ArticleThe Journal of clinical investigation2022
JAGGED1/NOTCH3 activation promotes aortic hypermuscularization and stenosis in elastin deficiency.
Article in The Journal of clinical investigation, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 34 citations in OpenAlex.
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- Development of immune-derived molecular markers for coronary heart disease via multimachine learning.iScience · 2026Article
- Chromatin Remodeling in VSMC Phenotype Switching During Vascular Remodeling: From Mechanism to Therapeutic Potential.Biomolecules · 2026Review
- Review
- Sphingosine kinase 1 is integral for elastin deficiency-induced arterial hypermuscularization.Nature cardiovascular research · 2026Article
- Research progress on targeted regulatory proteins in the prevention and treatment of atherosclerosis.Frontiers in immunology · 2026Review
- Case Report: Newly discovered ELN gene mutation in congenital heart disease: case analysis and review.Frontiers in pediatrics · 2026Article
- Role of Estrogen Signaling in Notch Pathway Activation in Sertoli Cells.Reproductive sciences (Thousand Oaks, Calif.) · 2025Article
- Pictures of stroke and cerebral vasculature: novel insights and detailed visualisation of U-shaped elastin distribution and disorganised fibre arrangement at carotid bifurcations by advanced techniques.Stroke and vascular neurology · 2025Article
- CADASIL orFrontiers in neurology · 2025Review
- Prognostic Significance and Biologic Associations of Senescence-Associated Secretory Phenotype Biomarkers in Heart Failure.Journal of the American Heart Association · 2024Article
- Genetic Testing for Supravalvar Aortic Stenosis: What to Do When It Is Not Williams Syndrome.Journal of the American Heart Association · 2024Article
- Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy.iScience · 2024Article
- Age-related loss of Notch3 underlies brain vascular contractility deficiencies, glymphatic dysfunction, and neurodegeneration in mice.The Journal of clinical investigation · 2024Article
- Association of NOTCH3 With Elastic Fiber Dispersion in the Infrarenal Abdominal Aorta of Cynomolgus Monkeys.Arteriosclerosis, thrombosis, and vascular biology · 2023Article
- Extracellular Matrix Remodeling in Vascular Disease: Defining Its Regulators and Pathological Influence.Arteriosclerosis, thrombosis, and vascular biology · 2023Review
- Vascular pathobiology of pulmonary hypertension.The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation · 2023Review
- Caveolin-1 inhibition mediates the opposing effects of alcohol on γ-secretase activity in arterial endothelial and smooth muscle cells.Physiological reports · 2023Article
- LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin.Circulation research · 2022Article
- Elastin, arterial mechanics, and stenosis.American journal of physiology. Cell physiology · 2022Review
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16 authors at 7 institutions in 4 countries.
Funding
Abstract
Obstructive arterial diseases, including supravalvular aortic stenosis (SVAS), atherosclerosis, and restenosis, share 2 important features: an abnormal or disrupted elastic lamellae structure and excessive smooth muscle cells (SMCs). However, the relationship between these pathological features is poorly delineated. SVAS is caused by heterozygous loss-of-function, hypomorphic, or deletion mutations in the elastin gene (ELN), and SVAS patients and elastin-mutant mice display increased arterial wall cellularity and luminal obstructions. Pharmacological treatments for SVAS are lacking, as the underlying pathobiology is inadequately defined. Herein, using human aortic vascular cells, mouse models, and aortic samples and SMCs derived from induced pluripotent stem cells of ELN-deficient patients, we demonstrated that elastin insufficiency induced epigenetic changes, upregulating the NOTCH pathway in SMCs. Specifically, reduced elastin increased levels of γ-secretase, activated NOTCH3 intracellular domain, and downstream genes. Notch3 deletion or pharmacological inhibition of γ-secretase attenuated aortic hypermuscularization and stenosis in Eln-/- mutants. Eln-/- mice expressed higher levels of NOTCH ligand JAGGED1 (JAG1) in aortic SMCs and endothelial cells (ECs). Finally, Jag1 deletion in SMCs, but not ECs, mitigated the hypermuscular and stenotic phenotype in the aorta of Eln-/- mice. Our findings reveal that NOTCH3 pathway upregulation induced pathological aortic SMC accumulation during elastin insufficiency and provide potential therapeutic targets for SVAS.
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