Nuclear factor of activated T-cells (NFAT) regulates soluble fms-like tyrosine kinase-1 secretion (sFlt-1) from human placenta

Louie Ye, Amy Gratton, Natalie J. Hannan, Ping Cannon, Minh Deo, Kirsten R. Palmer, Steven Tong, Tu'uhevaha J. Kaitu'u-Lino, Fiona C Brownfoot

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5 Citations (Scopus)

Abstract

Introduction: 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.

Methods: 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.

Results: 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.

Discussion: 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.
Original languageEnglish
Pages (from-to)110-118
Number of pages9
JournalPlacenta
Volume48
DOIs
Publication statusPublished - Dec 2016

Keywords

  • Preeclampsia
  • Hypoxia
  • sFlt-1
  • NFAT

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