title: PAD4 Deficiency Decreases Inflammation and Susceptibility to Pregnancy Loss in a Mouse Model.
abstract: Inflammation is thought to play a critical role in the pathogenesis of placentation disorders such as recurrent miscarriages, growth restriction, and preeclampsia. Recently, neutrophil extracellular traps (NETs) have emerged as a potential mechanism for promoting inflammation in both infectious and noninfectious disorders. To investigate a pathogenic role for NETs in placentation disorders, we studied a model of antiangiogenic factor-mediated pregnancy loss in wild-type (WT) mice and in mice deficient in peptidylarginine deiminase 4 (Padi4-/-) that are unable to form NETs. Overexpression of soluble fms-like tyrosine kinase 1 (sFlt-1), an antiangiogenic protein that is pathogenically linked with abnormal placentation disorders during early gestation, resulted in pregnancy loss and large accumulation of neutrophils and NETs in WT placentas. Interestingly, sFlt-1 overexpression in Padi4-/-mice resulted in dramatically lower inflammatory and thrombotic response, which was accompanied by significant reduction in pregnancy losses. Inhibition of NETosis may serve as a novel target in disorders of impaired placentation.
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts luise.erpenbeck@med.uni-goettingen.de.
authors.forename: Luise
authors.initials: L
authors.lastname: Erpenbeck
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.|Laboratory for Prenatal Medicine, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Chanchal Sur
authors.initials: CS
authors.lastname: Chowdhury
authors.affiliation: Departments of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Zsuzsanna K
authors.initials: ZK
authors.lastname: Zsengellér
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Maureen
authors.initials: M
authors.lastname: Gallant
authors.affiliation: Departments of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Suzanne D
authors.initials: SD
authors.lastname: Burke
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Stephen
authors.initials: S
authors.lastname: Cifuni
authors.affiliation: Laboratory for Prenatal Medicine, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
authors.forename: Sinuhe
authors.initials: S
authors.lastname: Hahn
authors.affiliation: Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.|Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.|Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.affiliation: Departments of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
mesh_terms: D000022:Abortion, Spontaneous / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D065206:Extracellular Traps / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006867:Hydrolases / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D000080002:Protein-Arginine Deiminase Type 4; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D006867:Hydrolases; D000080002:Protein-Arginine Deiminase Type 4; C552151:peptidylarginine deiminase 4, mouse
keywords: NETs; angiogenesis; inflammation; placenta; preeclampsia