title: Factor VII-activating protease deficiency promotes neointima formation by enhancing leukocyte accumulation.
abstract: Essentials Factor VII-activating protease (FSAP) is a plasma protease involved in vascular processes. Neointima formation was investigated after vascular injury in FSAP-/-mice. The neointimal lesion size and the accumulation of macrophages were increased in FSAP-/-mice. This was due to an increased activity of the chemokine (C-C motif) ligand 2 (CCL2).
  
  
  
  Background Factor VII-activating protease (FSAP) is a multifunctional circulating plasma serine protease involved in thrombosis and vascular remodeling processes. The Marburg I single-nucleotide polymorphism (MI-SNP) in the FSAP-coding gene is characterized by low proteolytic activity, and is associated with increased rates of stroke and carotid stenosis in humans. Objectives To determine whether neointima formation after vascular injury is increased in FSAP-/-mice. Methods and Results The neointimal lesion size and the proliferation of vascular smooth muscle cells (VSMCs) were significantly enhanced in FSAP-/-mice as compared with C57BL/6 control mice after wire-induced injury of the femoral artery. Accumulation of leukocytes and macrophages was increased within the lesions of FSAP-/-mice at day 3 and day 14. Quantitative zymography demonstrated enhanced activity of gelatinases/matrix metalloproteinase (MMP)-2 and MMP-9 within the neointimal lesions of FSAP-/-mice, and immunohistochemistry showed particular costaining of MMP-9 with accumulating leukocytes. Using intravital microscopy, we observed that FSAP deficiency promoted the intravascular adherence and the subsequent transmigration of leukocytes in vivo in response to chemokine ligand 2 (CCL2). CCL2 expression was increased in FSAP-/-monocytes but not in the vessel wall. There was no difference in the expression of platelet-derived growth factor (PDGF-BB). Conclusions FSAP deficiency causes an increase in CCL2 expression and CCL2-mediated infiltration of leukocytes into the injured vessel, thereby promoting SMC proliferation and migration by the activation of leukocyte-derived gelatinases. These results provide a possible explanation for the observed association of the loss-of-function MI-SNP with vascular proliferative diseases.
authors.affiliation: Department of Biochemistry, Justus-Liebig-Universität Giessen, Giessen, Germany.|Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: J-M
authors.initials: JM
authors.lastname: Daniel
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-Universität München, Munich, Germany.|Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: C A
authors.initials: CA
authors.lastname: Reichel
authors.affiliation: Department of Biochemistry, Justus-Liebig-Universität Giessen, Giessen, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Schmidt-Woell
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Dutzmann
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-Universität München, Munich, Germany.|Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Zuchtriegel
authors.affiliation: Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Krombach
authors.affiliation: Department of Cardiology, Angiology and Pneumology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Herold
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Bauersachs
authors.affiliation: Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany.
authors.forename: D G
authors.initials: DG
authors.lastname: Sedding
authors.affiliation: Department of Biochemistry, Justus-Liebig-Universität Giessen, Giessen, Germany. sandip.kanse@medisin.uio.no.|Oslo University Hospital and University of Oslo, Oslo, Norway. sandip.kanse@medisin.uio.no.
authors.forename: S M
authors.initials: SM
authors.lastname: Kanse
mesh_terms: D000818:Animals; D000077214:Becaplermin; D001835:Body Weight; D016893:Carotid Stenosis; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics; D002633:Chemotaxis; D005263:Femoral Artery / Q000473:pathology; D007962:Leukocytes / Q000166:cytology*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000166:cytology; D058426:Neointima / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D012697:Serine Endopeptidases / Q000097:blood / Q000172:deficiency* / Q000235:genetics*
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; C520095:FSAP protein, mouse; D012697:Serine Endopeptidases
keywords: leukocyte; metalloproteases; neointima; serine proteases; smooth muscle