title: S156C mutation in tissue inhibitor of metalloproteinases-3 induces increased angiogenesis.
abstract: Tissue Inhibitor of metalloproteinases-3 (TIMP-3) is a potent matrix-bound angiogenesis inhibitor. Mutations in TIMP-3 cause Sorsby Fundus Dystrophy, a dominant inherited, early onset macular degenerative disease, with choroidal neovascularization causing a loss of vision in the majority of patients. Here we report that expression of S156C TIMP-3 mutation in endothelial cells results in an abnormal localization of the protein, increased glycosylation, decreased matrix metalloproteinase inhibitory activity, and increased vascular endothelial growth factor (VEGF) binding with a consequent increase in VEGF-dependent migration and tube formation. These enhanced signaling events appear to be mediated as a consequence of a post-transcriptionally regulated increase in the expression of membrane-associated VEGFR-2 in endothelial cells of Timp-3(156/156) mutant mice as well as in human Sorsby fundus dystrophy eyes. Understanding the mechanism(s) by which mutant TIMP-3 can induce abnormal neovascularization provides important insight into the pathophysiology of a number of diseases with increased angiogenesis.
authors.affiliation: Department of Opthalmology, Cole Eye Institute, Cleveland Clinic Lerner College of Medicine at Case Western Reserve University, Cleveland, Ohio 44195, USA.
authors.forename: Jian Hua
authors.initials: JH
authors.lastname: Qi
authors.forename: Ganying
authors.initials: G
authors.lastname: Dai
authors.forename: Philip
authors.initials: P
authors.lastname: Luthert
authors.forename: Shyam
authors.initials: S
authors.lastname: Chaurasia
authors.forename: Joe
authors.initials: J
authors.lastname: Hollyfield
authors.forename: Bernhard H F
authors.initials: BH
authors.lastname: Weber
authors.forename: Heidi
authors.initials: H
authors.lastname: Stöhr
authors.forename: Bela
authors.initials: B
authors.lastname: Anand-Apte
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000166:cytology; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005123:Eye / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006031:Glycosylation; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011485:Protein Binding; D013552:Swine; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; C088390:TIMP3 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2