Notch1 haploinsufficiency causes ascending aortic aneurysms in mice

Area of Science:

• Cardiovascular Biology
• Genetics
• Developmental Biology

Background:

• Ascending aortic aneurysm (AscAA) is a serious condition with an unclear molecular basis.
• NOTCH1 mutations are associated with bicuspid aortic valve (BAV), a risk factor for AscAA.

Purpose of the Study:

• To investigate the role of Notch1 in AscAA.
• To determine if Notch1 deficiency in the second heart field (SHF) lineage contributes to AscAA.

Main Methods:

• Utilized Marfan syndrome mouse models with Notch1 haploinsufficiency.
• Performed heterozygous deletion of Notch1 in the SHF lineage.
• Analyzed gene expression in mouse aortic roots using RNA sequencing.

Main Results:

• Notch1 haploinsufficiency worsened aortic root dilation in Marfan syndrome mice.
• Heterozygous Notch1 deletion in the SHF lineage replicated the exacerbated phenotype.
• Notch1+/- mice developed aortic root dilation, indicating Notch1 loss is sufficient to cause AscAA.
• RNA sequencing revealed gene expression changes consistent with AscAA in Notch1+/- mice.

Conclusions:

• This study demonstrates a novel, SHF lineage-specific role for Notch1 in AscAA.
• Genes associated with BAV may also play a role in the development of associated aortopathy.