title: Matrix metalloproteinase-9 is essential for ischemia-induced neovascularization by modulating bone marrow-derived endothelial progenitor cells.
abstract: OBJECTIVE
  Both matrix metalloproteinases (MMPs) and endothelial progenitor cells (EPCs) have been implicated in the process of neovascularization. Here we show that the impaired neovascularization in mice lacking MMP-9 is related to a defect in EPC functions in vasculogenesis.
  
  
  RESULTS
  Hindlimb ischemia surgery was conducted in MMP-9(-/-) mice and wild-type (MMP-9(+/+)) mice. Blood flow recovery was markedly impaired in MMP-9(-/-) mice when compared with that in wild-type mice as determined by laser Doppler imaging. Flow cytometry demonstrated that the number of EPC-like cells (Sca-1(+)/Flk-1(+)) in peripheral blood increased in wild-type mice after hindlimb ischemia surgery and exogenous vascular endothelial growth factor stimulation, but not in MMP-9(-/-) mice. Plasma levels and bone marrow concentrations of soluble Kit-ligand (sKitL) were significantly elevated in wild-type mice in response to tissue ischemia, but not in MMP-9(-/-) mice. C-kit positive bone marrow cells of MMP-9(-/-) mice have attenuated adhesion and migration than those isolated from wild-type mice. In in vitro studies, incubation with selective MMP-9 inhibitor suppressed the colony formation, migration, and tube formation capacities of EPC. Transplantation of bone marrow cells from wild-type mice restored collateral flow formation in MMP-9(-/-) mice.
  
  
  CONCLUSIONS
  These findings suggest that MMP-9 deficiency impairs ischemia-induced neovascularization, and these effects may occur through a reduction in releasing the stem cell-active cytokine, and EPC mobilization, migration, and vasculogenesis functions.
authors.affiliation: Division of Cardiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shih-Pai Road, Taipei, Taiwan.
authors.forename: Po-Hsun
authors.initials: PH
authors.lastname: Huang
authors.forename: Yung-Hsiang
authors.initials: YH
authors.lastname: Chen
authors.forename: Chao-Hung
authors.initials: CH
authors.lastname: Wang
authors.forename: Jia-Shiong
authors.initials: JS
authors.lastname: Chen
authors.forename: Hsiao-Ya
authors.initials: HY
authors.lastname: Tsai
authors.forename: Feng-Yen
authors.initials: FY
authors.lastname: Lin
authors.forename: Wei-Yuh
authors.initials: WY
authors.lastname: Lo
authors.forename: Tao-Cheng
authors.initials: TC
authors.lastname: Wu
authors.forename: Masataka
authors.initials: M
authors.lastname: Sata
authors.forename: Jaw-Wen
authors.initials: JW
authors.lastname: Chen
authors.forename: Shing-Jong
authors.initials: SJ
authors.lastname: Lin
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001854:Bone Marrow Cells / Q000473:pathology*; D002465:Cell Movement; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D005434:Flow Cytometry; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000201:enzymology / Q000473:pathology*; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000473:pathology; D013234:Stem Cells / Q000473:pathology*
chemical_list: D020780:Matrix Metalloproteinase 9