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MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix.

Chun TH, Sabeh F, Ota I, Murphy H, McDonagh KT, Holmbeck K, Birkedal-Hansen H, Allen ED, Weiss SJ - J. Cell Biol. (2004)

Bottom Line: Extracellular matrix-degradative enzymes, including the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, are thought to play key roles in angiogenesis by binding to docking sites on the cell surface after activation by plasmin- and/or membrane-type (MT) 1-MMP-dependent processes.Unexpectedly, neither MMP-2, MMP-9, their cognate cell-surface receptors (i.e., beta3 integrin and CD44), nor plasminogen are essential for collagenolytic activity, endothelial cell invasion, or neovessel formation.Instead, the membrane-anchored MMP, MT1-MMP, confers endothelial cells with the ability to express invasive and tubulogenic activity in a collagen-rich milieu, in vitro or in vivo, where it plays an indispensable role in driving neovessel formation.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

ABSTRACT
During angiogenesis, endothelial cells initiate a tissue-invasive program within an interstitial matrix comprised largely of type I collagen. Extracellular matrix-degradative enzymes, including the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, are thought to play key roles in angiogenesis by binding to docking sites on the cell surface after activation by plasmin- and/or membrane-type (MT) 1-MMP-dependent processes. To identify proteinases critical to neovessel formation, an ex vivo model of angiogenesis has been established wherein tissue explants from gene-targeted mice are embedded within a three-dimensional, type I collagen matrix. Unexpectedly, neither MMP-2, MMP-9, their cognate cell-surface receptors (i.e., beta3 integrin and CD44), nor plasminogen are essential for collagenolytic activity, endothelial cell invasion, or neovessel formation. Instead, the membrane-anchored MMP, MT1-MMP, confers endothelial cells with the ability to express invasive and tubulogenic activity in a collagen-rich milieu, in vitro or in vivo, where it plays an indispensable role in driving neovessel formation.

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Neovessel outgrowth from MMP-9– and CD44- explants. (A) Capillary outgrowth from control littermate (left) and MMP-9– mouse aortic rings (right) suspended in type I collagen gels and stimulated with VEGF–HGF in 5% autologous serum do not exhibit obvious differences in capillary number, length, or morphology, as assessed by phase-contrast microscopy (top) or in hematoxylin and eosin (H&E)–stained cross sections (bottom) at day 7. (B) Capillary sprouting from wild-type and CD44- aortic explants prepared as in A, as assessed by phase-contrast microscopy (top) or in H&E–stained cross sections (bottom) after 7 d. (C) Mean neovessel length and density from aortic explants isolated from MMP-2−/−, β3 integrin−/−, MMP-9−/−, and CD44−/− mice and incubated in type I collagen gels for 7 d with VEGF–HGF in 5% autologous serum are expressed as percent control of the respective wild-type littermate (mean ± 1 SD, n = 4).
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fig3: Neovessel outgrowth from MMP-9– and CD44- explants. (A) Capillary outgrowth from control littermate (left) and MMP-9– mouse aortic rings (right) suspended in type I collagen gels and stimulated with VEGF–HGF in 5% autologous serum do not exhibit obvious differences in capillary number, length, or morphology, as assessed by phase-contrast microscopy (top) or in hematoxylin and eosin (H&E)–stained cross sections (bottom) at day 7. (B) Capillary sprouting from wild-type and CD44- aortic explants prepared as in A, as assessed by phase-contrast microscopy (top) or in H&E–stained cross sections (bottom) after 7 d. (C) Mean neovessel length and density from aortic explants isolated from MMP-2−/−, β3 integrin−/−, MMP-9−/−, and CD44−/− mice and incubated in type I collagen gels for 7 d with VEGF–HGF in 5% autologous serum are expressed as percent control of the respective wild-type littermate (mean ± 1 SD, n = 4).

Mentions: In a fashion similar to that described for MMP-2, MMP-9 has also been linked to tissue-invasive events and angiogenesis, in part, by associating with its cell surface–binding partner, CD44 (Yu and Stamenkovic, 1999; Davis et al., 2002). However, capillary outgrowth and vessel morphogenesis were not affected by the deletion of either MMP-9 or CD44 (Fig. 3).


MT1-MMP-dependent neovessel formation within the confines of the three-dimensional extracellular matrix.

