Pravastatin prevents miscarriages in mice: role of tissue factor in placental and fetal injury.
Pregnancy loss and intrauterine growth restriction (IUGR) are serious pregnancy complications, and the triggers and mediators of placental and fetal damage are not completely understood. Using a mouse model of recurrent spontaneous miscarriages (DBA/2-mated CBA/J mice) that shares features with human recurrent miscarriage and fetal growth restriction, we identified tissue factor (TF) as an essential participating factor in placental and fetal injury. We have previously shown that C5a releases antiangiogenic molecule sFlt-1 in monocytes that causes defective placental development and fetal death in DBA/2-mated CBA/J mice. In this study, we found that TF not only activates the coagulation pathway, but it also mediates sFlt-1 release in monocytes causing defective placental development and fetal death. Blockade of TF with a monoclonal antibody inhibited sFlt-1 release, prevented the pathological activation of the coagulation pathway, restored placental blood flow, prevented placental oxidative stress, and rescued pregnancies. We also demonstrated that pravastatin, by down-regulating TF expression on monocytes and trophoblasts, prevented placental damage and protected pregnancies in DBA/2-mated CBA/J mice. These studies indicate that TF is an important mediator in fetal death and growth restriction and that statins may be a good treatment for women with recurrent miscarriages and IUGR.
Redecha
Patricia
P
Department of Medicine, Weill Medical College at Cornell University, New York, NY, USA.
van Rooijen
Nico
N
Torry
Donald
D
Girardi
Guillermina
G
D000022:Abortion, Spontaneous / Q000378:metabolism* / Q000517:prevention & control*; D000818:Animals; D000831:Animals, Newborn / Q000293:injuries / Q000378:metabolism; D000925:Anticoagulants / Q000494:pharmacology; D000990:Antithrombin III / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D018384:Oxidative Stress; D010920:Placenta / Q000098:blood supply / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology*; D011247:Pregnancy; D011485:Protein Binding; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism*; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism
D000925:Anticoagulants; D009589:Nitrogen Oxides; D000990:Antithrombin III; D013925:Thromboplastin; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D013917:Thrombin; D017035:Pravastatin