JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Genetics

Background:

• Obstructive arterial diseases like SVAS involve disrupted elastic lamellae and excess smooth muscle cells (SMCs).
• Supravalvular aortic stenosis (SVAS) stems from elastin gene (ELN) mutations, leading to arterial wall thickening and obstruction.
• The precise link between elastin defects and SMC overgrowth in SVAS remains unclear, hindering treatment development.

Purpose of the Study:

• To investigate the molecular mechanisms linking elastin insufficiency to pathological smooth muscle cell accumulation in SVAS.
• To identify potential therapeutic targets for supravalvular aortic stenosis by elucidating the role of the NOTCH pathway.

Main Methods:

• Utilized human aortic vascular cells, ELN-deficient patient-derived iPSCs, and mouse models.
• Analyzed epigenetic changes, NOTCH pathway activation (NOTCH3, γ-secretase, JAG1), and SMC/endothelial cell (EC) function.
• Assessed the impact of NOTCH3 deletion, γ-secretase inhibition, and JAG1 deletion on aortic pathology in Eln-/- mice.

Main Results:

• Elastin deficiency induced epigenetic changes, upregulating the NOTCH3 pathway in SMCs via increased γ-secretase activity.
• NOTCH3 activation and increased JAG1 expression in SMCs and ECs correlated with aortic hypermuscularization and stenosis in Eln-/- mice.
• NOTCH3 deletion, γ-secretase inhibition, and SMC-specific JAG1 deletion ameliorated the SVAS phenotype in Eln-/- mutants.

Conclusions:

• NOTCH3 pathway upregulation drives pathological aortic SMC accumulation in elastin insufficiency.
• Targeting the NOTCH3 pathway, including γ-secretase and JAG1, offers potential therapeutic strategies for SVAS.