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.
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9 November 2016
PAD4 Deficiency Decreases Inflammation and Susceptibility to Pregnancy Loss in a Mouse Model
Luise Erpenbeck,
Chanchal sur Chowdhury,
Zsuzsanna K. Zsengellér,
Maureen Gallant,
Suzanne D. Burke,
Stephen Cifuni,
Sinuhe Hahn,
Denisa D. Wagner,
S. Ananth Karumanchi
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Biology of Reproduction
Vol. 95 • No. 6
December 2016
Vol. 95 • No. 6
December 2016
angiogenesis
Inflammation
NETs
placenta
preeclampsia