Pravastatin induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model
Keiichi KumasawaMasahito IkawaHiroyasu KidoyaHidetoshi HasuwaTomoko Saito‐FujitaYuka MoriokaNobuyuki TakakuraTadashi KimuraMasaru Okabe
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Preeclampsia is a relatively common pregnancy-related disorder. Both maternal and fetal lives will be endangered if it proceeds unabated. Recently, the placenta-derived anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG), have attracted attention in the progression of preeclampsia. Here, we established a unique experimental model to test the role of sFLT1 in preeclampsia using a lentiviral vector-mediated placenta-specific expression system. The model mice showed hypertension and proteinuria during pregnancy, and the symptoms regressed after parturition. Intrauterine growth restriction was also observed. We further showed that pravastatin induced the VEGF-like angiogenic factor placental growth factor (PGF) and ameliorated the symptoms. We conclude that our experimental preeclamptic murine model phenocopies the human case, and the model identifies low-dose statins and PGF as candidates for preeclampsia treatment.Keywords:
Intrauterine growth restriction
Placentation
Preeclampsia and intrauterine growth restriction are both characterized by placental malfunction. The pathological processes of abnormal trophoblast invasion, partial absence of maternal spiral artery modification, increased apoptosis of trophoblast cells, and placental ischemia are all associated with the release of specific molecules. These proteins, as well as cell‐free fetal DNA and RNA might be detected in the maternal peripheral circulation, quantified, and used for early identification and prediction of preeclampsia and intrauterine growth restriction, prior to the appearance of the clinical symptoms. As preeclampsia and intrauterine growth restriction are associated with increased maternal, perinatal, and neonatal morbidity and mortality, early identification of these pregnancy associated complications will permit the design of appropriate preventive measures. In this review a variety of factors reported to be useful as potential markers for early detection of pregnancies at increased risk will be discussed. Molecules associated with the establishment of the placenta and essential in fetal–maternal interactions, like interleukin 2‐receptor, insulinlike growth factor‐1, and insulinlike growth factor binding protein‐1, placenta growth factor, hepatocyte growth factor, inhibin A, activin A, and human chorionic gonadotrophin seem to be the most likely candidates for presymptomatic markers for preeclampsia and/or intrauterine growth restriction. Detection and discrimination of these molecules through the placental RNA in maternal plasma based strategy has become a realistic option.
Intrauterine growth restriction
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Preeclampsia is a serious pregnancy disorder that lacks effective treatments other than delivery. Improper sensing of oxygen changes during placentation by prolyl hydroxylases (PHDs), specifically PHD2, causes placental hypoxia-inducible factor-1 (HIF1) buildup and abnormal downstream signaling in early-onset preeclampsia, yet therapeutic targeting of HIF1 has never been attempted. Here we generated a conditional (placenta-specific) knockout of Phd2 in mice (Phd2–/– cKO) to reproduce HIF1 excess and to assess anti-HIF therapy. Conditional deletion of Phd2 in the junctional zone during pregnancy increased placental HIF1 content, resulting in abnormal placentation, impaired remodeling of the uterine spiral arteries, and fetal growth restriction. Pregnant dams developed new-onset hypertension at midgestation (E9.5) in addition to proteinuria and renal and cardiac pathology, hallmarks of severe preeclampsia in humans. Daily injection of acriflavine, a small molecule inhibitor of HIF1, to pregnant Phd2–/– cKO mice from E7.5 (prior to hypertension) or E10.5 (after hypertension had been established) to E14.5 corrected placental dysmorphologies and improved fetal growth. Moreover, it reduced maternal blood pressure and reverted renal and myocardial pathology. Thus, therapeutic targeting of the HIF pathway may improve placental development and function, as well as maternal and fetal health, in preeclampsia.
