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ADAMTS-7 inhibits re-endothelialization of injured arteries and promotes vascular remodeling via cleavage of thrombospondin-1.
Circulation 131, 1191-1201 (2015)
BACKGROUND: -ADAMTS-7, a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, is recently identified to be genome-wide significantly associated with coronary artery disease (CAD). However, the mechanisms that link ADAMTS-7 and CAD risk remain elusive. We have previously demonstrated that ADAMTS-7 promotes vascular smooth muscle cell migration and post-injury neointima formation via degradation of a matrix protein cartilage oligomeric matrix protein (COMP). Because delayed endothelium repair renders neointima and atherosclerosis plaque formation after vessel injury, we examined whether ADAMTS-7 also inhibits re-endothelialization. METHODS AND RESULTS: -Wire-injury of the carotid artery and Evans blue staining were performed in Adamts7(-/-) and wildtype mice. Adamts-7 deficiency greatly promoted re-endothelialization at 3, 5, and 7 days after injury. Consequently, Adamts-7 deficiency substantially ameliorated neointima formation in mice at days 14 and 28 after injury compared with the wildtype. In vitro studies further indicated that ADAMTS-7 inhibited both endothelial cell proliferation and migration. Surprisingly, COMP deficiency did not affect endothelial cell proliferation/migration and re-endothelialization in mice. In a further examination of other potential vascular substrates of ADAMTS-7, a label-free LC MS/MS secretome analysis revealed thrombospondin-1 (TSP-1) as a potential ADAMTS-7 target. The subsequent studies showed that ADAMTS-7 was directly associated with TSP-1 by its C-terminus and degraded TSP-1 in vivo and in vitro. The inhibitory effect of ADAMTS-7 on post-injury endothelium recovery was circumvented in Tsp1(-/-) mice. CONCLUSIONS: -Our study revealed a novel mechanism by which ADAMTS-7 affects neointima formation. Thus, ADAMTS-7 is a promising treatment target for post-injury vascular intima hyperplasia.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Metalloproteinase ; Neointima ; Reendothelialization ; Vascular Remodeling; Smooth-muscle-cells; Oligomeric Matrix Protein; Eluting Stent Thrombosis; Neointima Formation; Carotid-artery; Angiogenesis; Reendothelialization; Migration; Integrin; Disease