title: Activin and NADPH-oxidase in preeclampsia: insights from in vitro and murine studies.
abstract: OBJECTIVE
  Clinical management of preeclampsia has remained unchanged for almost 5 decades. We now understand that maternal endothelial dysfunction likely arises because of placenta-derived vasoactive factors. Activin A is one such antiangiogenic factor that is released by the placenta and that is elevated in maternal serum in women with preeclampsia. Whether activin has a role in the pathogenesis of preeclampsia is not known.
  
  
  METHODS
  To assess the effects of activin on endothelial cell function, we cultured human umbilical vein endothelial cells in the presence of activin or serum from normal pregnant women or pregnant women with preeclampsia, with or without follistatin, a functional activin antagonist or apocynin, a NADPH oxidase (Nox2) inhibitor. We also administered activin to pregnant C57Bl6 mice, with or without apocynin, and studied maternal and fetal outcomes. Last, we assessed endothelial cell Nox2 and nitric oxide synthase expression in normal pregnant women and pregnant women with preeclampsia.
  
  
  RESULTS
  Activin and preeclamptic serum induced endothelial cell oxidative stress by Nox2 up-regulation and endothelial cell dysfunction, which are effects that are mitigated by either follistatin or apocynin. The administration of activin to pregnant mice induced endothelial oxidative stress, hypertension, proteinuria, fetal growth restriction, and preterm littering. Apocynin prevented all of these effects. Compared with normal pregnant women, women with preeclampsia had increased endothelial Nox2 expression.
  
  
  CONCLUSIONS
  An activin-Nox2 pathway is a likely link between an injured placenta, endothelial dysfunction, and preeclampsia. This offers opportunities that are not novel therapeutic approaches to preeclampsia.
authors.affiliation: The Ritchie Centre, Monash Institute of Medical Research, Clayton, VIC, Australia; Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Lim
authors.affiliation: The Ritchie Centre, Monash Institute of Medical Research, Clayton, VIC, Australia.
authors.forename: Rutu
authors.initials: R
authors.lastname: Acharya
authors.affiliation: Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia.
authors.forename: Pavitra
authors.initials: P
authors.lastname: Delpachitra
authors.affiliation: Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia; Women's and Children's Program, Monash Health, Monash Medical Centre, Clayton, VIC, Australia.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hobson
authors.affiliation: Department of Pharmacology, Monash University, Clayton, VIC, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: Department of Pharmacology, Monash University, Clayton, VIC, Australia.
authors.forename: Grant R
authors.initials: GR
authors.lastname: Drummond
authors.affiliation: The Ritchie Centre, Monash Institute of Medical Research, Clayton, VIC, Australia; Department of Obstetrics and Gynecology, Monash University, Clayton, VIC, Australia; Women's and Children's Program, Monash Health, Monash Medical Centre, Clayton, VIC, Australia. Electronic address: euan.wallace@monash.edu.
authors.forename: Euan M
authors.initials: EM
authors.lastname: Wallace
mesh_terms: D028341:Activins / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000502:physiology*; D018384:Oxidative Stress; D011225:Pre-Eclampsia / Q000209:etiology*; D011247:Pregnancy; D015854:Up-Regulation
chemical_list: D028341:Activins; D019255:NADPH Oxidases
keywords: NADPH oxidase; activin; endothelium; oxidative stress; preeclampsia