Protocol for a randomised, placebo-controlled, double-blinded clinical trial on the effect of oestrogen replacement on physical performance to muscle resistance exercise for older women with osteoarthritis of knee joint: the EPOK trial.

BACKGROUND: Knee osteoarthritis (KOA) is highly prevalent in older women, and previous studies suggest the involvement of hormonal factors play a role in the pathogenesis of osteoarthritis. KOA causes musculoskeletal impairment, resulting in decreased physical activity, muscle mass, and strength, which leads to sarcopenia and further increases the burden on healthcare systems. Oestrogen replacement therapy (ERT) improves joint pain and muscle performance in early menopausal women. Muscle resistance exercise (MRE) is a non-pharmacological method that preserves the physical functions of patients with KOA. However, data on short-term oestrogen administration combined with MRE in postmenopausal women, especially in those aged > 65 years, are limited. Therefore, this study presents a protocol of a trial aimed to examine the synergistic effect of ERT and MRE on lower-limb physical performance in older women with KOA. METHODS: We will conduct a double-blinded, randomised placebo-controlled trial in 80 Japanese women aged > 65 years living independently with knee pain. The participants will be randomly categorised into two groups: (1) 12-week MRE programme with transdermal oestrogen gel containing 0.54 mg oestradiol per push and (2) 12-week MRE programme with placebo gel. The primary outcome measured using the 30-s chair stand test, and secondary outcomes (body composition, lower-limb muscle strength, physical performance, self-reported measure of knee pain, and quality of life) will be measured at baseline, 3 months, and 12 months, and these outcomes will be analysed based on the intention-to-treat. DISCUSSION: The EPOK trial is the first study to focus on the efficacy of ERT on MRE among women aged > 65 years with KOA. This trial will provide an effective MRE to prevent KOA-induced lower-limb muscle weakness, confirming the benefit of short-term oestrogen administration. TRIAL REGISTRATION: Japan Registry of Clinical Trials: jRCTs061210062. Registered 17th December 2021, https://jrct.niph.go.jp/en-latest-detail/jRCTs061210062 .

Diffuse myometrium thinning and placenta accreta spectrum in a patient with systemic lupus erythematosus (SLE): a case report and review of the literature.

BACKGROUND: Cases of uterine wall thinning and placental abnormalities complicated with systemic lupus erythematosus (SLE) during pregnancy have been reported in Asian countries for ten years. Long-term steroid use can cause muscle degeneration, but the mechanism of myometrium thinning was not known. Through the review of published articles, this report is the first review of cases to discuss the pathogenesis and clinical features of thinned myometrium and placenta accreta spectrum (PAS) in pregnant patients with SLE. CASE PRESENTATION: A twenty-nine-year-old primigravida with a history of lupus enteritis and paralytic ileus had a natural conception after less than two years of steroid treatment. An ultrasonographic study showed a thin uterine wall with a widespread thick placenta on the entire surface of the uterine cavity in the third trimester. At the 39th gestational week, she underwent a cesarean section due to the failure of the uterus to contract, even though the injection of oxytocin. There were several engorged vessels on the surface of the anterior uterine wall at the time of laparotomy. We decided to perform a hysterectomy because diffuse PAS replaced her uterus. CONCLUSION: A review of reported cases and our case shows an unusual complication of SLE that might be related to the particular condition of the estrogen-mediated immune system. Clinicians should always pay attention to the possibility of uterine wall thinning as uterine atony and the structural abnormality of the placenta for SLE patients with the unscarred uterus.

Obesity's Influence on Insulin Resistance in Pregnant Women with Polycystic Ovary Syndrome.

Polycystic ovary syndrome (PCOS) is a common endocrine metabolic disorder that is associated with high insulin resistance and obesity. However, ~70% of women with PCOS in Japan are non-obese. We retrospectively analyzed the cases of 163 Japanese women with PCOS who visited our Ob/Gyn department in 2006-2018 to determine which has a greater effect on insulin resistance: PCOS or obesity. We reviewed the women's medical records and calculated their insulin resistance and insulin secretion. The women's mean age and pre-pregnancy body mass index (BMI) were 30±5.8 years and 24.8±5.6 kg/m2, respectively; their mean ± SD fasting plasma glucose, 94.1±13.7 mg/dL; HOMA-IR, 2.1±2.0; QUICKI, 0.4±0.0; and HOMA-ß, 108.9±88.0%. Sixtyeight women were pregnant, and 37% (n=25) were obese (BMI ≥ 25 kg/m2). Obesity had a greater effect on insulin resistance: fasting plasma glucose F(1, 53)=6.134, p<0.05; fasting insulin F(1, 53)=31.606, p<0.01; HOMA-IR F(1, 53)=31.670, p<0.01; QUICKI F(1, 53)=16.156, p<0.01. There was no significant difference in values other than QUICKI and testosterone between the women with and without PCOS. Obesity thus had a greater effect on increased insulin resistance in pregnant women with PCOS. Further studies of the insulin resistance of non-obese women with PCOS is needed, as non-obese women with PCOS are common in Asia.

