E ndothelial cells (ECs) play an essential role in the modulation of vascular homeostasis. During aging and specifically during the development of atherosclerosis, ECs are exposed to various damaging stimuli and are thereby prone to injury.1 Rapid endothelial recovery, or re-endothelialization, correlates with diminished plaque formation. 2 Likewise, coronary intervention-induced vascular injury requires an Background-ADAMTS-7, a member of the disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, was recently identified to be significantly associated genomewide with coronary artery disease. However, the mechanisms that link ADAMTS-7 and coronary artery disease risk remain elusive. We have previously demonstrated that ADAMTS-7 promotes vascular smooth muscle cell migration and postinjury neointima formation via degradation of a matrix protein cartilage oligomeric matrix protein. 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 wild-type 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 in comparison with the wild type. In vitro studies further indicated that ADAMTS-7 inhibited both endothelial cell proliferation and migration. Surprisingly, cartilage oligomeric matrix protein 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 labelfree liquid chromatography-tandem mass spectrometry secretome analysis revealed thrombospondin-1 as a potential ADAMTS-7 target. The subsequent studies showed that ADAMTS-7 was directly associated with thrombospondin-1 by its C terminus and degraded thrombospondin-1 in vivo and in vitro. The inhibitory effect of ADAMTS-7 on postinjury 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 postinjury vascular intima hyperplasia. potentially because they inhibit not only vascular smooth muscle cell (VSMC) proliferation/migration, but also reendothelialization. 6,7 Therefore, new strategies that aim to promote endothelial recovery, and simultaneously inhibit VSMC activation, as well, are needed for the effective prevention and treatment of atherosclerosis and postinjury restenosis.Metalloproteinases are critical in vascular wall remodeling through matrix or nonmatrix degradation. 8 Recently, we described ADAMTS-7, a member of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family, in the mediation of VSMC migration and the promotion of neointima formation following ar...