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.3-hydroxy-3-methyl-glutaryl-CoA | hemolytic anemia, elevated liver enzymes, and low platelet count | trophoblast P reeclampsia originates from placental insufficiency and is observed in ≈5% of pregnant females (1). Although preeclampsia is a major cause of maternal and infantile morbidity and mortality worldwide, the fundamental therapy available is to terminate the pregnancy. Therefore understanding the pathogenesis of preeclampsia is highly important and the generation of an appropriate animal model would be helpful to develop therapeutic drugs. In preeclamptic women, Maynard et al. found that increased soluble fms-like tyrosine kinase-1 (sFLT1) associated with decreased circulating levels of free VEGF and placental growth factor (PGF) (2). Because sFLT1 is a truncated form of VEGF receptor 1 and antagonizes VEGF and PGF function, impaired angiogenic signaling most likely results in endothelial dysfunction and preeclampsia (3).To establish an animal model of preeclampsia, placenta-specific gene manipulation is preferable because preeclampsia originates from a failure in placentation, and factors up-/ or down-regulated in the impaired placenta accentuate the symptoms. However, the lack of a facile and efficient method for placenta-specific gene manipulation has hampered the investigation of preeclampsia. The systemic administration of adenoviral vector (AdV-) expressing sFLT1 into pregnant rats resulted in classic signs of preeclampsia such as hypertension, proteinuria, and glomerular endotheliosis. However, unlike in patients, the sFLT1 expression in the rat model was transient and was mainly produced in the maternal liver, not in the placenta (2, 4). Previously, we and other groups have reported the placenta-specific transgenesis and expression by transducing blastocysts-stage embryos with HIV-I-based self-inactivating lentiviral vectors (5-7). The lentiviral vectors transduced the outermost layer of the blastocyst, the trophectoderm, that provides most of the main and functional components of the future placenta. By contrast, the vectors were not ab...

Preeclampsia, a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation, is the leading cause of maternal and perinatal morbidity and mortality. Maternal endothelial dysfunction caused by placental factors has long been accepted with respect to the pathophysiology of preeclampsia. Over the past decade, increased production of placental antiangiogenic factors has been identified as a placental factor leading to maternal endothelial dysfunction and systemic vascular dysfunction. This review summarizes the recent advances in understanding the molecular mechanisms of endothelial dysfunction caused by placental antiangiogenic factors, and the novel clinical strategies based on these discoveries.

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Of infants born to women with idiopathic thrombocytopenic purpura (ITP), about 10-15% have transient neonatal immune thrombocytopenic purpura (NITP). Of concern is the lack of a reliable predictor for NITP. We conducted a retrospective study of all pregnancies with ITP at Osaka University Hospital over the past 16 years analyzing a total of 127 pregnancies in 88 women with ITP to assess the predictive value of various clinical factors regarding neonatal platelet count in the current pregnancy. We also reviewed the literature concerning ITP in pregnancy and NITP prediction. Neonatal platelet counts were less than 100 3 10 9 /L in 20 of 130 neonates (15.4%), less than 50 3 10 9 /L in 11 neonates (8.5%), and less than 20 3 10 9 /L in three neonates (2.3%). There was a strong correlation between the first and second sibling regarding the occurrence and the severity of NITP with Spearman correlation coefficient of 0.55 (P 5 0.001) at birth and 0.63 (P < 0.0001) at nadir after birth. A maternal platelet count less than 100 3 10 9 /L at delivery showed a statistical trend for an association with the occurrence of NITP (P 5 0.043). Moreover, maternal ITP refractory to splenectomy correlated with a higher risk for fetal or neonatal ICH according to the review of the literature. In conclusion, pregnant women who have had a previous offspring with NITP or who have ITP refractory to splenectomy may be at particular risk of delivering an offspring with significant NITP. Management decisions, including mode of delivery, may be altered by the degree of risk for potentially severe NITP. Am. J. Hematol. 87:15-21, 2012. V

Preeclampsia is a systemic vascular disorder characterized by new-onset hypertension and proteinuria after 20 weeks of gestation. This condition targets several organs, including the kidneys, liver and brain, and is the leading cause of maternal and perinatal morbidity and mortality. Furthermore, recent evidence has revealed preeclampsia as a significant risk factor for future cardiovascular diseases in these women. Over the past decade, increasing evidence has indicated that maternal angiogenic imbalances caused by placental antiangiogenic factors play a central role in the systemic vascular dysfunction underling preeclampsia. The severity of the maternal antiangiogenic state correlates closely with maternal and perinatal outcomes. Assessing angiogenic imbalance and several vascular function tests have also emerged as a way of detecting systemic vascular dysfunction during pregnancy. This review summarizes the current understanding of the pathophysiology of preeclampsia, its clinical applications and clinical evidence for future cardiovascular risks.