Placentation
Intrauterine growth restriction
Conditional gene knockout
Hypoxia
Trophoblast
Knockout mouse
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OBJECTIVE Previous studies have shown decreased levels of placenta growth factor in serum of pregnant women with preeclampsia. The aim of this study was to investigate whether levels of placenta growth factor are decreased before the clinical onset of preeclampsia, and whether placenta growth factor levels are decreased in pregnancies complicated by intrauterine growth restriction. METHODS From an ongoing longitudinal study, 101 plasma samples were collected from 72 pregnant women at weeks 11–21 of gestation. Placenta growth factor levels were determined retrospectively in plasma using an enzyme-linked immunosorbent assay. Correlations between plasma concentrations of placenta growth factor and pregnancy outcome were evaluated. RESULTS Plasma samples of 72 patients were analyzed. Forty-four patients had no pregnancy complications, 18 developed preeclampsia, and 10 women had pregnancies complicated by intrauterine growth restriction. Between week 17 and week 21 of pregnancy, a significantly lower level of placenta growth factor was found in plasma of patients who later developed preeclampsia (n = 10), compared with control pregnancies (n = 25, P = .004). In women with a growth-restricted baby at birth (n = 5), levels of placenta growth factor were also low. CONCLUSIONS Our results show that plasma placenta growth factor levels are decreased before preeclampsia is clinically evident. The data suggest that placenta growth factor may be useful to determine the relative risk of developing preeclampsia and intrauterine growth restriction.
Intrauterine growth restriction
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Preeclampsia is a relatively common pregnancy-related disorder. Both maternal and fetal lives will be endangered if it proceeds unabated. Recently, the placenta-derived anti-angiogenic factors, such as soluble fms-like tyrosine kinase-1 (sFLT1) and soluble endoglin (sENG), have attracted attention in the progression of preeclampsia. Here, we established a unique experimental model to test the role of sFLT1 in preeclampsia using a lentiviral vector-mediated placenta-specific expression system. The model mice showed hypertension and proteinuria during pregnancy, and the symptoms regressed after parturition. Intrauterine growth restriction was also observed. We further showed that pravastatin induced the VEGF-like angiogenic factor placental growth factor (PGF) and ameliorated the symptoms. We conclude that our experimental preeclamptic murine model phenocopies the human case, and the model identifies low-dose statins and PGF as candidates for preeclampsia treatment.
Intrauterine growth restriction
Placentation
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The multifactorial etiology of preeclampsia is contrasted by the fact that at the same time the presence of the placenta is a prerequisite for its development. Preeclampsia is related to a failure of the differentiation pathway of the villous trophoblast leading to an abnormal release of material into the maternal circulation. These factors shed from the placenta are involved in finally causing an inflammatory response of the mother. But the underlying cause and the developmental changes within the placenta leading to the placental dysfunction are unclear. Here we want to shed light on putative placental origins of preeclampsia, new markers that may be able to predict this syndrome already in the first trimester of pregnancy, and new strategies for putative therapeutics. These new therapies may be used to reduce the severity of the syndrome or even to stop the development of the clinical symptoms. Preeclampsia is a disease of placentation with a cause somewhen very early in gestation and the maternal systemic inflammatory response is the subject of clear debate and has led to the proposal of new treatment paradigms. Keywords: Preeclampsia, IUGR, placenta, trophoblast, apoptosis, aponecrosis, complement
Placentation
Trophoblast
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Intrauterine growth restriction
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Abstract Preeclampsia is a pregnancy-specific cardiovascular disorder and a leading cause of morbidity and mortality in pregnancy. Although inappropriate placental development and growth are recognized as root causes of preeclampsia, pathogenic mechanisms are poorly understood due to limited models of the disease, particularly in early pregnancy. Here, we first confirm the aberrant expression of important vascular and inflammatory proteins, FK506-binding protein like (FKBPL) and galectin-3 (Gal-3), in human plasma and placental tissue from women with/without preeclampsia. We then employ a 3D microfluidic placental model incorporating human umbilical vein endothelial cells (HUVECs) and a first trimester trophoblast cell line (ACH-3P) to investigate FKBPL and Gal-3 signalling in inflammatory conditions. In human samples, both circulating (n = 17 controls; n = 30 preeclampsia) and placental (n ≥ 6) FKBPL and Gal-3 levels were increased in preeclampsia compared to heathy controls (plasma: FKBPL, p < 0.0001; Gal-3, p < 0.01; placenta: FKBPL, p < 0.05; Gal-3, p < 0.01), indicative of vascular dysfunction in preeclampsia. In our placenta-on-a-chip model, we show that endothelial cells are critical for trophoblast-mediated migration and that trophoblasts effectively remodel the vasculature recapitulating placental development. Inflammatory cytokine tumour necrosis factor-α (10ng/ml) modulates both FKBPL and Gal-3 signalling in conjunction with trophoblast migration and impairs vasculature (p < 0.005). Our placenta-on-a-chip recapitulates aspects of aberrant placentation in preeclampsia and represents a promising platform for further placental research.
