title: Nuclear factor of activated T-cells (NFAT) regulates soluble fms-like tyrosine kinase-1 secretion (sFlt-1) from human placenta.
abstract: Preeclampsia is a serious complication affecting 5-8% of pregnancies. Central to its pathogenesis is placental hypoxia and inflammation which leads to secretion of soluble fms-like tyrosine kinase 1 (sFlt-1). sFlt-1 causes widespread endothelial dysfunction. The molecular mechanisms regulating sFlt-1 production remain poorly understood. Recently, a binding site for the nuclear factor activated T cells (NFAT) transcription factor has been found on fms-like tyrosine kinase 1 (FLT-1) promoter.
  
  
  
  We assessed whether inhibiting NFAT impacts FLT-1, sFlt-1 and cytokine expression, as well as sFlt-1 secretion in primary cytotrophoblasts, placental explants and human umbilical vein endothelial cells (HUVECs). We investigated whether NFAT is regulated by hypoxia in primary cytotrophoblasts. We characterised the expression of NFAT1-4 in preterm preeclamptic compared to gestationally matched placentas.
  
  
  
  Inhibiting NFAT reduced FLT-1 and sFlt-1 splice variant e15a transcription, concordant with reduced total sFlt-1 and sFlt-1 e15a secretion from primary human cytotrophoblasts. This effect appeared tissue specific as inhibiting NFAT did not change sFlt-1 secretion from endothelial cells. Inhibiting NFAT also reduced transcription of inflammatory cytokines IL-1β and IL-10 in primary cytotrophoblasts. NFAT1 and NFAT3 mRNA expression were significantly increased under hypoxia (1% O2). Inhibiting NFAT under hypoxia significantly reduced FLT-1 and sFlt-1 e15a transcription, but did not reduce sFlt-1 secretion. NFAT mRNA and protein localisation was not different in preeclamptic compared to gestationally matched placenta.
  
  
  
  NFAT positively regulates placental FLT-1 and sFlt-1 e15a, secretion of sFlt-1 and inflammatory cytokine expression. It may be involved in the pathophysiology of preeclampsia.
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.
authors.forename: Louie
authors.initials: L
authors.lastname: Ye
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.
authors.forename: Amy
authors.initials: A
authors.lastname: Gratton
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.
authors.forename: Ping
authors.initials: P
authors.lastname: Cannon
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.
authors.forename: Minh
authors.initials: M
authors.lastname: Deo
authors.affiliation: Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, 246 Clayton Rd, Clayton, 3168, Victoria, Australia.
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Palmer
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia. Electronic address: t.klino@unimelb.edu.au.
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
authors.affiliation: Translational Obstetrics Group, The Department of Obstetrics and Gynaecology, Mercy Hospital for Women, University of Melbourne, 163 Studley Rd, Heidelberg, 3084, Victoria, Australia.
authors.forename: Fiona C
authors.initials: FC
authors.lastname: Brownfoot
mesh_terms: D015687:Cell Hypoxia / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism*; D011247:Pregnancy; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D050778:NFATC Transcription Factors; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Hypoxia; NFAT; Preeclampsia; sFlt-1