ArticleScience signaling2015
Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice.
Article in Science signaling, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 51 citations in OpenAlex.
- Lisinopril activates BI1 to reprogram lipid metabolism and restore autophagy in ALS.Communications biology · 2026Article
- Novel Aortic Dissection Model Links Endothelial Dysfunction and Immune Infiltration.Circulation research · 2025Article
- Induction of cardiac fibulin-4 protects against pressure overload-induced cardiac hypertrophy and heart failure.Communications biology · 2025Article
- Fibrillin-1 G234D mutation in the hybrid1 domain causes tight skin associated with dysregulated elastogenesis and increased collagen cross-linking in mice.Matrix biology : journal of the International Society for Matrix Biology · 2025Article
- Increased vascular smooth muscle cell senescence in aneurysmal Fibulin-4 mutant mice.npj aging · 2024Article
- LIM kinases in cardiovascular health and disease.Frontiers in physiology · 2024Review
- Genetics and mechanisms of thoracic aortic disease.Nature reviews. Cardiology · 2023Review
- Protective Role of Endothelial Fibulin-4 in Valvulo-Arterial Integrity.Journal of the American Heart Association · 2023Article
- Article
- Transforming Growth Factor-β and the Renin-Angiotensin System in Syndromic Thoracic Aortic Aneurysms: Implications for Treatment.Cardiovascular drugs and therapy · 2021Review
- The actin depolymerizing factor destrin serves as a negative feedback inhibitor of smooth muscle cell differentiation.American journal of physiology. Heart and circulatory physiology · 2021Article
- Contribution of PDGFRα-positive cells in maintenance and injury responses in mouse large vessels.Scientific reports · 2021Article
- Review
- Simultaneous Upregulation of Elastolytic and Elastogenic Factors Are Necessary for Regulated Collateral Diameter Expansion.Frontiers in cardiovascular medicine · 2021Article
- Lysyl hydroxylase 1 (LH1) deficiency promotes angiotensin II (Ang II)-induced dissecting abdominal aortic aneurysm.Theranostics · 2021Article
- Bio-chemo-mechanics of the thoracic aorta.Vascular biology (Bristol, England) · 2021Review
- Vascular dysfunction and pathology: focus on mechanical forces.Vascular biology (Bristol, England) · 2021Review
- Numerical knockouts-In silico assessment of factors predisposing to thoracic aortic aneurysms.PLoS computational biology · 2020Article
- Matrix mechanotransduction mediated by thrombospondin-1/integrin/YAP in the vascular remodeling.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Elastic fibers and biomechanics of the aorta: Insights from mouse studies.Matrix biology : journal of the International Society for Matrix Biology · 2020Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 3 countries.
Funding
Abstract
Smooth muscle cells (SMCs) and the extracellular matrix (ECM) are intimately associated in the aortic wall. Fbln4(SMKO) mice with an SMC-specific deletion of the Fbln4 gene, which encodes the vascular ECM component fibulin-4, develop ascending aortic aneurysms that have increased abundance of angiotensin-converting enzyme (ACE); inhibiting angiotensin II signaling within the first month of life prevents aneurysm development. We used comparative proteomics analysis of Fbln4(SMKO) aortas from postnatal day (P) 1 to P30 mice to identify key molecules involved in aneurysm initiation and expansion. At P14, the actin depolymerizing factor cofilin was dephosphorylated and thus activated, and at P7, the abundance of slingshot-1 (SSH1) phosphatase, an activator of cofilin, was increased, leading to actin cytoskeletal remodeling. Also, by P7, biomechanical changes and underdeveloped elastic lamina-SMC connections were evident, and the abundance of early growth response 1 (Egr1), a mechanosensitive transcription factor that stimulates ACE expression, was increased, which was before the increases in ACE abundance and cofilin activation. Postnatal deletion of Fbln4 in SMCs at P7 prevented cofilin activation and aneurysm formation, suggesting that these processes required disruption of elastic lamina-SMC connections. Phosphoinositide 3-kinase (PI3K) is involved in the angiotensin II-mediated activation of SSH1, and administration of PI3K inhibitors from P7 to P30 decreased SSH1 abundance and prevented aneurysms. These results suggest that aneurysm formation arises from abnormal mechanosensing of SMCs resulting from the loss of elastic lamina-SMC connections and from increased SSH1 and cofilin activity, which may be potential therapeutic targets for treating ascending aortic aneurysms.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.