title: Proteolytic cleavage of versican and involvement of ADAMTS-1 in VEGF-A/VPF-induced pathological angiogenesis.
abstract: Malignant tumors and chronic inflammatory diseases induce angiogenesis by overexpressing vascular endothelial growth factor A (VEGF-A/VPF). VEGF-A-induced pathological angiogenesis can be mimicked in immunoincompetent mice with an adenoviral vector expressing VEGF-A(164) (Ad-VEGF-A(164)). The initial step is generation of greatly enlarged "mother" vessels (MV) from preexisting normal venules by a process involving degradation of their rigid basement membranes. Immunohistochemical and Western blot analyses revealed that versican, an extracellular matrix component in the basement membranes of venules, is degraded early in the course of MV formation, resulting in the appearance of a versican N-terminal DPEAAE fragment associated with MV endothelial cells. The protease ADAMTS-1, known to cleave versican near its N terminus to generate DPEAAE, is also upregulated by VEGF-A in parallel with MV formation and localizes to the endothelium of the developing MV. The authors also show that MMP-15 (MT-2 MMP), a protease that activates ADAMTS-1, is upregulated by VEGF-A in endothelial cells in vitro and in vivo. These data suggest VEGF-A initiates MV formation, in part, by inducing the expression of endothelial cell proteases such as ADAMTS-1 and MMP-15 that act in concert to degrade venular basement membrane versican. Thus, versican is actively processed during the early course of VEGF-A-induced pathological angiogenesis.
authors.affiliation: The Center for Vascular Biology Research and Departments of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Yineng
authors.initials: Y
authors.lastname: Fu
authors.forename: Janice A
authors.initials: JA
authors.lastname: Nagy
authors.forename: Lawrence F
authors.initials: LF
authors.lastname: Brown
authors.forename: Shou-Ching
authors.initials: SC
authors.lastname: Shih
authors.forename: Pamela Y
authors.initials: PY
authors.lastname: Johnson
authors.forename: Christina K
authors.initials: CK
authors.lastname: Chan
authors.forename: Harold F
authors.initials: HF
authors.lastname: Dvorak
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Wight
mesh_terms: D051722:ADAM Proteins / Q000096:biosynthesis / Q000502:physiology*; D000071097:ADAMTS1 Protein; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D053517:Matrix Metalloproteinase 15 / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D012867:Skin / Q000098:blood supply / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*; D053675:Versicans / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D053675:Versicans; D051722:ADAM Proteins; D000071097:ADAMTS1 Protein; C103859:ADAMTS1 protein, human; D053517:Matrix Metalloproteinase 15