Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-cells signaling

Cissy C. Zhou, Shakil Ahmad, Tiejuan Mi, Shahrzad Abbasi, Lingwei Xia, Mary-Clare Day, Susan M. Ramin, Asif Ahmed, Rodney E. Kellems, Yang Xia

Research output: Contribution to journalArticle

Abstract

Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Recent evidence indicates that maternal endothelial dysfunction in preeclampsia results from increased soluble Fms-like tyrosine kinase-1 (sFlt-1), a circulating antiangiogenic protein. Factors responsible for excessive production of sFlt-1 in preeclampsia have not been identified. We tested the hypothesis that angiotensin II type 1 (AT1) receptor activating autoantibodies, which occur in women with preeclampsia, contribute to increased production of sFlt-1. IgG from women with preeclampsia stimulates the synthesis and secretion of sFlt-1 via AT1 receptor activation in pregnant mice, human placental villous explants, and human trophoblast cells. Using FK506 or short-interfering RNA targeted to the calcineurin catalytic subunit mRNA, we determined that calcineurin/nuclear factor of activated T-cells signaling functions downstream of the AT1 receptor to induce sFlt-1 synthesis and secretion by AT1-receptor activating autoantibodies. AT1-receptor activating autoantibody–induced sFlt-1 secretion resulted in inhibition of endothelial cell migration and capillary tube formation in vitro. Overall, our studies demonstrate that an autoantibody from women with preeclampsia induces sFlt-1 production via angiotensin receptor activation and downstream calcineurin/nuclear factor of activated T-cells signaling. These autoantibodies represent potentially important targets for diagnosis and therapeutic intervention.
Original languageEnglish
Pages (from-to)1010-1019
Number of pages10
JournalHypertension
Volume51
Issue number4
DOIs
Publication statusPublished - 2 Jul 2008

Bibliographical note

© 2008, Wolters Kluwer Health

Keywords

  • preeclampsia
  • renin-angiotensin system
  • angiotensin receptor
  • autoantibody
  • angiogenesis
  • cell signaling

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