Notch1 haploinsufficiency causes ascending aortic aneurysms in mice

JCI Insight. 2017 Nov 2;2(21):e91353. doi: 10.1172/jci.insight.91353.

Abstract

An ascending aortic aneurysm (AscAA) is a life-threatening disease whose molecular basis is poorly understood. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV), which is associated with AscAA. Here, we describe a potentially novel role for Notch1 in AscAA. We found that Notch1 haploinsufficiency exacerbated the aneurysmal aortic root dilation seen in the Marfan syndrome mouse model and that heterozygous deletion of Notch1 in the second heart field (SHF) lineage recapitulated this exacerbated phenotype. Additionally, Notch1+/- mice in a predominantly 129S6 background develop aortic root dilation, indicating that loss of Notch1 is sufficient to cause AscAA. RNA sequencing analysis of the Notch1.129S6+/- aortic root demonstrated gene expression changes consistent with AscAA. These findings are the first to our knowledge to demonstrate an SHF lineage-specific role for Notch1 in AscAA and suggest that genes linked to the development of BAV may also contribute to the associated aortopathy.

Publication types

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

MeSH terms

  • Animals
  • Aorta
  • Aortic Aneurysm / genetics*
  • Aortic Aneurysm / pathology
  • Aortic Valve / abnormalities*
  • Aortic Valve / diagnostic imaging
  • Aortic Valve / pathology
  • Bicuspid Aortic Valve Disease
  • Disease Models, Animal
  • Gene Expression
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Haploinsufficiency*
  • Heart Valve Diseases
  • Mice
  • Mice, Knockout
  • Mutation
  • Phenotype
  • Receptor, Notch1 / genetics*

Substances

  • Notch1 protein, mouse
  • Receptor, Notch1