title: Placental expression of miR-517a/b and miR-517c contributes to trophoblast dysfunction and preeclampsia.
abstract: Preeclampsia is a pregnancy specific hypertensive disease that confers significant maternal and fetal risks. While the exact pathophysiology of preeclampsia is unknown, it is widely accepted that placental dysfunction is mechanistically involved. Recent studies reported aberrant expression of placenta-specific microRNAs (miRNAs) in preeclampsia including miR-517a/b and miR-517c. Using placental biopsies from a preeclampsia case-control study, we found increased expression of miR-517a/b in term and preterm preeclampsia vs controls, while, miR-517c was increased only in preterm preeclampsia vs controls. To determine if miR-517a/b and miR-517c are regulated by hypoxia, we treated first trimester primary extravillous trophoblast cells (EVTs) with a hypoxia mimetic and found both were induced. To test for a mechanistic role in placental function, we overexpressed miR-517a/b or miR-517c in EVTs which resulted in decreased trophoblast invasion. Additionally, we found that miR-517a/b and miR-517c overexpression increased expression of the anti-angiogenic protein, sFLT1. The regulation of sFLT1 is mostly unknown, however, TNFSF15, a cytokine involved in FLT1 splicing, was also increased by miR-517a/b and miR-517c in EVTs. In summary, we demonstrate that miR-517a/b and miR-517c contribute to the development of preeclampsia and suggest that these miRNAs play a critical role in regulating trophoblast and placental function.
authors: Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Lauren
authors: L
authors: Anton
authors: Genomics and Computational Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pharmacology and the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Anthony O
authors: AO
authors: Olarerin-George
authors: Genomics and Computational Biology Graduate Group, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Department of Pharmacology and the Institute for Translational Medicine and Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: John B
authors: JB
authors: Hogenesch
authors: Maternal and Child Health Research Program, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors: Michal A
authors: MA
authors: Elovitz
mesh_terms: D016022:Case-Control Studies; D015687:Cell Hypoxia; D002465:Cell Movement; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010920:Placenta / Q000503:physiopathology*; D000072483:Placenta Growth Factor; D011225:Pre-Eclampsia / Q000235:genetics / Q000503:physiopathology*; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000032:analysis; D012326:RNA Splicing; D014327:Trophoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000235:genetics
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D035683:MicroRNAs; C000608036:PGF protein, human; D011257:Pregnancy Proteins; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D003035:Cobalt; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; C018021:cobaltous chloride