GM-CSF contributes to aortic aneurysms resulting from SMAD3 deficiency

J Clin Invest. 2013 May;123(5):2317-31. doi: 10.1172/JCI67356. Epub 2013 Apr 15.


Heterozygous loss-of-function SMAD3 (Mothers against decapentaplegic homolog 3) mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3 had a vascular phenotype similar to AOS, marked by the progressive development of aneurysms. These aneurysms were associated with various pathological changes in transmural inflammatory cell infiltration. Bone marrow transplants from Smad3-/- mice induced aortitis and aortic root dilation in irradiated WT recipient mice. Transplantation of CD4+ T cells from Smad3-/- mice also induced aortitis in Smad3+/+ recipient mice, while depletion of CD4+ T cells in Smad3-/- mice reduced the infiltration of inflammatory cells in the aortic root. Furthermore, IFN-γ deficiency increased, while IL-17 deficiency decreased, disease severity in Smad3+/- mice. Cytokine secretion was measured using a cytokine quantibody array, and Smad3-/- CD4+ T cells secreted more GM-CSF than Smad3+/+ CD4+ T cells. GM-CSF induced CD11b+Gr-1+Ly-6Chi inflammatory monocyte accumulation in the aortic root, but administration of anti-GM-CSF mAb to Smad3-/- mice resulted in significantly less inflammation and dilation in the aortic root. We also identified a missense mutation (c.985A>G) in a family of thoracic aortic aneurysms. Intense inflammatory infiltration and GM-CSF expression was observed in aortas specimens of these patients, suggesting that GM-CSF is potentially involved in the development of AOS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aortic Aneurysm / metabolism*
  • CD11b Antigen / metabolism
  • CD4-Positive T-Lymphocytes / cytology
  • Crosses, Genetic
  • Echocardiography
  • Female
  • Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Humans
  • Inflammation
  • Interferon-gamma / metabolism
  • Interleukin-17 / metabolism
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Smad3 Protein / deficiency*
  • Smad3 Protein / metabolism*


  • CD11b Antigen
  • Interleukin-17
  • Smad3 Protein
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor