Matrix metalloproteinase-9 is required for adequate angiogenic revascularization of ischemic tissues: potential role in capillary branching.

Johnson C, Sung HJ, Lessner SM, Fini ME, Galis ZS
Circ Res. 2004 94 (2): 262-8

PMID: 14670843 · PMCID: PMC6716372 · DOI:10.1161/01.RES.0000111527.42357.62

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.

MeSH Terms (19)

Animals Bone Marrow Transplantation Capillaries Enzyme Induction Femoral Artery Genes, Reporter Hindlimb Ischemia Lac Operon Ligation Macrophages Matrix Metalloproteinase 9 Mice Mice, Inbred C57BL Mice, Inbred Strains Mice, Knockout Neovascularization, Physiologic Promoter Regions, Genetic Radiation Chimera

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