title: Recanalization and flow regulate venous thrombus resolution and matrix metalloproteinase expression in vivo.
abstract: OBJECTIVE
  We examined the role of thrombus recanalization and ongoing blood flow in the process of thrombus resolution by comparing two murine in vivo models of deep venous thrombosis.
  
  
  METHODS
  In CD1 mice, we performed surgical inferior vena cava ligation (stasis thrombosis), stenosis (thrombosis with recanalization), or sham procedure. We analyzed thrombus weight over time as a measure of thrombus resolution and quantified the messenger RNA and protein levels of membrane-type matrix metalloproteinases (MT-MMPs) as well as effectors of the plasmin complex at days 4, 8, and 12 after surgery.
  
  
  RESULTS
  Despite similar initial thrombus size, the presence of ongoing blood flow (stenosis model) was associated with a 45.91% subsequent improvement in thrombus resolution at day 8 and 12.57% at day 12 compared with stasis thrombosis (ligation model). Immunoblot and real-time polymerase chain reaction analysis demonstrated a difference in MMP-2 and MMP-9 activity at day 8 between the two models (P = .03 and P = .006, respectively) as well as a difference in MT2-MMP gene expression at day 8 (P = .044) and day 12 (P = .03) and MT1-MMP protein expression at day 4 (P = .021). Histologic analyses revealed distinct areas of recanalization in the thrombi of the stenosis model compared with the ligation model as well as the recruitment of inflammatory cells, especially macrophages, and a focal pattern of localized expression of MT1-MMP and MT3-MMP proteins surrounding the areas of recanalization in the stenosis model.
  
  
  CONCLUSIONS
  Recanalization and ongoing blood flow accelerate deep venous thrombus resolution in vivo and are associated with distinct patterns of MT1-MMP and MT3-MMP expression and macrophage localization in areas of intrathrombus recanalization.
authors.affiliation: Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Md; Department of Surgery, School of Medicine, University of Maryland, Baltimore, Md.
authors.forename: Christine
authors.initials: C
authors.lastname: Chabasse
authors.affiliation: Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Md; Department of Surgery, School of Medicine, University of Maryland, Baltimore, Md.
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Siefert
authors.affiliation: Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Md; Department of Surgery, School of Medicine, University of Maryland, Baltimore, Md.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Chaudry
authors.affiliation: Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Md; Department of Surgery, School of Medicine, University of Maryland, Baltimore, Md.
authors.forename: Mark H
authors.initials: MH
authors.lastname: Hoofnagle
authors.affiliation: Department of Surgery, School of Medicine, University of Maryland, Baltimore, Md.
authors.forename: Brajesh K
authors.initials: BK
authors.lastname: Lal
authors.affiliation: Center for Vascular and Inflammatory Diseases, School of Medicine, University of Maryland, Baltimore, Md; Department of Surgery, School of Medicine, University of Maryland, Baltimore, Md. Electronic address: rsarkar@smail.umaryland.edu.
authors.forename: Rajabrata
authors.initials: R
authors.lastname: Sarkar
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020778:Matrix Metalloproteinase 2; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000097:blood* / Q000235:genetics; D000090023:Metallothionein 3; D051379:Mice; D012333:RNA, Messenger / Q000032:analysis; D014682:Vena Cava, Inferior / Q000601:surgery*; D020246:Venous Thrombosis / Q000201:enzymology* / Q000503:physiopathology / Q000601:surgery*
chemical_list: D000090023:Metallothionein 3; C000715430:Mt3 protein, mouse; D012333:RNA, Messenger; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D020778:Matrix Metalloproteinase 2