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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; 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.

Correspondence to Yang Xia, Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030. E-mail yang.xia{at}uth.tmc.edu

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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