Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic Activity
| Autor: | Natalie K Binder, Alexis Shub, Louie Ye, Stephen Tong, Tu'uhevaha J Kaitu'u-Lino, Roxanne Hastie, Ping Cannon, Kirsten R Palmer, Natalie J. Hannan, Laura Tuohey, Terrance Grant Johns |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Vascular Endothelial Growth Factor A medicine.medical_specialty Placenta Blotting Western Angiogenesis Inhibitors Biology Preeclampsia chemistry.chemical_compound Pre-Eclampsia Cell Movement Pregnancy Internal medicine Human Umbilical Vein Endothelial Cells Internal Medicine medicine Animals Humans Protein Isoforms Endothelial dysfunction Cells Cultured Vascular Endothelial Growth Factor Receptor-1 Reverse Transcriptase Polymerase Chain Reaction Infant Newborn Kinase insert domain receptor medicine.disease Trophoblasts Mice Inbred C57BL Vascular endothelial growth factor B Endothelial stem cell Vascular endothelial growth factor Vascular endothelial growth factor A Endocrinology Microscopy Fluorescence Vascular endothelial growth factor C chemistry embryonic structures Female RNA Interference Signal Transduction |
| Zdroj: | Hypertension. 66:1251-1259 |
| ISSN: | 1524-4563 0194-911X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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