• Hypertension · Dec 2015

    Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity.

    • Kirsten R Palmer, Tu'uhevaha J Kaitu'u-Lino, Roxanne Hastie, Natalie J Hannan, Louie Ye, Natalie Binder, Ping Cannon, Laura Tuohey, Terrance G Johns, Alexis Shub, and Stephen Tong.
    • From the Translational Obstetrics Group (K.R.P., T.J.K.-L., R.H., N.J.H., L.Y., N.B., P.C., L.T., S.T.) and Department of Obstetrics and Gynaecology(K.R.P., T.J.K.-L., R.H., N.J.H., L.Y., N.B., P.C., L.T., A.S., S.T.), University of Melbourne, Mercy Hospital for Women, Heidelberg, Victoria, Australia; and Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia (T.G.J.).
    • Hypertension. 2015 Dec 1; 66 (6): 1251-9.

    AbstractIn preeclampsia, the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) is released from placenta into the maternal circulation, causing endothelial dysfunction and organ injury. A recently described splice variant, sFLT-1 e15a, is primate specific and the most abundant placentally derived sFLT-1. Therefore, it may be the major sFLT-1 isoform contributing to the pathophysiology of preeclampsia. sFLT-1 e15a protein remains poorly characterized: its bioactivity has not been comprehensively examined, and serum levels in normal and preeclamptic pregnancy have not been reported. We generated and validated an sFLT-1 e15a-specific ELISA to further characterize serum levels during pregnancy, and in the presence of preeclampsia. Furthermore, we performed assays to examine the bioactivity and antiangiogenic properties of sFLT-1 e15a protein. sFLT-1 e15a was expressed in the syncytiotrophoblast, and serum levels rose across pregnancy. Strikingly, serum levels were increased 10-fold in preterm preeclampsia compared with normotensive controls. We confirmed sFLT-1 e15a is bioactive and is able to inhibit vascular endothelial growth factor signaling of vascular endothelial growth factor receptor 2 and block downstream Akt phosphorylation. Furthermore, sFLT-1 e15a has antiangiogenic properties. sFLT-1 e15a decreased endothelial cell migration, invasion, and inhibited endothelial cell tube formation. Administering sFLT-1 e15a blocked vascular endothelial growth factor induced sprouts from mouse aortic rings ex vivo. We have demonstrated that sFLT-1 e15a is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Future development of diagnostics and therapeutics for preeclampsia should consider targeting placentally derived sFLT-1 e15a. © 2015 American Heart Association, Inc.

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