Non-Invasive Prenatal Genetic Testing (NIPT) Leading to Prenatal Diagnosis of Trisomy 21 Mosaicism and 18q Deletion Syndrome: Two Cases.

NIPT is non-definitive testing to estimate the possibility that fetuses have trisomy 21, trisomy 18, or trisomy 13. However, in NIPT-positive and indeterminate cases, rare chromosomal disease may become apparent, requiring advanced genetic considerations and counseling skills. We experienced two such cases, a trisomy 21 mosaicism case triggered by NIPT-positive status and 18q deletion syndrome triggered by NIPT-indeterminate status. These cases have two clinical implications for NIPT. First, it was revealed that trisomy mosaicism might be found in NIPT-positive cases that have lower Z-Scores than those inferred from the fraction of fetal cfDNA in the case of standard trisomy. Second, it is possible that microdeletion syndrome could be the reason for an indeterminate NIPT result. Today's genetic counseling requires more expertise in ethics and communication as well as genetic science because NIPT can lead to totally unexpected results.

Clinical Course of 60 Cesarean Scar Pregnancies.

Early diagnosis and therapy are important in a cesarean scar pregnancy (CSP), which can cause uterine rupture with resultant massive bleeding. However, there are some reports of CSPs continued to term. The optimal management of CSPs remains unclear; therefore, we investigated the clinical courses of CSPs diagnosed and treated at perinatal institutions in the Chugoku and Shikoku regions of Japan. We enrolled 60 women diag-nosed with CSP at 21 institutions from January 2006 to December 2015. Of the 60 women diagnosed with CSP, 57 were treated. Pregnancy was terminated in 48 women and continued in 9. Thirteen women underwent transabdominal hysterectomy; they experienced no postoperative complications or allogeneic blood transfu-sion. Nine women received therapies such as dilation and curettage, and 26 received non-surgical therapies such as methotrexate and topical administration of potassium chloride. Among 9 women who chose to con-tinue with their CSP, 7 successfully delivered newborns, 2 had uterine ruptures in the second trimester, and all women required transabdominal hysterectomy. Diagnosis and therapy in the first trimester of pregnancy are important in the management strategy of a CSP. When continuing a CSP, the risk of uterine rupture and trans-abdominal hysterectomy must be considered.

EG-VEGF Induces Invasion of a Human Trophoblast Cell Line via PROKR2.

Extravillous trophoblast (EVT) invasion is important for embryo implantation, placental development, and successful remodeling of the uterine spiral artery. Endocrine gland derived-vascular endothelial growth factor (EG-VEGF) and matrix metalloproteinases (MMPs) are implicated in EVT invasion; however, the high con-centrations found in pregnancy pathologies have not been investigated in non-tumor trophoblasts. The roles of EG-VEGF, prokineticin receptors (PROKR1/2), MMP-2, and MMP-9 in EVT invasion during spiral artery remodeling were evaluated using human EVT from HTR-8/SVneo cell lines. The expression of MMP-2, MMP-9, and mitogen-activated protein kinase (MAPK), and Akt pathways in HTR-8/SVneo cells treated with recom-binant EG-VEGF alongside anti-PROKR1 and/or anti-PROKR2 antibodies was evaluated using quantitative reverse transcription-PCR and western blotting. Wound-healing and cell invasion assays were performed to assess the migration and invasion of these treated cells. Interestingly, 20 nM EG-VEGF activated ERK1/2 sig-naling and upregulated MMP-2 and MMP-9. This effect was suppressed by anti-PROKR2 antibody via ERK1/2 downregulation. Anti-PROKR2 antibody inhibited the migration and invasion of EG-VEGF-stimulated HTR-8/SVneo cells. Elevated concentrations of EG-VEGF enhance EVT invasion in a human trophoblast cell line by upregulating MMP-2 and MMP-9 via PROKR2. These new insights into the regulation of epithelial cell invasion may help in developing therapeutic interventions for placental-related diseases during pregnancy.

Assessment of glucose kinetics with real-time continuous glucose monitoring during labor.

AIM: Changes in glucose levels during labor have not been sufficiently investigated in pregnant women. Using real-time continuous glucose monitoring, we aimed to assess glucose kinetics during labor among pregnant women with gestational diabetes mellitus (PwGDM), and those with normal glucose tolerance (PwNGT). METHODS: Japanese PwGDM and PwNGT who had planned a transvaginal delivery at Okayama University Hospital were enrolled. The correlation between changes in glucose levels during labor among the PwGDM and PwNGT groups at four time periods was assessed: (i) active phase of 1st stage of labor; (ii) 2nd stage of labor; (iii) postpartum 0-12 h; and (iv) postpartum 12-48 h. RESULTS: In total, 18 and 22 PwGDM and PwNGT, respectively, were enrolled. During labor, both groups had similar changes in glucose levels over time, which peaked during period 3. The main effect of glucose level changes was the labor period (P < 0.001), not the presence of gestational diabetes mellitus. Furthermore, differences in glucose levels in the PwGDM group were observed between periods 1 and 2 (P = 0.037), 1 and 3 (P = 0.024), 3 and 4 (P = 0.005); differences in glucose levels in the PwNGT group were observed between periods 3 and 4 (P = 0.024). CONCLUSION: During labor, both PwGDM and PwNGT groups showed similar changes in glucose levels over time. During delivery, the PwGDM who regularly measured their own glucose levels could be managed using the same nutritional management methods as those for PwNGT.

Relationship between Intracellular Signaling of the (Pro)renin Receptor and the Pathogenesis of Preeclampsia.

An association between preeclampsia and (pro)renin was recently reported. Intracellular signaling of the (pro) renin receptor [(P)RR] increases the expressions of TGF-ß and PAI-1. In this study we sought to clarify the involvement of (pro)renin in the pathogenesis of preeclampsia via the intracellular signaling of (P)RR on preeclampsia placentas. Activated (pro)renin plasma concentrations were compared between pregnant women with (n=15) and without (n=28) preeclampsia. The placentas were immunohistochemically evaluated with anti-HIF-1α and anti-(P)RR antibodies. HTR-8/SVneo cells were cultured under hypoxic conditions and treated with human recombinant (pro)renin. The mRNA expressions of HIF-1α, (P)RR, PAI-1, TGF-ß, and ET-1 were also examined by real-time RCR. The activated (pro)renin plasma concentration was significantly higher in the third vs. the second trimester in the preeclampsia patients. HIF-1α and (P)RR expressions were significantly increased in the preeclampsia placentas. The mRNA expressions of PAI-1, TGF-ß, and ET-1 were significantly increased in the experiments using recombinant (pro)renin vs. hypoxic conditions. (P)RR expression in preeclampsia placentas is increased by persistent hypoxia through the second and third trimesters, and PAI-1, TGF-ß, and ET-1 production is increased via (P)RR. Our results suggest that ET-1 production via the intracellular signaling of (P)RR is important in the pathogenesis of preeclampsia.

Successful Delivery after Abdominal Radical Trachelectomy, Using Transabdominal Cerclage in Early Pregnancy.

Radical trachelectomy (RT) is a fertility-sparing surgery for cervical cancer. Postoperative pregnancies have a high risk of abortion and prematurity. To prevent this, a procedure involving transabdominal cerclage (TAC) was devised for shortened cervical canals post-RT. Here we describe the successful management of a pregnancy after abdominal RT (ART). The 34-year-old patient was gravida 1, para 0. When she was 27, she underwent ART for stage Ib1 cervical cancer, and she became pregnant 7 years later. Because her cervical canal was 16.7 mm during early pregnancy, we performed TAC at 12 weeks of pregnancy. Post-surgery, we administered an infusion of ritodrine hydrochloride for tocolysis. A selective caesarean section was performed at 36 weeks, with the delivery of a healthy infant.

A Case of Nager Syndrome Diagnosed Before Birth.

