title: Novel expression of EGFL7 in placental trophoblast and endothelial cells and its implication in preeclampsia.
abstract: The mammalian placenta is the site of nutrient and gas exchange between the mother and fetus, and is comprised of two principal cell types, trophoblasts and endothelial cells. Proper placental development requires invasion and differentiation of trophoblast cells, together with coordinated fetal vasculogenesis and maternal vascular remodeling. Disruption in these processes can result in placental pathologies such as preeclampsia (PE), a disease characterized by late gestational hypertension and proteinuria. Epidermal Growth Factor Like Domain 7 (EGFL7) is a largely endothelial-restricted secreted factor that is critical for embryonic vascular development, and functions by modulating the Notch signaling pathway. However, the role of EGFL7 in placental development remains unknown. In this study, we use mouse models and human placentas to begin to understand the role of EGFL7 during normal and pathological placentation. We show that Egfl7 is expressed by the endothelium of both the maternal and fetal vasculature throughout placental development. Importantly, we uncovered a previously unknown site of EGFL7 expression in the trophoblast cell lineage, including the trophectoderm, trophoblast stem cells, and placental trophoblasts. Our results demonstrate significantly reduced Egfl7 expression in human PE placentas, concurrent with a downregulation of Notch target genes. Moreover, using the BPH/5 mouse model of PE, we show that the downregulation of Egfl7 in compromised placentas occurs prior to the onset of characteristic maternal signs of PE. Together, our results implicate Egfl7 as a possible factor in normal placental development and in the etiology of PE.
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, Box 60, New York, NY 10065, United States. Electronic address: lal2018@med.cornell.edu.
authors.forename: Lauretta A
authors.initials: LA
authors.lastname: Lacko
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Electronic address: micol9@libero.it.
authors.forename: Micol
authors.initials: M
authors.lastname: Massimiani
authors.affiliation: Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T9-014 Veterinary Research Tower, Ithaca, NY 14853, United States. Electronic address: jll74@cornell.edu.
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Sones
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, 1300 York Avenue, New York, NY 10065, United States. Electronic address: roh2002@med.cornell.edu.
authors.forename: Romulo
authors.initials: R
authors.lastname: Hurtado
authors.affiliation: Department of Gynecology and Obstetrics, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, 00168 Rome, Italy. Electronic address: silvia.salvi@edu.rm.unicatt.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Salvi
authors.affiliation: Department of Gynecology and Obstetrics, Catholic University of the Sacred Heart, Largo Agostino Gemelli 8, 00168 Rome, Italy. Electronic address: s.ferrazzani@rm.unicatt.it.
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrazzani
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, Box 60, New York, NY 10065, United States; Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, T9-014 Veterinary Research Tower, Ithaca, NY 14853, United States. Electronic address: rld2002@med.cornell.edu.
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
authors.affiliation: Department of Biomedicine and Prevention, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy. Electronic address: campagno@med.uniroma2.it.
authors.forename: Luisa
authors.initials: L
authors.lastname: Campagnolo
authors.affiliation: Department of Cell and Developmental Biology, Weill Cornell Medical College, 1300 York Avenue, Box 60, New York, NY 10065, United States. Electronic address: hes2011@med.cornell.edu.
authors.forename: Heidi
authors.initials: H
authors.lastname: Stuhlmann
mesh_terms: D000328:Adult; D000818:Animals; D002135:Calcium-Binding Proteins; D016022:Case-Control Studies; D019070:Cell Lineage; D004195:Disease Models, Animal; D015536:Down-Regulation; D066255:EGF Family of Proteins; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D016228:Endothelial Growth Factors / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D010920:Placenta / Q000378:metabolism* / Q000473:pathology; D010929:Placentation; D011225:Pre-Eclampsia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D014327:Trophoblasts / Q000378:metabolism / Q000473:pathology
chemical_list: D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C527877:EGFL7 protein, human; C479627:Egfl7 protein, mouse; D016228:Endothelial Growth Factors; D011506:Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch
keywords: EGFL7; Endothelium; Notch signaling; Placenta; Preeclampsia; Trophoblast
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