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 (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.
Zhou
Cissy Chenyi
CC
Department of Biochemistry and Molecular Biology, Medical School, University of Birmingham, Edgbaston, Birmingham, West Midlands, United Kingdom.
Ahmad
Shakil
S
Mi
Tiejuan
T
Abbasi
Shahrzad
S
Xia
Lingwei
L
Day
Mary-Clare
MC
Ramin
Susan M
SM
Ahmed
Asif
A
Kellems
Rodney E
RE
Xia
Yang
Y
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*
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