Nager syndrome is a rare disease involving severe micrognathia and upper limb shortening. In this report, we describe a case in which micrognathia of the fetus was suspected based on the observation of upper limb shortening during detailed B mode and 3D/4D ultrasonographic observation, and combined fetal MRI and 3D-CT led to a prenatal diagnosis of Nager syndrome. Upon birth, because severe micrognathia caused airway obstruction and made it difficult to spread the larynx for intubation, effective ventilation could not be carried out and a tracheostomy was necessary. Since a differential diagnosis of Nager syndrome can be made based on the fact that micrognathia typically co-occurs with upper limb shortening, it is possible to diagnose the disease before birth and prepare for life-saving measures accordingly.

Upregulation of Angiogenic Factors via Protein Kinase C and Hypoxia-induced Factor-1α Pathways under High-glucose Conditions in the Placenta.

Abnormal glucose metabolism during pregnancy is an established risk factor for preeclampsia (PE). Disruption of the balance between placental angiogenic factors is linked to PE pathophysiology. We examined whether hypoxia-induced factor-1α (HIF-1α) and protein kinase Cß (PKCß) are involved in the regulation of placental angiogenic factors under high-glucose conditions in vitro. The human choriocarcinoma cell lines BeWo and JEG-3, and the human trophoblast cell line HTR-8/SVneo were cultured with 10 and 25 mmol/L glucose [control glucose group (CG) and high-glucose group (HG), respectively]. We examined the changes in HIF-1α, soluble fms-like tyrosine kinase-1 (sFlt-1), placental growth factor (PlGF), and vascular endothelial growth factor (VEGF) expression in the CG and HG by real-time PCR and ELISA. PKC activation was also measured by ELISA. The expressions of HIF-1α, sFlt-1, PlGF, and VEGF were significantly higher in the HG than in the CG. PKC activity was significantly increased in the HG. High glucose affected the expression of angiogenic factors in choriocarcinoma cells via the PKCß and HIF-1α pathways, suggesting their involvement in PE pathogenesis.

Discrepancy between Non-invasive Prenatal Genetic Testing (NIPT) and Amniotic Chromosomal Test due to Placental Mosaicism: A Case Report and Literature Review.

We experienced a case of advanced maternal age in which a fetus was found to be positive for trisomy 18 at re-examination following indeterminate non-invasive prenatal genetic testing (NIPT), the amniotic fluid chromosomal test revealed a normal karyotype, and confined placental mosaicism (CPM) was observed in an SNP microarray analysis of the placenta. The child was born with no defects or complications. In the present case, the result of the original NIPT at week 15 of pregnancy was indeterminate and the subsequent re-examination result was positive; since the definitive normal diagnosis was not reported until the latter half of week 21, the pregnant patient was subjected to psychological stress for a long period of time. The problem with NIPT is that most of the fetus-derived cell-free DNA in the maternal blood is not derived directly from the fetus but from the villus cells of the placenta, leading to indefinite diagnoses; for that reason, the pregnant patient was subjected to psychological stress for a long period of time. Of the 18,251 cases undergoing NIPT in the past 2 years in Japan, 51 had indeterminate results; this was the second case in which a subsequent re-examination gave a positive result for trisomy 18.

Comparison of Kidney Function between Gestational Hypertension and Preeclampsia.

Although gestational hypertension (GH) is thought to be different from preeclampsia (PE), in Japan GH and PE are usually treated as the same disease (i.e., pregnancy-induced hypertension). Here we sought to determine whether there are any differences in fetal growth and maternal kidney function between pregnancies with PE and those with GH. We retrospectively analyzed 61 GH patients and 60 PE patients with singleton pregnancies who delivered at Okayama University Hospital (2008-2015). We compared maternal and perinatal outcomes and maternal kidney function parameters between the GH and PE pregnancies. The mean values of maternal age (p=0.01), gestational age at delivery (p<0.0001), placental weight (p=0.002), birth weight and height (p<0.0001, p=0.0001), and head circumference standard deviation score (p=0.007) of newborns of the GH group were significantly higher than those of the PE group. The duration until termination of PE or GH was not significantly correlated with kidney function. The birth weight percentile was significantly correlated with kidney function in PE but not GH. However, GH patients with poor kidney function and small-for-gestational age infants showed perinatal outcomes similar to those of the PE group. Monitoring kidney function is thus important for determining the severity of PE and GH.

Prenatal Diagnosis of Interrupted Aortic Arch: Usefulness of Three-Vessel and Four-Chamber Views.

