scholarly journals Functional interplay between endothelial nitric oxide synthase and membrane type 1–matrix metalloproteinase in migrating endothelial cells

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 2916-2923 ◽  
Author(s):  
Laura Genís ◽  
Pilar Gonzalo ◽  
Antonio S. Tutor ◽  
Beatriz G. Gálvez ◽  
Antonio Martínez-Ruiz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Matrix Metalloproteinase ◽  
Molecular Mechanisms ◽  
Type I Collagen ◽  
Tube Formation ◽  
Type I ◽  
Endothelial Migration ◽  
Membrane Type

Abstract Nitric oxide (NO) is essential for vascular homeostasis and is also a critical modulator of angiogenesis; however, the molecular mechanisms of NO action during angiogenesis remain elusive. We have investigated the potential relationship between NO and membrane type 1–matrix metalloproteinase (MT1-MMP) during endothelial migration and capillary tube formation. Endothelial NO synthase (eNOS) colocalizes with MT1-MMP at motility-associated structures in migratory human endothelial cells (ECs); moreover, NO is produced at these structures and is released into the medium during EC migration. We have therefore addressed 2 questions: (1) the putative regulation of MT1-MMP by NO in migratory ECs; and (2) the requirement for MT1-MMP in NO-induced EC migration and tube formation. NO upregulates MT1-MMP membrane clustering on migratory human ECs, and this is accompanied by increased degradation of type I collagen substrate. MT1-MMP membrane expression and localization are impaired in lung ECs from eNOS-deficient mice, and these cells also show impaired migration and tube formation in vitro. Inhibition of MT1-MMP with a neutralizing antibody impairs NOinduced tube formation by human ECs, and NO-induced endothelial migration and tube formation are impaired in lung ECs from mice deficient in MT1-MMP. MT1-MMP thus appears to be a key molecular effector of NO during the EC migration and angiogenic processes, and is a potential therapeutic target for NO-associated vascular disorders.

scholarly journals Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) Ubiquitination at Lys581Increases Cellular Invasion through Type I Collagen

2012 ◽  
Vol 287 (14) ◽  
pp. 11533-11545 ◽  
Author(s):  
Patricia A. Eisenach ◽  
Pedro Corrêa de Sampaio ◽  
Gillian Murphy ◽  
Christian Roghi
Keyword(s):  
Matrix Metalloproteinase ◽  
Type I Collagen ◽  
Type I ◽  
Cellular Invasion ◽  
Membrane Type

scholarly journals Type I Collagen Abrogates the Clathrin-mediated Internalization of Membrane Type 1 Matrix Metalloproteinase (MT1-MMP) via the MT1-MMP Hemopexin Domain

2005 ◽  
Vol 281 (10) ◽  
pp. 6826-6840 ◽  
Author(s):  
Marc A. Lafleur ◽  
Francesca A. Mercuri ◽  
Neeracha Ruangpanit ◽  
Motoharu Seiki ◽  
Hiroshi Sato ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Type I Collagen ◽  
Type I ◽  
Membrane Type ◽  
Hemopexin Domain

scholarly journals Molecular Dissection of the Structural Machinery Underlying the Tissue-invasive Activity of Membrane Type-1 Matrix Metalloproteinase

2008 ◽  
Vol 19 (8) ◽  
pp. 3221-3233 ◽  
Author(s):  
Xiao-Yan Li ◽  
Ichiro Ota ◽  
Ikuo Yana ◽  
Farideh Sabeh ◽  
Stephen J. Weiss
Keyword(s):  
Matrix Metalloproteinase ◽  
Type I Collagen ◽  
Cell Function ◽  
Catalytic Domain ◽  
Transmembrane Domain ◽  
Type I ◽  
Cell Trafficking ◽  
Membrane Type

