title: Antiphospholipid antibodies attenuate endothelial repair and promote neointima formation in mice.
abstract: BACKGROUND
  Antiphospholipid syndrome patients have antiphospholipid antibodies (aPLs) that promote thrombosis, and they have increased cardiovascular disease risk. Although the basis for the thrombosis has been well delineated, it is not known why antiphospholipid syndrome patients also have an increased prevalence of nonthrombotic vascular occlusion. The aims of this work were to determine if aPLs directly promote medial hypertrophy or neointima formation in mice and to identify the underlying mechanisms.
  
  
  RESULTS
  Medial hypertrophy and neointima formation invoked by carotid artery endothelial denudation were evaluated in mice administered normal human IgG or aPLs. While aPLs had no effect on medial hypertrophy, they caused exaggerated neointima development. This was related to an aPL-induced impairment in reendothelialization post denudation, and scratch assays in cell culture revealed that there are direct effects of aPLs on endothelium that retard cell migration. Further experiments showed that aPL antagonism of endothelial migration and repair is mediated by antibody recognition of β2-glycoprotein I, apolipoprotein E receptor 2, and a decline in bioavailable NO. Consistent with these mechanisms, the adverse impacts of aPLs on reendothelialization and neointima formation were fully prevented by the NO donor molsidomine.
  
  
  CONCLUSIONS
  APLs blunt endothelial repair, and there is related aPL-induced exaggeration in neointima formation after endothelial injury in mice. The initiating process entails NO deficiency mediated by β2-glycoprotein I recognition by aPLs and apolipoprotein E receptor 2. The modulation of endothelial apolipoprotein E receptor 2 function or NO bioavailability may represent new interventions to prevent the nonthrombotic vascular occlusion and resulting cardiovascular disorders that afflict antiphospholipid syndrome patients.
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX (V.U., W.R.L., S.K., P.W.S., C.M.).
authors.forename: Victoria
authors.initials: V
authors.lastname: Ulrich
authors.affiliation: Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH (E.S.K., D.Y.H.).
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Konaniah
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX (V.U., W.R.L., S.K., P.W.S., C.M.).
authors.forename: Wan-Ru
authors.initials: WR
authors.lastname: Lee
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX (V.U., W.R.L., S.K., P.W.S., C.M.).
authors.forename: Sadiksha
authors.initials: S
authors.lastname: Khadka
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX (Y.M.S.).
authors.forename: Yu-Min
authors.initials: YM
authors.lastname: Shen
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX (J.H.).
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.affiliation: Department of Medicine, Hospital for Special Surgery, Weill Cornell Medical College, New York, NY (J.E.S.).
authors.forename: Jane E
authors.initials: JE
authors.lastname: Salmon
authors.affiliation: Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH (E.S.K., D.Y.H.).
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX (V.U., W.R.L., S.K., P.W.S., C.M.).
authors.forename: Philip W
authors.initials: PW
authors.lastname: Shaul
authors.affiliation: Center for Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX (V.U., W.R.L., S.K., P.W.S., C.M.).
authors.forename: Chieko
authors.initials: C
authors.lastname: Mineo
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology / Q000378:metabolism*; D016736:Antiphospholipid Syndrome / Q000276:immunology / Q000503:physiopathology; D001682:Biological Availability; D020212:Carotid Artery Injuries / Q000473:pathology* / Q000503:physiopathology; D002465:Cell Movement / Q000276:immunology / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology*; D006984:Hypertrophy / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000276:immunology / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism*; D011897:Random Allocation; D012680:Sensitivity and Specificity
chemical_list: D017152:Antibodies, Antiphospholipid; D009569:Nitric Oxide
keywords: antiphospholipid syndrome; endothelium; neointima hyperplasia; nitric oxide