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

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


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.

MeSH terms

  • Abortion, Spontaneous / genetics
  • Abortion, Spontaneous / metabolism*
  • Animals
  • Disease Models, Animal
  • Disease Susceptibility
  • Extracellular Traps / genetics
  • Extracellular Traps / metabolism*
  • Female
  • Hydrolases / genetics
  • Hydrolases / metabolism*
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Mice
  • Mice, Knockout
  • Neutrophils / metabolism
  • Placenta / metabolism
  • Pregnancy
  • Protein-Arginine Deiminase Type 4
  • Vascular Endothelial Growth Factor Receptor-1 / genetics
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism


  • Flt1 protein, mouse
  • Vascular Endothelial Growth Factor Receptor-1
  • Hydrolases
  • Protein-Arginine Deiminase Type 4
  • peptidylarginine deiminase 4, mouse