Calponin 3 (CNN3), an actin binding molecule, negatively regulates trophoblast differentiation and fusion. CNN3 phosphorylation modulates the actin-binding capacity of CNN3 and most probably regulates cytoskeleton remodeling that renders cells capable of undergoing fusion.

BackgroundSheehan’s syndrome occurs because of severe postpartum hemorrhage causing ischemic pituitary necrosis. Sheehan’s syndrome is a well-known condition that is generally diagnosed several years postpartum. However, acute Sheehan’s syndrome is rare, and clinicians have little exposure to it. It can be life-threatening. There have been no reviews of acute Sheehan’s syndrome and no reports of successful pregnancies after acute Sheehan’s syndrome. We present such a case, and to understand this rare condition, we have reviewed and discussed the literature pertaining to it. An electronic search for acute Sheehan’s syndrome in the literature from January 1990 and May 2014 was performed.Case presentationA 27-year-old woman had massive postpartum hemorrhage (approximately 5000 mL) at her first delivery due to atonic bleeding. She was transfused and treated with uterine embolization, which successfully stopped the bleeding. The postpartum period was uncomplicated through day 7 following the hemorrhage. However, on day 8, the patient had sudden onset of seizures and subsequently became comatose. Laboratory results revealed hypothyroidism, hypoglycemia, hypoprolactinemia, and adrenal insufficiency. Thus, the patient was diagnosed with acute Sheehan’s syndrome. Following treatment with thyroxine and hydrocortisone, her condition improved, and she was discharged on day 24.Her next pregnancy was established 2 years after her first delivery. She required induction of ovulation for the next conception. The pregnancy, delivery, and postpartum period were uneventful. An electronic search of the literature yielded 21 cases of acute Sheehan’s syndrome. Presenting signs varied, including adrenal insufficiency (12 cases), diabetes insipidus (4 cases), hypothyroidism (2 cases), and panhypopituitarism (3 cases), with a median time of presentation after delivery for each of those conditions being 7.9, 4, 18, and 9 days, respectively. Serial changes in magnetic resonance imaging were reported in some cases of acute Sheehan’s syndrome.ConclusionClinicians should be aware of the risk of acute Sheehan’s syndrome after a massive postpartum hemorrhage in order to diagnose it accurately and treat it promptly.

Hypertensive disorder of pregnancy (HDP) is a serious pregnancy complication that is life threatening to both the mother and fetus. Understanding HDP pathophysiology is important for developing medical treatments. This study demonstrates the involvement of autophagy deficiency in adverse maternal and fetal outcomes using trophoblast-specific autophagy related (Atg)7, an autophagy-related protein, knockout mice. Atg7 conditional knockout (cKO) placentas were significantly smaller than controls in the spongiotrophoblast layer but not the labyrinth layer, which significantly elevated blood pressure in dams. A marker of autophagy deficiency, sequestosome 1/p62, was accumulated in giant trophoblast cells and in the spongiotrophoblast layer, accompanying increased apoptosis. However, neither proteinuria in dams nor fetal growth restriction was observed. Regarding trophoblast function, the number of trophoblasts migrating into the maternal decidua was significantly reduced, and the wall/lumen ratio of the spiral arteries was significantly increased in cKO placentas, suggesting shallow trophoblast invasion and inadequate vascular remodeling. The relative expression of placental growth factor mRNA was significantly decreased in cKO placentas compared with the control, likely causing poor placentation; however, other factors were unchanged in cKO placentas. This is the first report of autophagy deficiency leading to impaired placentation complicated by maternal HDP attributable to trophoblast dysfunction, and it suggests that placental autophagy is required for normal placentation.