title: Postinjury vascular intimal hyperplasia in mice is completely inhibited by CD34+ bone marrow-derived progenitor cells expressing membrane-tethered anticoagulant fusion proteins.
abstract: BACKGROUND
  Coagulation proteins promote neointimal hyperplasia and vascular remodelling after vessel injury, but the precise mechanisms by which they act in vivo remain undetermined.
  
  
  OBJECTIVE
  This study, using an injury model in which the neointima is derived from bone marrow (BM)-derived cells, compared inhibition of tissue factor or thrombin on either BM-derived or existing vascular smooth muscle cells.
  
  
  METHODS
  Two transgenic (Tg) mouse strains expressing membrane-tethered tissue factor pathway inhibitor (TFPI) or hirudin (Hir) fusion proteins driven by an alpha smooth muscle actin (SMA) promoter were generated (alpha-TFPI-Tg and alpha-Hir-Tg) and the phenotype after wire-induced endovascular injury was compared with that in wild-type (WT) controls.
  
  
  RESULTS
  WT mice developed progressive neointimal expansion, whereas injury in either Tg was followed by repair back to a preinjured state. This was also seen when WT mice were reconstituted with BM from Tg mice but not when Tgs were reconstituted with WT BM, in which injury was followed by slowly progressive neointimal expansion. Injection of CD34+ cells from Tg mice into injured WT mice resulted in the accumulation of fusion protein-expressing cells from day 3 onwards and an absence of neointimal hyperplasia in those areas.
  
  
  CONCLUSIONS
  Neointimal development after wire-induced endovascular injury in mice was completely inhibited when BM-derived cells infiltrating the damaged artery expressed membrane tethered anticoagulant fusion proteins under an alpha-SMA promoter. These findings enhance our understanding of the pathological role that coagulation proteins play in vascular inflammation.
authors.affiliation: Department of Immunology, Imperial College London, Hammersmith Hospital, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Chen
authors.forename: M
authors.initials: M
authors.lastname: Weber
authors.forename: P G
authors.initials: PG
authors.lastname: Shiels
authors.forename: R
authors.initials: R
authors.lastname: Dong
authors.forename: Z
authors.initials: Z
authors.lastname: Webster
authors.forename: J H
authors.initials: JH
authors.lastname: McVey
authors.forename: G
authors.initials: G
authors.lastname: Kemball-Cook
authors.forename: E G D
authors.initials: EG
authors.lastname: Tuddenham
authors.forename: R I
authors.initials: RI
authors.lastname: Lechler
authors.forename: A
authors.initials: A
authors.lastname: Dorling
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000378:metabolism*; D018952:Antigens, CD34 / Q000096:biosynthesis*; D001011:Aorta / Q000378:metabolism; D001161:Arteriosclerosis / Q000628:therapy; D001808:Blood Vessels / Q000473:pathology; D001854:Bone Marrow Cells / Q000378:metabolism*; D002339:Carotid Arteries / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation; D051379:Mice; D008822:Mice, Transgenic; D009130:Muscle, Smooth / Q000378:metabolism; D010641:Phenotype; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D018952:Antigens, CD34; D011993:Recombinant Fusion Proteins