scholarly journals Coordinated regulation by Cdc42, integrin alpha2beta1, and membrane type‐1 metalloproteinase‐dependant signaling of capillary tube formation in 3D collagen matrices

2007 ◽  
Vol 21 (5) ◽  
Author(s):  
Wonshill Koh ◽  
Anastasia Sacharidou ◽  
Kevin E. Fisher ◽  
George E. Davis
Keyword(s):  
Capillary Tube ◽  
Tube Formation ◽  
Collagen Matrices ◽  
Integrin Alpha2beta1 ◽  
3D Collagen ◽  
Coordinated Regulation ◽  
Membrane Type

scholarly journals Endothelial lumen signaling complexes control 3D matrix–specific tubulogenesis through interdependent Cdc42- and MT1-MMP–mediated events

Blood ◽  
2010 ◽  
Vol 115 (25) ◽  
pp. 5259-5269 ◽  
Author(s):  
Anastasia Sacharidou ◽  
Wonshill Koh ◽  
Amber N. Stratman ◽  
Anne M. Mayo ◽  
Kevin E. Fisher ◽  
...  
Keyword(s):  
Tube Formation ◽  
Dominant Negative ◽  
Collagen Matrices ◽  
Signaling Complex ◽  
Vascular Morphogenesis ◽  
Cytoplasmic Tails ◽  
3D Matrix ◽  
Dependent Signal ◽  
3D Collagen ◽  
Membrane Type

Abstract Here, we define an endothelial cell (EC) lumen signaling complex involving Cdc42, Par6b, Par3, junction adhesion molecule (Jam)–B and Jam-C, membrane type 1–matrix metalloproteinase (MT1-MMP), and integrin α2β1, which coassociate to control human EC tubulogenesis in 3D collagen matrices. Blockade of both Jam-B and Jam-C using antibodies, siRNA, or dominant-negative mutants completely interferes with lumen and tube formation resulting from a lack of Cdc42 activation, inhibition of Cdc42-GTP–dependent signal transduction, and blockade of MT1-MMP–dependent proteolysis. This process requires interdependent Cdc42 and MT1-MMP signaling, which involves Par3 binding to the Jam-B and Jam-C cytoplasmic tails, an interaction that is necessary to physically couple the components of the lumen signaling complex. MT1-MMP proteolytic activity is necessary for Cdc42 activation during EC tube formation in 3D collagen matrices but not on 2D collagen surfaces, whereas Cdc42 activation is necessary for MT1-MMP to create vascular guidance tunnels and tube networks in 3D matrices through proteolytic events. This work reveals a novel interdependent role for Cdc42-dependent signaling and MT1-MMP–dependent proteolysis, a process that occurs selectively in 3D collagen matrices and that requires EC lumen signaling complexes, to control human EC tubulogenesis during vascular morphogenesis.

scholarly journals Endothelial cell lumen and vascular guidance tunnel formation requires MT1-MMP–dependent proteolysis in 3-dimensional collagen matrices

Blood ◽  
2009 ◽  
Vol 114 (2) ◽  
pp. 237-247 ◽  
Author(s):  
Amber N. Stratman ◽  
W. Brian Saunders ◽  
Anastasia Sacharidou ◽  
Wonshill Koh ◽  
Kevin E. Fisher ◽  
...  
Keyword(s):  
Network Formation ◽  
Collagen Matrices ◽  
Matrix Type ◽  
Lumen Formation ◽  
3 Dimensional ◽  
Signaling Mechanisms ◽  
Matrix Surface ◽  
3D Collagen ◽  
Tube Morphogenesis

Abstract Here we show that endothelial cells (EC) require matrix type 1-metalloproteinase (MT1-MMP) for the formation of lumens and tube networks in 3-dimensional (3D) collagen matrices. A fundamental consequence of EC lumen formation is the generation of vascular guidance tunnels within collagen matrices through an MT1-MMP-dependent proteolytic process. Vascular guidance tunnels represent a conduit for EC motility within these spaces (a newly remodeled 2D matrix surface) to both assemble and remodel tube structures. Interestingly, it appears that twice as many tunnel spaces are created than are occupied by tube networks after several days of culture. After tunnel formation, these spaces represent a 2D migratory surface within 3D collagen matrices allowing for EC migration in an MMP-independent fashion. Blockade of EC lumenogenesis using inhibitors that interfere with the process (eg, integrin, MMP, PKC, Src) completely abrogates the formation of vascular guidance tunnels. Thus, the MT1-MMP-dependent proteolytic process that creates tunnel spaces is directly and functionally coupled to the signaling mechanisms required for EC lumen and tube network formation. In summary, a fundamental and previously unrecognized purpose of EC tube morphogenesis is to create networks of matrix conduits that are necessary for EC migration and tube remodeling events critical to blood vessel assembly.

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.

Sign in / Sign up

Export Citation Format

Share Document