Interrupted aortic arch (IAA) is fatal if not diagnosed. Prenatal diagnosis is helpful, but it is difficult to detect IAA and even more so to differentiate types A and B prenatally. Our objectives were to find a way to detect IAA using 2 views-three-vessel view (3VV) and four-chamber view (4CV)-and to differentiate between types A and B. We retrospectively analyzed fetal echocardiographic images and medical records of eight IAA patients. All eight patients had a ventricular septal defect (VSD) on 4CV. The aorta/main pulmonary artery (Ao/MPA) diameter ratio on 3VV was significantly low, which is characteristic of type B IAA. The left/right ventricular diameter (LV/RV) ratio on 4CV was 0.61± 0.17 for type A and almost 1.0 for type B. The thymus was not observed on 3VV in some type B IAA patients. These findings suggest that we could increase the number of prenatal diagnoses of IAA using the Ao/MPA ratio on 3VV and the presence of VSD on 4CV. Additionally, we could differentiate types A and B with the LV/RV ratio on 4CV, the Ao/MPA ratio, and the presence of a thymus on 3VV, which results in better management of IAA after birth.

Intrauterine twin environment and genetic factors subliminally affecting general movements in preterm infants.

BACKGROUND: Understanding background factors is beneficial for interpreting general movements (GMs). This study examines the factors involved in preterm-writhing GMs by comparing twins and singletons. METHOD: The subjects were 107 infants cared for at Oita University. The cohort consisted of very-low-birth-weight infants, including twins with a birth weight < 2000 g. The median gestational age (GA) was 29 weeks 1 day. The subjects consisted of 75 singletons, 32 twins (16 pairs), 20 monochorionic twins (M-twins), and 12 dichorionic twins (D-twins). GMs were scored according to the GMs optimality score (GMOS) and integrated into 6 items: the quality, neck-trunk and space, amplitude-speed, rotation, onset-offset and cramped, and tremulous score at 32-34 weeks, 35-36 weeks, and 37-42 weeks' GA. A hierarchical cluster analysis was performed using integrated GMOS, and the characteristics of clusters were examined according to clinical backgrounds. RESULTS: Three clusters were identified. Cluster 1 was characterized by good-quality GMs, cluster 2 by a poor repertoire but optimal space and rotatory components, and cluster 3 by overall poor-quality GMs, respectively. The mean GMOSs were 36.6, 31.8 and 24.3 in clusters 1, 2, and 3, respectively. There were no marked differences in proportions within clusters with respect to sex and twins. Small-for-gestational age (SGA) was significantly more frequent in cluster 3 at 32-34 weeks' GA than in other clusters. Perinatal brain injury had a significantly lower proportion in cluster 1 and a higher proportion in cluster 3 at 35-36 weeks' GA and 37-42 weeks' GA. M-twin pairs tended to belong to the same clusters at 35-36 weeks' GA. CONCLUSION: Preterm writhing GMs are associated with SGA and perinatal brain injury. Cluster matching in M-twins suggests that certain genetic factors may substantially influence GMs.

The adenosine deaminase family acting on RNA 1 can be a useful diagnostic biomarker in chorioamnionitis.

INTRODUCTION: Chorioamnionitis (CAM) involves infection and inflammation of the chorion and amniotic membrane, but there are still no effective diagnostic biomarkers for CAM. METHODS: We investigated the correlation between RNA editing enzyme Adenosine deaminase family acting on RNA 1 (ADAR1) and CAM in chorion and amniotic membrane specimens derived from premature rupture of the membrane (PROM), CAM (pathologically diagnosed), and clinical CAM (clinically diagnosed) patients using reverse transcription polymerase chain reaction (RT-PCR). RESULTS: ADAR1 was upregulated in the chorion and amniotic membrane specimens of CAM and clinical CAM patients (p < 0.001 and p = 0.005). ADAR1 had a significantly higher area under the curve (AUC) (0.735 and 0.828) than markers of inflammation characteristics in diagnosing CAM and clinical CAM patients. ADAR1 also had significantly higher AUC (0.701 and 0.837) than clinical characteristics for CAM and clinical CAM patients. DISCUSSION: ADAR1 can be a useful diagnostic biomarker in CAM patients.

Assessing the efficacy of simulation-based education for paramedics in extended focused assessment with sonography for trauma under physician guidance.