Membrane type-1 matrix metalloproteinase (MT1-MMP) drives cell invasion through three-dimensional (3-D) extracellular matrix (ECM) barriers dominated by type I collagen or fibrin. Based largely on analyses of its impact on cell function under two-dimensional culture conditions, MT1-MMP is categorized as a multifunctional molecule with 1) a structurally distinct, N-terminal catalytic domain; 2) a C-terminal hemopexin domain that regulates substrate recognition as well as conformation; and 3) a type I transmembrane domain whose cytosolic tail controls protease trafficking and signaling cascades. The MT1-MMP domains that subserve cell trafficking through 3-D ECM barriers in vitro or in vivo, however, remain largely undefined. Herein, we demonstrate that collagen-invasive activity is not confined strictly to the catalytic, hemopexin, transmembrane, or cytosolic domain sequences of MT1-MMP. Indeed, even a secreted collagenase supports invasion when tethered to the cell surface in the absence of the MT1-MMP hemopexin, transmembrane, and cytosolic tail domains. By contrast, the ability of MT1-MMP to support fibrin-invasive activity diverges from collagenolytic potential, and alternatively, it requires the specific participation of MT-MMP catalytic and hemopexin domains. Hence, the tissue-invasive properties of MT1-MMP are unexpectedly embedded within distinct, but parsimonious, sequences that serve to tether the requisite matrix-degradative activity to the surface of migrating cells.

scholarly journals Decreased Nitric Oxide Synthesis in Human Endothelial Cells Cultured on Type I Collagen

2002 ◽  
Vol 90 (5) ◽  
pp. 539-545 ◽  
Author(s):  
L. González-Santiago ◽  
S. López-Ongil ◽  
M. Rodríguez-Puyol ◽  
D. Rodríguez-Puyol
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Type I Collagen ◽  
Type I ◽  
Nitric Oxide Synthesis ◽  
Human Endothelial Cells ◽  
Cells Cultured

scholarly journals Membrane Type 1-Matrix Metalloproteinase Is Activated during Migration of Human Endothelial Cells and Modulates Endothelial Motility and Matrix Remodeling

2001 ◽  
Vol 276 (40) ◽  
pp. 37491-37500 ◽  
Author(s):  
Beatriz G. Gálvez ◽  
Salomón Matı́as-Román ◽  
Juan P. Albar ◽  
Francisco Sánchez-Madrid ◽  
Alicia G. Arroyo
Keyword(s):  
Endothelial Cells ◽  
Matrix Metalloproteinase ◽  
Matrix Remodeling ◽  
Human Endothelial Cells ◽  
Membrane Type

Cdc42 and RhoA have opposing roles in regulating membrane type 1-matrix metalloproteinase localization and matrix metalloproteinase-2 activation

2008 ◽  
Vol 295 (3) ◽  
pp. C600-C610 ◽  
Author(s):  
Eric Ispanovic ◽  
Damiano Serio ◽  
Tara L. Haas
Keyword(s):  
Endothelial Cells ◽  
Cell Surface ◽  
Matrix Metalloproteinase ◽  
Actin Cytoskeleton ◽  
Cortical Actin ◽  
Rhoa Activity ◽  
Surface Localization ◽  
Cell Surface Localization ◽  
Membrane Type

Proteolysis of the basement membrane and interstitial matrix occurs early in the angiogenic process and requires matrix metalloproteinase (MMP) activity. Skeletal muscle microvascular endothelial cells exhibit robust actin stress fibers, low levels of membrane type 1 (MT1)-MMP expression, and minimal MMP-2 activation. Depolymerization of the actin cytoskeleton increases MT1-MMP expression and MMP-2 activation. Rho family GTPases are regulators of actin cytoskeleton dynamics, and their activity can be modulated in response to angiogenic stimuli such as vascular endothelial growth factor (VEGF). Therefore, we investigated their roles in MMP-2 and MT1-MMP production. Endothelial cells treated with H1152 [an inhibitor of Rho kinase (ROCK)] induced stress fiber depolymerization and an increase in cortical actin. Both MMP-2 and MT1-MMP mRNA increased, which translated into greater MMP-2 protein production and activation. ROCK inhibition rapidly increased cell surface localization of MT1-MMP and increased PI3K activity, which was required for MMP-2 activation. Constitutively active Cdc42 increased cortical actin polymerization, phosphatidylinositol 3-kinase activity, MT1-MMP cell surface localization, and MMP-2 activation similarly to inhibition of ROCK. Activation of Cdc42 was sufficient to decrease RhoA activity. Capillary sprout formation in a three-dimensional collagen matrix was increased in cultures treated with RhoAN19 or Cdc42QL and, conversely, decreased in cultures treated with dominant negative Cdc42N17. VEGF stimulation also induced activation of Cdc42 while inhibiting RhoA activity. Furthermore, VEGF-dependent activation of MMP-2 was reduced by inhibition of Cdc42. These results suggest that Cdc42 and RhoA have opposing roles in regulating cell surface localization of MT1-MMP and MMP-2 activation.

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