title: SMAD3 deficiency promotes inflammatory aortic aneurysms in angiotensin II-infused mice via activation of iNOS.
abstract: BACKGROUND
  Ninety percent of the patients carrying distinct SMAD3 mutations develop aortic aneurysms and dissections, called aneurysms-osteoarthritis syndrome (AOS). However, the etiology and molecular events downstream of SMAD3 leading to the pathogenesis of aortic aneurysms in these patients still remain elusive. Therefore, we aimed to investigate the vascular phenotypes of SMAD3-knockout mice.
  
  
  RESULTS
  We have shown that angiotensin II-induced vascular inflammation, but not hypertension, leads to aortic aneurysms and dissections, ultimately causing aortic rupture and death in mice. Lipopolysaccharide-triggered inflammation confirmed that enhanced aortic macrophage recruitment was essential for aneurysm formation in angiotensin II-infused SMAD3-knockout mice. In contrast, phenylephrine-triggered hypertension alone was insufficient to induce aortic aneurysms in mice. Using uniaxial tensile and contractility tests, we showed that SMAD3 deficiency resulted in defective aortic biomechanics and physiological functions, which caused weakening of the aortic wall and predisposed the mice to aortic aneurysms. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that the underlying mechanism involved aberrant upregulation of inducible nitric oxide synthase (iNOS)-derived nitric oxide production and activation of elastolytic matrix metalloproteinases 2 and 9. Administration of clodronate-liposomes and iNOS inhibitor completely abrogated these aortic conditions, thereby identifying iNOS-mediated nitric oxide secretion from macrophages as the downstream event of SMAD3 that drives this severe pathology.
  
  
  CONCLUSIONS
  Macrophage depletion and iNOS antagonism represent 2 promising approaches for preventing aortic aneurysms related to SMAD3 mutations and merit further investigation as adjunctive strategies for the life-threatening manifestations of AOS.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Nanyang, Singapore.
authors.forename: Chek K
authors.initials: CK
authors.lastname: Tan
authors.forename: Eddie H
authors.initials: EH
authors.lastname: Tan
authors.forename: Baiwen
authors.initials: B
authors.lastname: Luo
authors.forename: Charlotte L
authors.initials: CL
authors.lastname: Huang
authors.forename: Joachim S
authors.initials: JS
authors.lastname: Loo
authors.forename: Cleo
authors.initials: C
authors.lastname: Choong
authors.forename: Nguan S
authors.initials: NS
authors.lastname: Tan
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001014:Aortic Aneurysm / Q000209:etiology* / Q000235:genetics; D001025:Aortitis / Q000209:etiology* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D010641:Phenotype; D051900:Smad3 Protein / Q000172:deficiency*
chemical_list: D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D000804:Angiotensin II; D052247:Nitric Oxide Synthase Type II
keywords: SMAD3; TGF‐β; aneurysm; iNOS; inflammation