Published Online
on February 7, 2008

A more recent version of this article appeared on April 1, 2008

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Submitted on July 10, 2007
Revised on July 31, 2007

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 Chenyi Zhou; Shakil Ahmad; Tiejuan Mi; Shahrzad Abbasi; Lingwei Xia; Mary-Clare Day; Susan M. Ramin; Asif Ahmed; Rodney E. Kellems; and Yang Xia^*

From the Departments of Biochemistry and Molecular Biology (C.C.Z., T.M., S.A., L.X., R.E.K., Y.X.), Obstetrics, Gynecology, and Reproductive Sciences (M.-C.D., S.M.R.), and Reproductive and Vascular Biology (S.A., A.A.), Medical School, University of Birmingham, Edgbaston, Birmingham, West Midlands, United Kingdom.

^* To whom correspondence should be addressed. E-mail: yang.xia{at}uth.tmc.edu.

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.

Key words: preeclampsia • renin-angiotensin system • angiotensin receptor • autoantibody • angiogenesis • cell signaling

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