title: Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity.
abstract: In 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.
authors.affiliation: 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.).
authors.forename: Kirsten R
authors.initials: KR
authors.lastname: Palmer
authors.affiliation: 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.).
authors.forename: Tu'uhevaha J
authors.initials: TJ
authors.lastname: Kaitu'u-Lino
authors.affiliation: 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.).
authors.forename: Roxanne
authors.initials: R
authors.lastname: Hastie
authors.affiliation: 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.).
authors.forename: Natalie J
authors.initials: NJ
authors.lastname: Hannan
authors.affiliation: 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.).
authors.forename: Louie
authors.initials: L
authors.lastname: Ye
authors.affiliation: 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.).
authors.forename: Natalie
authors.initials: N
authors.lastname: Binder
authors.affiliation: 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.).
authors.forename: Ping
authors.initials: P
authors.lastname: Cannon
authors.affiliation: 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.).
authors.forename: Laura
authors.initials: L
authors.lastname: Tuohey
authors.affiliation: 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.).
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
authors.affiliation: 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.).
authors.forename: Alexis
authors.initials: A
authors.lastname: Shub
authors.affiliation: 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.). stong@unimelb.edu.au.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tong
mesh_terms: D000328:Adult; D020533:Angiogenesis Inhibitors / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007231:Infant, Newborn; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010920:Placenta / Q000378:metabolism*; D011225:Pre-Eclampsia / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D014327:Trophoblasts / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism* / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D020533:Angiogenesis Inhibitors; D020033:Protein Isoforms; D042461:Vascular Endothelial Growth Factor A; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: angiogenesis inhibitors; endothelial cells; preeclampsia; pregnancy; vascular endothelial growth factor A