title: Translational analysis of mouse and human placental protein and mRNA reveals distinct molecular pathologies in human preeclampsia.
abstract: Preeclampsia (PE) adversely impacts ~5% of pregnancies. Despite extensive research, no consistent biomarkers or cures have emerged, suggesting that different molecular mechanisms may cause clinically similar disease. To address this, we undertook a proteomics study with three main goals: (1) to identify a panel of cell surface markers that distinguish the trophoblast and endothelial cells of the placenta in the mouse; (2) to translate this marker set to human via the Human Protein Atlas database; and (3) to utilize the validated human trophoblast markers to identify subgroups of human preeclampsia. To achieve these goals, plasma membrane proteins at the blood tissue interfaces were extracted from placentas using intravascular silica-bead perfusion, and then identified using shotgun proteomics. We identified 1181 plasma membrane proteins, of which 171 were enriched at the maternal blood-trophoblast interface and 192 at the fetal endothelial interface with a 70% conservation of expression in humans. Three distinct molecular subgroups of human preeclampsia were identified in existing human microarray data by using expression patterns of trophoblast-enriched proteins. Analysis of all misexpressed genes revealed divergent dysfunctions including angiogenesis (subgroup 1), MAPK signaling (subgroup 2), and hormone biosynthesis and metabolism (subgroup 3). Subgroup 2 lacked expected changes in known preeclampsia markers (sFLT1, sENG) and uniquely overexpressed GNA12. In an independent set of 40 banked placental specimens, GNA12 was overexpressed during preeclampsia when co-incident with chronic hypertension. In the current study we used a novel translational analysis to integrate mouse and human trophoblast protein expression with human microarray data. This strategy identified distinct molecular pathologies in human preeclampsia. We conclude that clinically similar preeclampsia patients exhibit divergent placental gene expression profiles thus implicating divergent molecular mechanisms in the origins of this disease.
authors: The Hospital for Sick Children, Program in Developmental and Stem Cell Biology, Toronto, Ontario, Canada.
authors: Brian
authors: B
authors: Cox
authors: Parveen
authors: P
authors: Sharma
authors: Andreas I
authors: AI
authors: Evangelou
authors: Kathie
authors: K
authors: Whiteley
authors: Vladimir
authors: V
authors: Ignatchenko
authors: Alex
authors: A
authors: Ignatchenko
authors: Dora
authors: D
authors: Baczyk
authors: Marie
authors: M
authors: Czikk
authors: John
authors: J
authors: Kingdom
authors: Janet
authors: J
authors: Rossant
authors: Anthony O
authors: AO
authors: Gramolini
authors: S Lee
authors: SL
authors: Adamson
authors: Thomas
authors: T
authors: Kislinger
mesh_terms: D000465:Algorithms; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D001185:Artificial Intelligence; D001499:Bayes Theorem; D015415:Biomarkers / Q000378:metabolism; D000071063:Endoglin; D004727:Endothelium / Q000378:metabolism; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015726:Giant Cells / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D011225:Pre-Eclampsia / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D012984:Software; D057170:Translational Research, Biomedical; D014327:Trophoblasts / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C064206:ENG protein, human; D000071063:Endoglin; D008565:Membrane Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D044365:GTP-Binding Protein alpha Subunits, G12-G13