ADAMTS-7 inhibits re-endothelialization of injured arteries and promotes vascular remodeling through cleavage of thrombospondin-1

Circulation. 2015 Mar 31;131(13):1191-201. doi: 10.1161/CIRCULATIONAHA.114.014072. Epub 2015 Feb 20.


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 label-free 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.

Keywords: matrix metalloproteinases; neointima; vascular remodeling.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAM Proteins / deficiency
  • ADAM Proteins / genetics
  • ADAM Proteins / physiology*
  • ADAMTS7 Protein
  • Amino Acid Sequence
  • Animals
  • Carotid Artery Injuries / enzymology*
  • Carotid Artery Injuries / pathology
  • Carotid Artery, Common / enzymology
  • Cell Division
  • Cells, Cultured
  • Endothelial Cells / metabolism
  • Femoral Artery / injuries*
  • Femoral Artery / pathology
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Sequence Data
  • Myocytes, Smooth Muscle / metabolism
  • Neointima / enzymology*
  • Neointima / pathology
  • Protein Interaction Mapping
  • RNA Interference
  • RNA, Small Interfering / pharmacology
  • Rats
  • Thrombospondin 1 / deficiency
  • Thrombospondin 1 / genetics
  • Thrombospondin 1 / physiology*
  • Vascular Remodeling / physiology*


  • RNA, Small Interfering
  • Thrombospondin 1
  • ADAM Proteins
  • ADAMTS7 Protein
  • ADAMTS7 protein, human
  • Adamts7 protein, mouse
  • Adamts7 protein, rat