on May 21, 2009
Published online before print May 21, 2009, doi: 10.1161/ATVBAHA.109.189175
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Submitted on August 27, 2008
Accepted on April 27, 2009
Matrix Metalloproteinase-9 Is Essential for Ischemia-Induced Neovascularization by Modulating Bone Marrow–Derived Endothelial Progenitor Cells
Po-Hsun Huang ;
From the Division of Cardiology, Department of Internal Medicine (P.-H.H., T.-C.W., J.-W.C., S.-J.L.), Taipei Veterans General Hospital; the Institute of Clinical Medicine (P.-H.H., H.-Y.T., S.-J.L.); and the Cardiovascular Research Center (P.-H.H., W.-Y.L., T.-C.W., J.-W.C., S.-J.L.), National Yang-Ming University, Taipei, Taiwan; the Department of Cardiovascular Medicine (P.-H.H., M.S.), University of Tokyo Graduate School of Medicine, Tokyo, Japan; the Graduate Institute of Integrated Medicine (Y.-H.C.), College of Chinese Medicine, China Medical University, Taichung, Taiwan; the Division of Cardiology, Department of Internal Medicine (C.-H.W.), Chang Gung Memorial Hospital, Keelung, Taiwan; Institute and Department of Pharmacology (J.-S.C., J.-W.C.), National Yang-Ming University; and the Division of Anesthesiology (F.-Y.L.), Taipei Medical University Hospital and Department of Anesthesiology, School of Medicine (F.-Y.L.), Taipei Medical University, Taipei, Taiwan.
* To whom correspondence should be addressed. E-mail: sjlin{at}vghtpe.gov.tw.
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.
Methods and 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.
Key words: matrix metalloproteinases • endothelial progenitor cells • neovascularization