized the delayed implantation model to artificially synchronize the timing of the pre‐implantation estrogen surge in BPH/5 females. Pregnant females were ovariectomized on e2.5, maintained on exogenous progesterone and given a single E2 injection to initiate implantation. Examination of BPH/5 pregnant females after artificial synchronization at e5.5 revealed a significant reduction in clustered embryos and normalization of implantation site Lif and Ptgs2 mRNA expression (n=6). Interestingly, artificially synchronized BPH/5 females showed an improvement in fetoplacental development with increased trophoblast invasion and improved umbilical blood flow (50.3±3.3 mm/sec, n=34) as compared to unsynchronized BPH/5 females (36.1±3.3, n=25, p<0.05) at e12.5. Correction of embryo clustering and fetoplacental defects, shallow trophoblast invasion and reduced fetoplacental perfusion, after artificial synchronization in early BPH/5 pregnancy suggests that ovarian hormone signaling may be central to the adverse pregnancy outcomes associated with PE in this model. These data highlight the importance of ovarian hormones, particularly E2, and successful pregnancy outcomes in PE pregnancies.Support or Funding InformationRLD (Qatar National Research Fund, NPRP09‐1099‐279; NIH HL063887, HL084207), SKD (March of Dimes, 3‐FY12‐127, 33‐FY13‐543; NIH HD068524, CA7783), JLS (AHA 12POST11250010), AKW (AHA 09PRE2120035), JC (NIH F30AG040858).