Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching.
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.
Johnson
Chad
C
Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology/Emory University School of Medicine, Atlanta, Ga, USA.
Sung
Hak-Joon
HJ
Lessner
Susan M
SM
Fini
M Elizabeth
ME
Galis
Zorina S
ZS
D000818:Animals; D016026:Bone Marrow Transplantation; D002196:Capillaries / Q000254:growth & development / Q000648:ultrastructure; D004790:Enzyme Induction; D005263:Femoral Artery; D017930:Genes, Reporter; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D007763:Lac Operon; D008026:Ligation; D008264:Macrophages / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011828:Radiation Chimera
D020780:Matrix Metalloproteinase 9