ADAMTS-7 Inhibits Re-Endothelialization of Injured Arteries and Promotes Vascular Remodeling Via Cleavage of Thrombospondin-1
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.
- Received November 4, 2014.
- Revision received January 16, 2015.
- Accepted January 20, 2015.