Membrane-type 1 Matrix Metalloproteinase Regulates Macrophage-dependent Elastolytic Activity and Aneurysm Formation in Vivo
Open Access
- 1 January 2009
- journal article
- Published by Elsevier BV
- Vol. 284 (3), 1765-1771
- https://doi.org/10.1074/jbc.m806239200
Abstract
During arterial aneurysm formation, levels of the membrane-anchored matrix metalloproteinase, MT1-MMP, are elevated dramatically. Although MT1-MMP is expressed predominately by infiltrating macrophages, the roles played by the proteinase in abdominal aortic aneurysm (AAA) formation in vivo remain undefined. Using a newly developed chimeric mouse model of AAA, we now demonstrate that macrophage-derived MT1-MMP plays a dominant role in disease progression. In wild-type mice transplanted with MT1-MMP-null marrow, aneurysm formation induced by the application of CaCl2 to the aortic surface was almost completely ablated. Macrophage infiltration into the aortic media was unaffected by MT1-MMP deletion, and AAA formation could be reconstituted when MT1-MMP+/+ macrophages, but not MT1-MMP+/+ lymphocytes, were infused into MT1-MMP-null marrow recipients. In vitro studies using macrophages isolated from either WT/MT1-MMP-/- chimeric mice, MMP-2-null mice, or MMP-9-null mice demonstrate that MT1-MMP alone plays a dominant role in macrophage-mediated elastolysis. These studies demonstrate that destruction of the elastin fiber network during AAA formation is dependent on macrophage-derived MT1-MMP, which unexpectedly serves as a direct-acting regulator of macrophage proteolytic activity.Keywords
This publication has 36 references indexed in Scilit:
- HIF1α Induces the Recruitment of Bone Marrow-Derived Vascular Modulatory Cells to Regulate Tumor Angiogenesis and InvasionCancer Cell, 2008
- Matrix Metalloproteinase-14 Deficiency in Bone Marrow–Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic PlaquesCirculation, 2008
- Elastin fragments drive disease progression in a murine model of emphysemaJCI Insight, 2006
- Cathepsin L expression and regulation in human abdominal aortic aneurysm, atherosclerosis, and vascular cellsAtherosclerosis, 2005
- MT1‐MMP: A potent modifier of pericellular microenvironmentJournal of Cellular Physiology, 2005
- Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMPThe Journal of cell biology, 2004
- Early MT-1 MMP expression following elastase exposure is associated with increased cleaved MMP-2 activity in experimental rodent aortic aneurysmsSurgery, 2004
- Ex vivo culture rescues hematopoietic stem cells with long-term repopulating capacity following harvest from lethally irradiated miceExperimental Hematology, 2004
- Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms.JCI Insight, 1998
- Unaltered Secretion of β-Amyloid Precursor Protein in Gelatinase A (Matrix Metalloproteinase 2)-deficient MicePublished by Elsevier BV ,1997