title: Angiotensin receptor agonistic autoantibody-mediated tumor necrosis factor-alpha induction contributes to increased soluble endoglin production in preeclampsia.
abstract: BACKGROUND
  Preeclampsia is a prevalent life-threatening hypertensive disorder of pregnancy. The circulating antiangiogenic factor, soluble endoglin (sEng), is elevated in the blood circulation of women with preeclampsia and contributes to disease pathology; however, the underlying mechanisms responsible for its induction in preeclampsia are unknown.
  
  
  RESULTS
  Here, we discovered that a circulating autoantibody, the angiotensin receptor agonistic autoantibody (AT(1)-AA), stimulates sEng production via AT(1) angiotensin receptor activation in pregnant mice but not in nonpregnant mice. We subsequently demonstrated that the placenta is a major source contributing to sEng induction in vivo and that AT(1)-AA-injected pregnant mice display impaired placental angiogenesis. Using drug screening, we identified tumor necrosis factor-alpha as a circulating factor increased in the serum of autoantibody-injected pregnant mice contributing to AT(1)-AA-mediated sEng induction in human umbilical vascular endothelial cells. Subsequently, among all the drugs screened, we found that hemin, an inducer of heme oxygenase, functions as a break to control AT(1)-AA-mediated sEng induction by suppressing tumor necrosis factor-alpha signaling in human umbilical vascular endothelial cells. Finally, we demonstrated that the AT(1)-AA-mediated decreased angiogenesis seen in human placenta villous explants was attenuated by tumor necrosis factor-alpha-neutralizing antibodies, soluble tumor necrosis factor-alpha receptors, and hemin by abolishing both sEng and soluble fms-like tyrosine kinase-1 induction.
  
  
  CONCLUSIONS
  Our findings demonstrate that AT(1)-AA-mediated tumor necrosis factor-alpha induction, by overcoming its negative regulator, heme oxygenase-1, is a key underlying mechanism responsible for impaired placental angiogenesis by inducing both sEng and soluble fms-like tyrosine kinase-1 secretion from human villous explants. Our results provide important new targets for diagnosis and therapeutic intervention in the management of preeclampsia.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas-Houston Medical School, Houston, TX 77030, USA.
authors.forename: Cissy Chenyi
authors.initials: CC
authors.lastname: Zhou
authors.forename: Roxanna A
authors.initials: RA
authors.lastname: Irani
authors.forename: Yujin
authors.initials: Y
authors.lastname: Zhang
authors.forename: Sean C
authors.initials: SC
authors.lastname: Blackwell
authors.forename: Tiejuan
authors.initials: T
authors.lastname: Mi
authors.forename: Jiaming
authors.initials: J
authors.lastname: Wen
authors.forename: Harnath
authors.initials: H
authors.lastname: Shelat
authors.forename: Yong-Jian
authors.initials: YJ
authors.lastname: Geng
authors.forename: Susan M
authors.initials: SM
authors.lastname: Ramin
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Kellems
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000494:pharmacology; D002824:Chorionic Villi / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D000071063:Endoglin; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000097:blood / Q000276:immunology; D010920:Placenta / Q000098:blood supply / Q000276:immunology / Q000378:metabolism; D011225:Pre-Eclampsia / Q000097:blood* / Q000276:immunology*; D011247:Pregnancy; D044140:Receptor, Angiotensin, Type 1 / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D001323:Autoantibodies; D000071063:Endoglin; C502004:Eng protein, mouse; D007074:Immunoglobulin G; D047908:Intracellular Signaling Peptides and Proteins; D044140:Receptor, Angiotensin, Type 1; D014409:Tumor Necrosis Factor-alpha; D051547:Heme Oxygenase-1