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Vol. 15, Issue 2, 678-687, February 2004
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*Departamento de Inmunología, Hospital Universitario de la Princesa, 28006 Madrid, Spain
Submitted July 24, 2003;
Revised November 7, 2003;
Accepted November 7, 2003
Monitoring Editor: Martin Schwartz
The extracellular matrix (ECM) distinctly modulates membrane type 1-matrix metalloproteinase (MT1-MMP) in human endothelial cells (ECs). Herein, ECM-dependent RhoA activation is shown to regulate MT1-MMP localization and activity as well as clathrin-independent internalization in confluent ECs. In this regard, caveolae are revealed as the major MT1-MMP endocytic pathway in human ECs. Thus, MT1-MMP is present at caveolae with caveolin-1 and both proteins together with
v
3 integrin colocalize at endothelial motility-associated extensions. Remarkably, caveolae traffic is required for proper MT1-MMP localization, activity, and function in migratory ECs as demonstrated by both treatment with caveolae-disrupting agents or selective targeting caveolin-1 expression by interference RNA. Thus, caveolae-mediated traffic constitutes a novel mechanism for MT1-MMP regulation in ECs during angiogenesis.
Abbreviations used: cdx, cyclodextrin; COL I, collagen type I; EC, endothelial cell; ECM, extracellular matrix; GEL, gelatin; MMP, matrix metalloproteinase; MT1-MMP, membrane-type 1 matrix metalloproteinase; TnfR, transferrin receptor.
Present address: Centro de Investigaciones Biológicas, CSIC, Madrid, Spain.
* Corresponding author. E-mail address: agarciaa.hlpr{at}salud.madrid.org.
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