title: Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase.
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.
authors.affiliation: Laboratory of Tumor and Development Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Recherche (GIGA-Cancer), University of Liège, Liège, Belgium;
authors.forename: Benoit
authors.initials: B
authors.lastname: Detry
authors.forename: Charlotte
authors.initials: C
authors.lastname: Erpicum
authors.forename: Jenny
authors.initials: J
authors.lastname: Paupert
authors.forename: Silvia
authors.initials: S
authors.lastname: Blacher
authors.forename: Catherine
authors.initials: C
authors.lastname: Maillard
authors.forename: Françoise
authors.initials: F
authors.lastname: Bruyère
authors.forename: Hélène
authors.initials: H
authors.lastname: Pendeville
authors.forename: Thibault
authors.initials: T
authors.lastname: Remacle
authors.forename: Vincent
authors.initials: V
authors.lastname: Lambert
authors.forename: Cédric
authors.initials: C
authors.lastname: Balsat
authors.forename: Sandra
authors.initials: S
authors.lastname: Ormenese
authors.forename: Françoise
authors.initials: F
authors.lastname: Lamaye
authors.forename: Els
authors.initials: E
authors.lastname: Janssens
authors.forename: Lieve
authors.initials: L
authors.lastname: Moons
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.forename: Frédéric
authors.initials: F
authors.lastname: Kridelka
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Marc
authors.initials: M
authors.lastname: Thiry
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.forename: Ingrid
authors.initials: I
authors.lastname: Struman
authors.forename: Agnès
authors.initials: A
authors.lastname: Noël
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D017364:Collagenases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D004625:Embryo, Nonmammalian; D045604:Extracellular Fluid / Q000201:enzymology / Q000378:metabolism; D005260:Female; D006801:Humans; D042583:Lymphangiogenesis / Q000235:genetics*; D042601:Lymphatic Vessels / Q000196:embryology* / Q000378:metabolism / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015027:Zebrafish
chemical_list: D024042:Collagen Type I; D017364:Collagenases; D020778:Matrix Metalloproteinase 2