title: Despite normal arteriogenic and angiogenic responses, hind limb perfusion recovery and necrotic and fibroadipose tissue clearance are impaired in matrix metalloproteinase 9-deficient mice.
abstract: OBJECTIVE
  The relative contributions of arteriogenesis, angiogenesis, and ischemic muscle tissue composition toward reperfusion after arterial occlusion are largely unknown. Differential loss of bone marrow-derived cell (BMC) matrix metalloproteinase 9 (MMP9), which has been implicated in all of these processes, was used to assess the relative contributions of these processes during limb reperfusion.
  
  
  METHODS
  We compared collateral growth (arteriogenesis), capillary growth (angiogenesis), and ischemic muscle tissue composition after femoral artery ligation in FVB/NJ mice that had been reconstituted with bone marrow from wild-type or MMP9(-/-) mice.
  
  
  RESULTS
  Laser Doppler perfusion imaging confirmed decreased reperfusion capacity in mice with BMC-specific loss of MMP9; however, collateral arteriogenesis was not affected. Furthermore, when accounting for the fact that muscle tissue composition changes markedly with ischemia (ie, necrotic, fibroadipose, and regenerating tissue regions are present), angiogenesis was also unaffected. Instead, BMC-specific loss of MMP9 caused an increase in the proportion of necrotic and fibroadipose tissue, which showed the strongest correlation with poor perfusion recovery. Similarly, the reciprocal loss of MMP9 from non-BMCs showed similar deficits in perfusion and tissue composition without affecting arteriogenesis.
  
  
  CONCLUSIONS
  By concurrently analyzing arteriogenesis, angiogenesis, and ischemic tissue composition, we determined that the loss of BMC-derived or non-BMC-derived MMP9 impairs necrotic and fibroadipose tissue clearance after femoral artery ligation, despite normal arteriogenic and angiogenic vascular growth. These findings imply that therapeutic revascularization strategies for treating peripheral arterial disease may benefit from additionally targeting necrotic tissue clearance or skeletal muscle regeneration, or both.
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, Va.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Meisner
authors.affiliation: Division of Cardiovascular Medicine, University of Virginia, Charlottesville, Va; Cardiovascular Research Center, University of Virginia, Charlottesville, Va.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Annex
authors.affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, Va; Cardiovascular Research Center, University of Virginia, Charlottesville, Va. Electronic address: rprice@virginia.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Price
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology / Q000473:pathology; D000818:Animals; D016026:Bone Marrow Transplantation; D003094:Collagen / Q000378:metabolism; D003097:Collateral Circulation; D004195:Disease Models, Animal; D005355:Fibrosis; D006614:Hindlimb; D007511:Ischemia / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency* / Q000235:genetics; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D009336:Necrosis; D018919:Neovascularization, Physiologic; D012039:Regional Blood Flow; D013997:Time Factors
chemical_list: D003094:Collagen; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse