Title: Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase
Authors: Detry, Benoit
Erpicum, Charlotte
Paupert, Jenny
Blacher, Silvia
Maillard, Catherine
Bruyère, Françoise
Pendeville, Hélène
Remacle, Thibault
Lambert, Vincent
Balsat, Cédric
Ormenese, Sandra
Lamaye, Françoise
Janssens, Els
Moons, Lieve
Cataldo, Didier
Kridelka, Frédéric
Carmeliet, Peter
Thiry, Marc
Foidart, Jean-Michel
Struman, Ingrid
Noel, Agnès # ×
Issue Date: May-2012
Publisher: W.B. Saunders
Series Title: Blood vol:119 issue:21 pages:5048-5056
Abstract: Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)-2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density, and cross-linking). Transmission electron microscopy and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LECs associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LECs negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis.
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Angiogenesis and Vascular Metabolism (Vesalius Research Center) (+)
× corresponding author
# (joint) last author

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