Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling

Arterioscler Thromb Vasc Biol. 2018 Jul;38(7):1537-1548. doi: 10.1161/ATVBAHA.117.310562. Epub 2018 Apr 5.


Objective: Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic ECM (extracellular matrix). The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteases has recently been implicated in TAA formation. This study aimed to investigate the contribution of ADAMTS-5 to TAA development.

Approach and results: A model of aortic dilatation by AngII (angiotensin II) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5Δcat). Adamts5Δcat mice showed an attenuated rise in blood pressure while displaying increased dilatation of the ascending aorta (AsAo). Interestingly, a proteomic comparison of the aortic ECM from AngII-treated wild-type and Adamts5Δcat mice revealed versican as the most upregulated ECM protein in Adamts5Δcat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of LRP1 (low-density lipoprotein-related protein 1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5, attenuated the generation of versikine, but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Δcat mice but was not sufficient to maintain versican processing and prevent aortic dilatation.

Conclusions: Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Further studies are needed to define the ECM substrates of the different ADAMTS proteases and their contribution to TAA formation.

Keywords: aneurysm; aorta; extracellular matrix; proteases; proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS1 Protein / metabolism
  • ADAMTS5 Protein / deficiency
  • ADAMTS5 Protein / genetics
  • ADAMTS5 Protein / metabolism*
  • Angiotensin II
  • Animals
  • Aorta, Thoracic / enzymology*
  • Aorta, Thoracic / pathology
  • Aortic Aneurysm, Thoracic / chemically induced
  • Aortic Aneurysm, Thoracic / enzymology*
  • Aortic Aneurysm, Thoracic / genetics
  • Aortic Aneurysm, Thoracic / pathology
  • Cells, Cultured
  • Dilatation, Pathologic
  • Disease Models, Animal
  • Extracellular Matrix / enzymology*
  • Extracellular Matrix / pathology
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-1 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-1 / metabolism
  • Male
  • Mice, Knockout
  • Muscle, Smooth, Vascular / enzymology
  • Myocytes, Smooth Muscle
  • Receptors, LDL / metabolism
  • Tumor Suppressor Proteins / metabolism
  • Vascular Remodeling*
  • Versicans / metabolism


  • LRP1 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-1
  • Lrp1 protein, mouse
  • Receptors, LDL
  • Tumor Suppressor Proteins
  • Vcan protein, mouse
  • Angiotensin II
  • Versicans
  • ADAMTS1 Protein
  • ADAMTS1 protein, human
  • ADAMTS5 Protein
  • ADAMTS5 protein, human
  • Adamts1 protein, mouse
  • Adamts5 protein, mouse