title: 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.
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 (AT(1)) 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 AT(1) 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 AT(1) receptor to induce sFlt-1 synthesis and secretion by AT(1)-receptor activating autoantibodies. AT(1)-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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical School, University of Birmingham, Edgbaston, Birmingham, West Midlands, United Kingdom.
authors.forename: Cissy Chenyi
authors.initials: CC
authors.lastname: Zhou
authors.forename: Shakil
authors.initials: S
authors.lastname: Ahmad
authors.forename: Tiejuan
authors.initials: T
authors.lastname: Mi
authors.forename: Shahrzad
authors.initials: S
authors.lastname: Abbasi
authors.forename: Lingwei
authors.initials: L
authors.lastname: Xia
authors.forename: Mary-Clare
authors.initials: MC
authors.lastname: Day
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ramin
authors.forename: Asif
authors.initials: A
authors.lastname: Ahmed
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D050778:NFATC Transcription Factors / Q000378:metabolism; D011225:Pre-Eclampsia / Q000276:immunology* / Q000378:metabolism; D011247:Pregnancy; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014327:Trophoblasts / Q000166:cytology / Q000276:immunology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D050778:NFATC Transcription Factors; D044140:Receptor, Angiotensin, Type 1; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D019703:Calcineurin