We investigated the effectiveness of simulation-based education in Focused Assessment with Sonography for Trauma (FAST) to increase the number of Emergency Medical Technicians (EMTs) capable of performing ultrasound examinations in vehicles under the guidance of a physician. Twenty-eight paramedics watched a 14-min video on the features of the ultrasound system, its use, and the scanning method for each part of the body. Each participant performed four FAST examinations using a portable ultrasound device, and the task performance was rated using the Task Specific Checklist (TSC) and Global Rating Scale (GRS). The time required for visualizing each examination site and each FAST was assessed. The mean time required for the first and fourth FAST was 144.6 ± 52.4 s and 90.5 ± 31.0 s, respectively. The time required for each test significantly decreased with repeated testing (p < 0.001). The time to complete FAST was significantly shortened for the pericardial cavity (33.4 ± 23.1/15.3 ± 10.6 s, p < 0.01), right thoracic cavity (25.2 ± 11.8/12.1 ± 8.3 s, p < 0.01), Morrison fossa (19.1 ± 10.8/10.8 ± 6.3 s, p < 0.05), and left thoracic cavity (19.0 ± 8.3/15.6 ± 8.3 s, p < 0.05). TSC and GRS scores were elevated, and all EMTs could obtain valid images. The combination of a brief video lecture and hands-on training significantly reduced the time required for FAST performance. Moreover, repeated practice enabled the EMTs to efficiently obtain accurate and clinically useful images.

Total laparoscopic wedge resection for an intramural ectopic pregnancy using an intraoperative ultrasound system: A case report.

Intramural pregnancy is a rare form of ectopic pregnancy, and the optimal treatment remains uncertain. We describe a 33-year-old woman (gravida 2, para 0) who visited our hospital with suspected ectopic pregnancy. The patient was asymptomatic and hemodynamically stable. Transvaginal ultrasonography revealed pregnancy at 6 weeks of gestation and a gestational sac and fetal heartbeat in the anterior muscular layer of the uterus, away from the endometrium. The fetal sac measured 26 mm. The serum human chorionic gonadotropin (hCG) level had increased to 27 655 mIU/mL. Accordingly, the patient was diagnosed with an intramural ectopic pregnancy and underwent total laparoscopic wedge resection using intraoperative ultrasonography. The postoperative course was uneventful, and she was discharged after 4 days. Her serum hCG level normalized at 26 days postoperatively. This case indicates that intraoperative laparoscopic ultrasonography seems viable for treating intramural pregnancies.

Endothelin-1 production via placental (pro)renin receptor in a mouse model of preeclampsia.

INTRODUCTION: Preeclampsia (PE) pathogenesis is explained by the two-stage disorder theory. However, mechanisms underlying hypertension and proteinuria in PE remain unclear. The role of (pro)renin receptor (PRR) in PE pathology has received special attention. We examined endothelin-1 (ET-1) production via placental PRR in a PE mouse model. METHODS: At 14.5 day-post-coitum (DPC), we performed a reduced uterine perfusion pressure (RUPP) operation, ligating the uterine arteriovenous vessels in female mice. We also infused these mice with a PRR inhibitor, decoy peptide in the handle region of prorenin (HRP) for mice (NH2-RIPLKKMPSV-COOH). At 18.5 DPC, blood, urine, and placenta were collected; fetus and placenta were weighed. We evaluated placental hypoxia using quantitative polymerase chain reaction (PCR), with hypoxia-inducible factor-1α (HIF-1α) as index. We also evaluated PRR, transforming growth factor-ß1 (TGF-ß1), and ET-1 expression in the placenta using quantitative PCR and western blotting. ET-1 concentration in blood plasma was assessed using enzyme-linked immunosorbent assay. RESULTS: Blood pressure and proteinuria significantly increased, and fetal and placental weights decreased in RUPP mice. HIF-1α, PRR, TGF-ß1, and ET-1 expressions considerably increased in RUPP mice placentas. ET-1 concentration in RUPP mice blood plasma was markedly increased. PRR inhibitor suppressed these changes. DISCUSSION: In PE model mice that underwent RUPP treatment, placental hypoxia increased PRR and ET-1 expression suggesting a causative relationship between ET-1 and intracellular PRR signaling. RUPP treatment, when combined with HRP, reversed the effect of elevated ET-1 levels in the model. This study may help to elucidate the pathogenesis of PE considering PRR and ET-1.