title: Soluble endoglin contributes to the pathogenesis of preeclampsia.
abstract: Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.
authors.affiliation: Center for Vascular Biology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Shivalingappa
authors.initials: S
authors.lastname: Venkatesha
authors.forename: Mourad
authors.initials: M
authors.lastname: Toporsian
authors.forename: Chun
authors.initials: C
authors.lastname: Lam
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Hanai
authors.forename: Tadanori
authors.initials: T
authors.lastname: Mammoto
authors.forename: Yeon M
authors.initials: YM
authors.lastname: Kim
authors.forename: Yuval
authors.initials: Y
authors.lastname: Bdolah
authors.forename: Kee-Hak
authors.initials: KH
authors.lastname: Lim
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Yuan
authors.forename: Towia A
authors.initials: TA
authors.lastname: Libermann
authors.forename: Isaac E
authors.initials: IE
authors.lastname: Stillman
authors.forename: Drucilla
authors.initials: D
authors.lastname: Roberts
authors.forename: Patricia A
authors.initials: PA
authors.lastname: D'Amore
authors.forename: Franklin H
authors.initials: FH
authors.lastname: Epstein
authors.forename: Frank W
authors.initials: FW
authors.lastname: Sellke
authors.forename: Roberto
authors.initials: R
authors.lastname: Romero
authors.forename: Vikas P
authors.initials: VP
authors.lastname: Sukhatme
authors.forename: Michelle
authors.initials: M
authors.lastname: Letarte
authors.forename: S Ananth
authors.initials: SA
authors.lastname: Karumanchi
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D000071063:Endoglin; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D005865:Gestational Age; D006439:Hemodynamics; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D008969:Molecular Sequence Data; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010920:Placenta / Q000378:metabolism / Q000473:pathology; D011225:Pre-Eclampsia / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D011247:Pregnancy; D011270:Pregnancy, Animal; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D052250:Nitric Oxide Synthase Type III; C501164:Flt1 protein, rat; D040281:Vascular Endothelial Growth Factor Receptor-1