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Updated: Apr 12, 2026
Murine Model of Thoracic Aortic Dissection Induced by Oral β-Aminopropionitrile and Subcutaneous Angiotensin II Infusion
Published on: May 16, 2025
Deficiency of MMP17/MT4-MMP proteolytic activity predisposes to aortic aneurysm in mice
Mara Martín-Alonso1, Ana B García-Redondo1, Dongchuan Guo1
1From the Department of Vascular Biology and Inflammation (M.M.-A., A.A., N.M.-B., A.P., J.M.R., A.G.A.), Proteomics Unit (E.C., J.V.) and Bioinformatics Unit (F.M.), Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Department of Pharmacology/Nephrology, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain (A.B.G.-R., M.S.); Department of Internal Medicine, University of Texas Health Science Center at Houston, TX (D.G., D.M.); Department of Basic Biomedical Sciences, Universidad Europea de Madrid, Villaviciosa de Odón, Madrid, Spain (C.S.-C.); Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ (D.T.D.); and Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo, Japan (M.S.).
Rationale:
Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries. These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome.
Objective:
To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology.
Methods And Results:
Screening of patients with inherited thoracic aortic aneurysms and dissections identified a missense mutation (R373H) in the MMP17 gene that prevented the expression of the protease in human transfected cells. Using a loss-of-function genetic mouse model, we demonstrated that the lack of Mmp17 resulted in the presence of dysfunctional vascular smooth muscle cells and altered extracellular matrix in the vessel wall; and it led to increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. We also showed that Mmp17-mediated osteopontin cleavage regulated vascular smooth muscle cell maturation via c-Jun N-terminal kinase signaling during aorta wall development. Some features of the arterial phenotype were prevented by re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment in Mmp17-null neonates.
Conclusions:
Mmp17 proteolytic activity regulates vascular smooth muscle cell phenotype in the arterial vessel wall, and its absence predisposes to thoracic aortic aneurysm in mice. The rescue of part of the vessel-wall phenotype by a lentiviral strategy opens avenues for therapeutic intervention in these life-threatening disorders.
Insights
The protease MMP17 is crucial for vascular smooth muscle cell function and arterial wall development. Its absence leads to thoracic aortic aneurysms, suggesting therapeutic potential for this protease in treating aortic diseases.
Area of Science:
- Cardiovascular Biology
- Protease Function
- Vascular Smooth Muscle Cell Biology
Background:
- Aortic aneurysms and dissections cause significant mortality, often linked to genetic factors affecting vascular cells and extracellular matrix.
- A substantial portion of patients with familial aortic aneurysms lack identified genetic causes, highlighting the need for further research.
Purpose of the Study:
- To investigate the function of the protease MMP17 (also known as MT4-MMP) in the arterial wall.
- To assess the relevance of MMP17 in the pathology of human aortic aneurysms.
Main Methods:
- Screening of patients with inherited thoracic aortic aneurysms for mutations in the MMP17 gene.
- Utilizing a loss-of-function genetic mouse model to study the effects of Mmp17 deficiency.
- Investigating Mmp17's role in osteopontin cleavage and downstream signaling pathways (c-Jun N-terminal kinase).
Main Results:
- A missense mutation (R373H) in MMP17 was identified in patients, impairing protease expression.
- Mmp17-null mice exhibited dysfunctional vascular smooth muscle cells, altered extracellular matrix, and increased susceptibility to aortic aneurysm.
- Mmp17-mediated osteopontin cleavage was found to regulate vascular smooth muscle cell maturation during aorta development.
Conclusions:
- MMP17 proteolytic activity is essential for maintaining vascular smooth muscle cell phenotype and arterial wall integrity.
- Absence of Mmp17 predisposes to thoracic aortic aneurysm, underscoring its role in vascular health.
- Partial rescue of arterial defects using a lentiviral strategy suggests potential therapeutic avenues for aortic disorders.