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Placentation
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The placenta plays a key role in sustaining fetal growth and development. Due to its position between mother and fetus, it is exposed to changes in the intrauterine environment in both circulations. The relative influence of changes in those circulations depends on the period of gestation. Early in pregnancy, maternal influences prevail and may affect the complex biological processes characteristic for this pregnancy period, such as placentation, early cell differentiation, and spiral artery remodeling. It is still unclear whether the placenta early in pregnancy is a friend or foe for the fetus. Later in pregnancy, when the fetal circulation is gradually establishing, fetal signals gain importance in regulating placental structure and function. Many of the placental alterations seen at term of pregnancy are the result of fetoplacental interactions often driven by fetal signals associated with maternal diabetes or obesity. These alterations, such as hypervascularization or enhanced cholesterol removal from placental endothelial cells, can be regarded as adaptations to maintain homeostasis at the fetoplacental interface and, thus, to protect the fetus. However, extreme conditions such as poorly controlled diabetes or pronounced obesity may exceed placental homeostatic capacity, with potentially adverse consequences for the fetus. Thus, in late pregnancy, the placenta acts mostly as a friend as long as the environmental perturbations do not exceed placental capacity for mounting adaptive responses.
Placentation
Fetal circulation
Spiral artery
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The etiology of preeclampsia consists of 2 stages, first, abnormal placentation which can increase ROS, and the inflammatory response then progresses to angiogenic imbalance. Pravastatin has a pleiotropic effect that can act as an antioxidant, anti-inflammatory, and anti-apoptotic, which is expected to be a vasodilator for angiogenic balance and reduce proinflammatory cytokines. This study aimed to examine the effect of pravastatin on the expression of angiogenic factors (sFlt-1 and VEGF) and inflammatory response (TNF-α and IL-10) in the placenta of preeclamptic rat models. This study is an experimental study, only post- test with a control group design using the placenta of preeclamptic rat models (L-NAME induced) and given pravastatin in 3 doses, namely 2 mg, 4 mg, and 8 mg.
Proinflammatory cytokine
Placentation
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Background. Although intrauterine presence of the placenta is essential in the etiology of preeclampsia (PE), case reports showed that the viability of the fetus influences the clinical course of PE and the intensity of the clinical symptoms. Aim. We examined the course of angiogenic factors soluble fms-like tyrosine kinase-1 receptors (sFlt-1) and placental growth factor (PlGF) in a case of severe early PE in week 22 + 1 of gestation, when fetal termination was required to stabilize maternal condition. Results. The cessation of the feto-placental perfusion via fetocide led to a reduction of the maternal sFlt-1 concentration of 8.3% which was associated with a decline of the sFlt-1/PlGF ratio from 405 to 334. Nevertheless, the highest change of the angiogenic factors was detected after ejection of the fetus and placenta. Conclusions. Our observations implicate that neither a vital fetus nor an intact feto-placental component is an obligatory prerequisite for the angiogenic imbalance that is associated with the preeclamptic phenotype.
Fetal circulation
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