Published online before print December 11, 2003, doi: 10.1161/01.RES.0000111527.42357.62
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© 2004 American Heart Association, Inc.
Integrative Physiology |
Matrix Metalloproteinase-9 Is Required for Adequate Angiogenic Revascularization of Ischemic Tissues
Potential Role in Capillary Branching
From the Wallace H. Coulter Department of Biomedical Engineering (C.J., H.-J.S., Z.S.G.), Georgia Institute of Technology/Emory University School of Medicine, Atlanta, Ga; Division of Cardiology (S.M.L., Z.S.G.), Emory School of Medicine, Atlanta, Ga; McKnight Vision Research Center (M.E.F.), Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Fla.
Correspondence to Zorina S. Galis, PhD, Medicine/Cardiology, 1639 Pierce Dr, WMB 319, Atlanta, GA 30322. E-mail zgalis{at}emory.edu
Angiogenesis, an essential component of a variety of physiological and pathological processes, offers attractive opportunities for therapeutic regulation. We hypothesized that matrix metalloproteinase-9 genetic deficiency (MMP-9-/-) will impair angiogenesis triggered by tissue ischemia, induced experimentally by femoral artery ligation in mice. To investigate the role of MMP-9, we performed a series of biochemical and histological analyses, including zymography, simultaneous detection of perfused capillaries, MMP-9 promoter activity, MMP-9 protein, and macrophages in MMP-9-/- and wild-type (WT) mice. We found that ischemia resulted in doubling of capillary density in WT and no change in the MMP-9-/- ischemic tissues, which translated into increased (39%) perfusion capacity only in the WT at 14 days after ligation. We also confirmed that capillaries in the MMP-9-/- presented significantly (P<0.05) less points of capillary intersections, interpreted by us as decreased branching. The combined conclusions from simultaneous localizations of MMP-9 expression, capillaries, and macrophages suggested that macrophage MMP-9 participates in capillary branching. Transplantation of WT bone marrow into the MMP-9-/-, restored capillary branching, further supporting the contribution of bone marrow–derived macrophages in supplying the necessary MMP-9. Our study indicates that angiogenesis triggered by tissue ischemia requires MMP-9, which may be involved in capillary branching, a potential novel role for this MMP that could be exploited to control angiogenesis.
Key Words: angiography • macrophage • imaging • microvessels • bone-marrow transplantation
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