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ADAMTS-2, a metalloproteinase containing a disintegrin domain and thrombospondin type I repeats, a new regulator of angiogenesis
Dubail, Johanne; Kesteloot, Frédéric; Motte, Patrick et al.
2005In Journal of Vascular Research, 42 (Suppl. 2), p. 76
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Abstract :
[en] Enzymes of the ADAMTS family are closely related to MMPs and ADAMs. They further contain specific domains, such as the “ThromboSpondin type I” (TSP1) repeats able to strongly repress angiogenesis. The primary function of ADAMTS-2 is to process procollagen type I, II, III and V into mature molecules by excising the amino-propeptide. We further hypothesized that it could modulate angiogenesis through its TSP1 repeats. Recombinant ADAMTS-2 induced morphological changes in HUVEC and HMEC cultured on gelatin, collagen and fibronectin. It also significantly reduced their proliferation, attachment and spreading. Similar effects were observed when using inactive ADAMTS-2 mutated at the Zn++-binding catalytic site. ADAMTS-2 did not alter the initial steps of formation of capillary-like structures by HUVEC in vitro. However, these structures appeared more rapidly disrupted in presence of ADAMTS-2 than in control conditions. Immunostaining with monoclonal antibodies against ADAMTS-2 indicate that it is tightly immobilized at the endothelial cell surface by an heparin-sensitive binding. With the aim to identify mechanism(s)leading to the modulation of angiogenesis by ADAMTS-2, we investigated various signalling pathways critical for EC. Phosphorylation status of FAK was not altered by ADAMTS-2 while a downregulation of phosphorylation of p42/44 MAPK was observed. Our data suggest that ADAMTS-2 reduces angiogenesis by regulating endothelial cell adhesion and proliferation, and by alteration of the stability of the capillary-like structures. These effects do not seem to be mediated by an integrin-dependent signaling pathway. Choroidal neovascularization induced in TS2+/+ or TS2-/- mice by LASER burns was used as in vivo model. Several genes involved in the healing and angiogenesis processes (fibrillar collagens, VEGF, TGF, CTGF, …) were not differently regulated in TS2+/+ and TS2-/- mice 5 days after the LASER impact. Wound capillaries visualized by confocal microscopy after FITC-conjugated dextran injection, were significantly increased (p<0,05) in TS2-/- mice suggesting an increased angiogenic response in the KO animals. The results obtained in in vivo and in vitro models indicate that ADAMTS-2 is involved in the control of angiogenesis. Additional investigations are being performed to determine which domain(s) of the molecule is (are) antiangiogenic and to identify the mechanism(s) underlying this regulatory function.
Disciplines :
Cardiovascular & respiratory systems
Anatomy (cytology, histology, embryology...) & physiology
Author, co-author :
Dubail, Johanne ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Kesteloot, Frédéric ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Motte, Patrick ;  Université de Liège - ULiège > Département des sciences de la vie > Génomique fonctionnelle et imagerie moléculaire végétale
Lambert, Vincent  ;  Centre Hospitalier Universitaire de Liège - CHU > Ophtalmologie
Rakic, Jean-Marie ;  Université de Liège - ULiège > Département des sciences cliniques > Ophtalmologie
Lapiere, Charles M;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Nusgens, Betty ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Département des sciences biomédicales et précliniques
Colige, Alain ;  Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Protéines et glycoprot. de matr.extracell. et membran.basal.
Language :
English
Title :
ADAMTS-2, a metalloproteinase containing a disintegrin domain and thrombospondin type I repeats, a new regulator of angiogenesis
Publication date :
2005
Event name :
3rd European Meeting on Vascular Biology and Medicine
Event organizer :
Raine Böger, Ingrid Fleming, Johannes Waltenberger
Event place :
Hamburg, Germany
Event date :
du 28/09/2005 au 30/09/2005
Audience :
International
Journal title :
Journal of Vascular Research
ISSN :
1018-1172
eISSN :
1423-0135
Publisher :
Karger, Basel, Switzerland
Volume :
42
Issue :
Suppl. 2
Pages :
76
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 07 January 2009

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