title: ApoE Receptor 2 Mediation of Trophoblast Dysfunction and Pregnancy Complications Induced by Antiphospholipid Antibodies in Mice.
abstract: OBJECTIVE
  Pregnancies in women with the antiphospholipid syndrome (APS) are frequently complicated by fetal loss and intrauterine growth restriction (IUGR). How circulating antiphospholipid antibodies (aPL) cause pregnancy complications in APS is poorly understood. We sought to determine whether the low-density lipoprotein receptor family member apolipoprotein E receptor 2 (ApoER2) mediates trophoblast dysfunction and pregnancy complications induced by aPL.
  
  
  METHODS
  Placental and trophoblast ApoER2 expression was evaluated by immunohistochemistry and immunoblotting. Normal human IgG and aPL were purified from healthy individuals and APS patients, respectively. The role of ApoER2 in aPL-induced changes in trophoblast proliferation and migration and in kinase activation was assessed using RNA interference in HTR-8/SVneo cells. The participation of ApoER2 in aPL-induced pregnancy loss and IUGR was evaluated in pregnant ApoER2(+/+) and ApoER2(-/-) mice injected with aPL or normal human IgG.
  
  
  RESULTS
  We found that ApoER2 is abundant in human and mouse placental trophoblasts and in multiple trophoblast-derived cell lines, including HTR-8/SVneo cells. ApoER2 and its interaction with the cell surface protein β2 -glycoprotein I were required for aPL-induced inhibition of cultured trophoblast proliferation and migration. In parallel, aPL antagonism of Akt kinase activation by epidermal growth factor in trophoblasts was mediated by ApoER2. Furthermore, in a murine passive-transfer model of pregnancy complications of APS, ApoER2(-/-) mice were protected from both aPL-induced fetal loss and aPL-induced IUGR.
  
  
  CONCLUSIONS
  ApoER2 plays a major role in the attenuation of trophoblast function by aPL, and the receptor mediates aPL-induced pregnancy complications in vivo in mice. ApoER2-directed interventions can now potentially be developed to combat the pregnancy complications associated with APS.
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Victoria
authors.initials: V
authors.lastname: Ulrich
authors.affiliation: Department of Obstetrics and Gynecology, Weill Cornell Medical College, New York, New York.
authors.forename: Shari E
authors.initials: SE
authors.lastname: Gelber
authors.affiliation: Department of Medicine, Hospital for Special Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Milena
authors.initials: M
authors.lastname: Vukelic
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Sacharidou
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Rolf T
authors.initials: RT
authors.lastname: Urbanus
authors.affiliation: Clinical Chemistry and Hematology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Philip G
authors.initials: PG
authors.lastname: de Groot
authors.affiliation: Department of Reproductive Medicine, University of California-San Diego, San Diego, California.
authors.forename: David R
authors.initials: DR
authors.lastname: Natale
authors.affiliation: Department of Reproductive Medicine, University of California-San Diego, San Diego, California.
authors.forename: Anirudha
authors.initials: A
authors.lastname: Harihara
authors.affiliation: Department of Medicine, Hospital for Special Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Patricia
authors.initials: P
authors.lastname: Redecha
authors.affiliation: Department of Obstetrics, Gynecology & Reproductive Sciences, Divisions of Reproductive Sciences and Maternal-Fetal Medicine, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Vikki M
authors.initials: VM
authors.lastname: Abrahams
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
authors.affiliation: Department of Medicine, Hospital for Special Surgery, Weill Cornell Medical College, New York, New York.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
mesh_terms: D000022:Abortion, Spontaneous / Q000276:immunology; D000818:Animals; D016736:Antiphospholipid Syndrome / Q000276:immunology*; D002460:Cell Line; D005260:Female; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D053552:Keratin-7 / Q000276:immunology; D026502:LDL-Receptor Related Proteins / Q000276:immunology*; D051379:Mice; D010920:Placenta / Q000276:immunology; D011247:Pregnancy; D011248:Pregnancy Complications / Q000276:immunology*; D034622:RNA Interference; D014162:Transfection; D014327:Trophoblasts / Q000166:cytology / Q000276:immunology*; D053482:beta 2-Glycoprotein I / Q000276:immunology
chemical_list: D053552:Keratin-7; D026502:LDL-Receptor Related Proteins; D053482:beta 2-Glycoprotein I; C098773:low density lipoprotein receptor-related protein 8