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Biol Reprod. 2016 Dec;95(6):132. doi: 10.1095/biolreprod.116.140293. Epub 2016 Nov 9.

PAD4 Deficiency Decreases Inflammation and Susceptibility to Pregnancy Loss in a Mouse Model.

Author information

1
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts luise.erpenbeck@med.uni-goettingen.de.
2
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts.
3
Laboratory for Prenatal Medicine, Department of Biomedicine, University Hospital Basel, Basel, Switzerland.
4
Departments of Medicine, Obstetrics and Gynecology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts.
5
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
6
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.

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.

KEYWORDS:

NETs; angiogenesis; inflammation; placenta; preeclampsia

PMID:
28007693
PMCID:
PMC5315429
DOI:
10.1095/biolreprod.116.140293
[Indexed for MEDLINE]
Free PMC Article

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