Chun TH, Sabeh F, Ota I, Murphy H, McDonagh KT, Holmbeck K, Birkedal-Hansen H, Allen ED, Weiss SJ - J. Cell Biol. (2004)

Neovessel outgrowth from MMP-9– and CD44- explants. (A) Capillary outgrowth from control littermate (left) and MMP-9– mouse aortic rings (right) suspended in type I collagen gels and stimulated with VEGF–HGF in 5% autologous serum do not exhibit obvious differences in capillary number, length, or morphology, as assessed by phase-contrast microscopy (top) or in hematoxylin and eosin (H&E)–stained cross sections (bottom) at day 7. (B) Capillary sprouting from wild-type and CD44- aortic explants prepared as in A, as assessed by phase-contrast microscopy (top) or in H&E–stained cross sections (bottom) after 7 d. (C) Mean neovessel length and density from aortic explants isolated from MMP-2−/−, β3 integrin−/−, MMP-9−/−, and CD44−/− mice and incubated in type I collagen gels for 7 d with VEGF–HGF in 5% autologous serum are expressed as percent control of the respective wild-type littermate (mean ± 1 SD, n = 4).
© Copyright Policy
Related In: Results  -  Collection

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fig3: Neovessel outgrowth from MMP-9– and CD44- explants. (A) Capillary outgrowth from control littermate (left) and MMP-9– mouse aortic rings (right) suspended in type I collagen gels and stimulated with VEGF–HGF in 5% autologous serum do not exhibit obvious differences in capillary number, length, or morphology, as assessed by phase-contrast microscopy (top) or in hematoxylin and eosin (H&E)–stained cross sections (bottom) at day 7. (B) Capillary sprouting from wild-type and CD44- aortic explants prepared as in A, as assessed by phase-contrast microscopy (top) or in H&E–stained cross sections (bottom) after 7 d. (C) Mean neovessel length and density from aortic explants isolated from MMP-2−/−, β3 integrin−/−, MMP-9−/−, and CD44−/− mice and incubated in type I collagen gels for 7 d with VEGF–HGF in 5% autologous serum are expressed as percent control of the respective wild-type littermate (mean ± 1 SD, n = 4).
Mentions: In a fashion similar to that described for MMP-2, MMP-9 has also been linked to tissue-invasive events and angiogenesis, in part, by associating with its cell surface–binding partner, CD44 (Yu and Stamenkovic, 1999; Davis et al., 2002). However, capillary outgrowth and vessel morphogenesis were not affected by the deletion of either MMP-9 or CD44 (Fig. 3).

Bottom Line: Extracellular matrix-degradative enzymes, including the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, are thought to play key roles in angiogenesis by binding to docking sites on the cell surface after activation by plasmin- and/or membrane-type (MT) 1-MMP-dependent processes.Unexpectedly, neither MMP-2, MMP-9, their cognate cell-surface receptors (i.e., beta3 integrin and CD44), nor plasminogen are essential for collagenolytic activity, endothelial cell invasion, or neovessel formation.Instead, the membrane-anchored MMP, MT1-MMP, confers endothelial cells with the ability to express invasive and tubulogenic activity in a collagen-rich milieu, in vitro or in vivo, where it plays an indispensable role in driving neovessel formation.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Medicine and Genetics, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

ABSTRACT
During angiogenesis, endothelial cells initiate a tissue-invasive program within an interstitial matrix comprised largely of type I collagen. Extracellular matrix-degradative enzymes, including the matrix metalloproteinases (MMPs) MMP-2 and MMP-9, are thought to play key roles in angiogenesis by binding to docking sites on the cell surface after activation by plasmin- and/or membrane-type (MT) 1-MMP-dependent processes. To identify proteinases critical to neovessel formation, an ex vivo model of angiogenesis has been established wherein tissue explants from gene-targeted mice are embedded within a three-dimensional, type I collagen matrix. Unexpectedly, neither MMP-2, MMP-9, their cognate cell-surface receptors (i.e., beta3 integrin and CD44), nor plasminogen are essential for collagenolytic activity, endothelial cell invasion, or neovessel formation. Instead, the membrane-anchored MMP, MT1-MMP, confers endothelial cells with the ability to express invasive and tubulogenic activity in a collagen-rich milieu, in vitro or in vivo, where it plays an indispensable role in driving neovessel formation.

Show MeSH