title: ADAMTS3 activity is mandatory for embryonic lymphangiogenesis and regulates placental angiogenesis.
abstract: The only documented activity of a subclass of ADAMTS proteases comprising ADAMTS2, 3 and 14 is the cleavage of the aminopropeptide of fibrillar procollagens. A limited number of in vitro studies suggested that ADAMTS3 is mainly responsible for procollagen II processing in cartilage. Here, we created an ADAMTS3 knockout mouse (Adamts3(-/-)) model to determine in vivo the actual functions of ADAMTS3. Heterozygous Adamts3(+/-) mice were viable and fertile, but their intercrosses demonstrated lethality of Adamts3(-/-) embryos after 15 days of gestation. Procollagens I, II and III processing was unaffected in these embryos. However, a massive lymphedema caused by the lack of lymphatics development, an abnormal blood vessel structure in the placenta and a progressive liver destruction were observed. These phenotypes are most probably linked to dysregulation of the VEGF-C pathways. This study is the first demonstration that an aminoprocollagen peptidase is crucial for developmental processes independently of its primary role in collagen biology and has physiological functions potentially involved in several human diseases related to angiogenesis and lymphangiogenesis.
authors.affiliation: Laboratory of Connective Tissues Biology, Tour de Pathologie, GIGA-R, University of Liege, B23/3, 4000, Sart Tilman, Belgium.
authors.forename: Lauriane
authors.initials: L
authors.lastname: Janssen
authors.affiliation: Laboratory of Connective Tissues Biology, Tour de Pathologie, GIGA-R, University of Liege, B23/3, 4000, Sart Tilman, Belgium.
authors.forename: Laura
authors.initials: L
authors.lastname: Dupont
authors.affiliation: Laboratory of Connective Tissues Biology, Tour de Pathologie, GIGA-R, University of Liege, B23/3, 4000, Sart Tilman, Belgium.
authors.forename: Mourad
authors.initials: M
authors.lastname: Bekhouche
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-R, University of Liege, 4000, Sart Tilman, Belgium.
authors.forename: Agnès
authors.initials: A
authors.lastname: Noel
authors.affiliation: Laboratory of Connective Tissues Biology, Tour de Pathologie, GIGA-R, University of Liege, B23/3, 4000, Sart Tilman, Belgium.
authors.forename: Cédric
authors.initials: C
authors.lastname: Leduc
authors.affiliation: Laboratory of Zebrafish Development and Disease Models, GIGA-R, University of Liege, 4000, Sart Tilman, Belgium.
authors.forename: Marianne
authors.initials: M
authors.lastname: Voz
authors.affiliation: Laboratory of Zebrafish Development and Disease Models, GIGA-R, University of Liege, 4000, Sart Tilman, Belgium.
authors.forename: Bernard
authors.initials: B
authors.lastname: Peers
authors.affiliation: Laboratory of Tumor and Developmental Biology, GIGA-R, University of Liege, 4000, Sart Tilman, Belgium.
authors.forename: Didier
authors.initials: D
authors.lastname: Cataldo
authors.affiliation: Department of Biomedical Engineering, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, 44195, USA.
authors.forename: Suneel S
authors.initials: SS
authors.lastname: Apte
authors.affiliation: Laboratory of Connective Tissues Biology, Tour de Pathologie, GIGA-R, University of Liege, B23/3, 4000, Sart Tilman, Belgium.|Department of Biomedical Engineering, Cleveland Clinic, Lerner Research Institute, Cleveland, OH, 44195, USA.
authors.forename: Johanne
authors.initials: J
authors.lastname: Dubail
authors.affiliation: Laboratory of Connective Tissues Biology, Tour de Pathologie, GIGA-R, University of Liege, B23/3, 4000, Sart Tilman, Belgium. acolige@ulg.ac.be.
authors.forename: Alain
authors.initials: A
authors.lastname: Colige
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D002356:Cartilage / Q000473:pathology; D003094:Collagen / Q000378:metabolism; D004487:Edema / Q000473:pathology; D020964:Embryo Loss / Q000378:metabolism / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006720:Homozygote; D007150:Immunohistochemistry; D008099:Liver / Q000196:embryology / Q000473:pathology; D042583:Lymphangiogenesis; D051379:Mice; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D010920:Placenta / Q000098:blood supply* / Q000473:pathology; D011247:Pregnancy; D011499:Protein Processing, Post-Translational; D012867:Skin / Q000473:pathology; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism
chemical_list: D042582:Vascular Endothelial Growth Factor C; D003094:Collagen; D051722:ADAM Proteins
keywords: ADAMTS; Angiogenesis; Collagen; Development; Lymphangiogenesis; Placenta