Nitric Oxide Mediates Aortic Disease in Mice Deficient in the Metalloprotease Adamts1 and in a Mouse Model of Marfan Syndrome

Nat Med. 2017 Feb;23(2):200-212. doi: 10.1038/nm.4266. Epub 2017 Jan 9.


Heritable thoracic aortic aneurysms and dissections (TAAD), including Marfan syndrome (MFS), currently lack a cure, and causative mutations have been identified for only a fraction of affected families. Here we identify the metalloproteinase ADAMTS1 and inducible nitric oxide synthase (NOS2) as therapeutic targets in individuals with TAAD. We show that Adamts1 is a major mediator of vascular homeostasis, given that genetic haploinsufficiency of Adamts1 in mice causes TAAD similar to MFS. Aortic nitric oxide and Nos2 levels were higher in Adamts1-deficient mice and in a mouse model of MFS (hereafter referred to as MFS mice), and Nos2 inactivation protected both types of mice from aortic pathology. Pharmacological inhibition of Nos2 rapidly reversed aortic dilation and medial degeneration in young Adamts1-deficient mice and in young or old MFS mice. Patients with MFS showed elevated NOS2 and decreased ADAMTS1 protein levels in the aorta. These findings uncover a possible causative role for the ADAMTS1-NOS2 axis in human TAAD and warrant evaluation of NOS2 inhibitors for therapy.

MeSH terms

  • ADAMTS1 Protein / genetics*
  • ADAMTS1 Protein / metabolism
  • Adult
  • Aged
  • Aneurysm, Dissecting / genetics*
  • Aneurysm, Dissecting / metabolism
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism*
  • Aortic Aneurysm / genetics*
  • Aortic Aneurysm / metabolism
  • Aortic Aneurysm, Thoracic / genetics
  • Aortic Aneurysm, Thoracic / metabolism
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Female
  • Fibrillin-1 / genetics
  • Gene Knockdown Techniques
  • Haploinsufficiency
  • Humans
  • Immunoblotting
  • Male
  • Marfan Syndrome / genetics*
  • Marfan Syndrome / metabolism
  • Mice
  • Middle Aged
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Nitric Oxide / metabolism*
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / genetics*
  • Nitric Oxide Synthase Type II / metabolism
  • Real-Time Polymerase Chain Reaction


  • Enzyme Inhibitors
  • Fbn1 protein, mouse
  • Fibrillin-1
  • Nitric Oxide
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • ADAMTS1 Protein
  • ADAMTS1 protein, human
  • Adamts1 protein, mouse
  • NG-Nitroarginine Methyl Ester

Supplementary concepts

  • Aortic Aneurysm, Familial Thoracic 1