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


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.

Publication DOI:
Divisions: College of Health & Life Sciences > School of Biosciences
College of Health & Life Sciences > School of Biosciences > Cellular and Molecular Biomedicine
College of Health & Life Sciences > Aston Medical School
College of Health & Life Sciences
Additional Information: © 2008, Wolters Kluwer Health
Uncontrolled Keywords: preeclampsia,renin-angiotensin system,angiotensin receptor,autoantibody,angiogenesis,cell signaling,Internal Medicine
Publication ISSN: 1524-4563
Last Modified: 31 May 2024 07:10
Date Deposited: 06 Oct 2014 10:55
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
http://hyper.ah ... ntent/51/4/1010 (Publisher URL)
PURE Output Type: Article
Published Date: 2008-07-02
Authors: Zhou, Cissy C.
Ahmad, Shakil (ORCID Profile 0000-0002-9294-0475)
Mi, Tiejuan
Abbasi, Shahrzad
Xia, Lingwei
Day, Mary-Clare
Ramin, Susan M.
Ahmed, Asif (ORCID Profile 0000-0002-8755-8546)
Kellems, Rodney E.
Xia, Yang



Version: Accepted Version

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