The thrombomodulin–protein C system is essential for the maintenance of pregnancy

Isermann, Berend; Sood, Rashmi; Pawliński, Rafał; Zogg, Mark; Kalloway, Shawn; Degen, Jay L.; Mackman, Nigel; Weiler, Hartmut

doi:10.1038/nm825

Cited by 245 publications

(229 citation statements)

References 45 publications

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“…Mouse trophoblast stem (TS) cells were obtained from J. Rossant (Hospital for Sick Children, Toronto, ON, Canada) and were maintained as stem cells or induced to differentiate as previously described (Isermann et al, 2003;Tanaka et al, 1998). Syncytiotrophoblast formation was monitored in nearly confluent TS cells differentiated for 6 days.…”

Section: Mouse Trophoblast Cell Culture and In Vitro Syncytium Formationmentioning

confidence: 99%

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

et al. 2011

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SUMMARYAbsence of the leucine zipper transcription factor p45NF-E2 results in thrombocytopenia, impaired placental vascularization and intrauterine growth restriction (IUGR) in mice. The mechanism underlying the p45NF-E2-dependent placental defect and IUGR remains unknown. Here, we show that the placental defect and IUGR of p45NF-E2 (Nfe2) null mouse embryos is unrelated to thrombocytopenia, establishing that embryonic platelets and platelet-released mediators are dispensable for placentation. Rather, p45NF-E2, which was hitherto thought to be specific to hematopoietic cells, is expressed in trophoblast cells, where it is required for normal syncytiotrophoblast formation, placental vascularization and embryonic growth. Expression of p45NF-E2 in labyrinthine trophoblast cells colocalizes with that of Gcm1, a transcription factor crucial for syncytiotrophoblast formation. In the absence of p45NF-E2, the width of syncytiotrophoblast layer 2 and the expression of Gcm1 and Gcm1-dependent genes (Synb and Cebpa) are increased. In vitro, p45NF-E2 deficiency results in spontaneous syncytiotrophoblast formation, which can be reversed by Gcm1 knockdown. Increased Gcm1 expression in the absence of p45NF-E2 is dependent on enhanced protein acetylation, including post-translational modification of Gcm1. Increasing and inhibiting acetylation in the placenta of wild-type control embryos phenocopies and corrects, respectively, the changes observed in p45NF-E2-deficient embryos. These studies identify a novel function of p45NF-E2 during placental development: in trophoblast cells, p45NF-E2 represses Gcm1 and syncytiotrophoblast formation via acetylation.

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Section: Mouse Trophoblast Cell Culture and In Vitro Syncytium Formationmentioning

confidence: 99%

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

et al. 2011

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“…1). The critical role of fibrin and fibrinogen degradation products in the maintenance of pregnancy is under investigation [8].…”

Section: Discussionmentioning

confidence: 99%

Pregnancy‐related thrombosis in a woman with congenital afibrinogenemia: A report of two successful pregnancies

et al. 2004

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We managed two pregnancies in a woman with congenital afibrinogenemia with increasing amounts of cryoprecipitate to achieve a pre-infusion fibrinogen level of 60 mg/dL. The first pregnancy resulted in placental abruption at 36 weeks, in spite of recent cryoprecipitate infusion. Both placentas showed infarction. Post-partum ovarian and renal vein thromboses complicated the second pregnancy. Mean FVIII (344%) and vWF Antigen (323%) were elevated prior to cryoprecipitate infusion, with mean post-infusion levels of 367% and 363%. The clearance of fibrinogen after cryoprecipitate infusion increased during the course of pregnancy. A paradoxical prothrombotic state with embolization may play a role in the observed complications of pregnancy. Am.

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“…However, thrombomodulin-deficient mice, which lack the important natural anticoagulant protein C pathway, are unable to carry their fetuses beyond 8.5 weeks gestational age, and dead fetuses are usually resorbed within 24 hours. (12) Elegant experiments have shown that fetal demise is caused by tissue factor-dependent activation of blood coagulation at the feto-maternal interface. Activated coagulation factors were found to induce cell death and inhibit growth of trophoblast cells.…”

mentioning

confidence: 99%

Low-molecular-weight heparins have no place in recurrent miscarriage: Debate – For the motion

Middeldorp

2011

Thrombosis Research

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The thrombomodulin–protein C system is essential for the maintenance of pregnancy

Cited by 245 publications

References 45 publications

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

p45NF-E2 represses Gcm1 in trophoblast cells to regulate syncytium formation, placental vascularization and embryonic growth

Pregnancy‐related thrombosis in a woman with congenital afibrinogenemia: A report of two successful pregnancies

Low-molecular-weight heparins have no place in recurrent miscarriage: Debate – For the motion

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