Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice

Sci Rep. 2017 Sep 27;7(1):12351. doi: 10.1038/s41598-017-12248-z.


Sporadic aortic aneurysm and dissections (AADs) are common vascular diseases that carry a high mortality rate. ADAMTS-4 (a disintegrin-like and metalloproteinase with thrombospondin motifs-4) is a secreted proteinase involved in inflammation and matrix degradation. We previously showed ADAMTS-4 levels were increased in human sporadic descending thoracic AAD (TAAD) samples. Here, we provide evidence that ADAMTS-4 contributes to aortic destruction and sporadic AAD development. In a mouse model of sporadic AAD induced by a high-fat diet and angiotensin II infusion, ADAMTS-4 deficiency (Adamts-4-/-) significantly reduced challenge-induced aortic diameter enlargement, aneurysm formation, dissection and aortic rupture. Aortas in Adamts-4-/- mice showed reduced elastic fibre destruction, versican degradation, macrophage infiltration, and apoptosis. Interestingly, ADAMTS-4 was directly involved in smooth muscle cell (SMC) apoptosis. Under stress, ADAMTS-4 translocated to the nucleus in SMCs, especially in apoptotic SMCs. ADAMTS-4 directly cleaved and degraded poly ADP ribose polymerase-1 (a key molecule in DNA repair and cell survival), leading to SMC apoptosis. Finally, we showed significant ADAMTS-4 expression in aortic tissues from patients with sporadic ascending TAAD, particularly in SMCs. Our findings indicate that ADAMTS-4 induces SMC apoptosis, degrades versican, promotes inflammatory cell infiltration, and thus contributes to sporadic AAD development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS4 Protein / genetics
  • ADAMTS4 Protein / metabolism*
  • Aged
  • Angiotensin II / administration & dosage
  • Angiotensin II / adverse effects
  • Animals
  • Aorta / pathology
  • Aortic Aneurysm, Thoracic / etiology
  • Aortic Aneurysm, Thoracic / pathology*
  • Aortic Aneurysm, Thoracic / surgery
  • Aortic Dissection / etiology
  • Aortic Dissection / pathology*
  • Apoptosis
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Middle Aged
  • Myocytes, Smooth Muscle / pathology
  • Proteolysis
  • Versicans / metabolism*


  • Vcan protein, mouse
  • Angiotensin II
  • Versicans
  • ADAMTS4 Protein
  • ADAMTS4 protein, human
  • Adamts4 protein, mouse