Thoracic Aortic Aneurysm Development Is Dependent on Membrane Type-1 Matrix Metalloproteinase Activity and Abundance

Area of Science:

• Cardiovascular Biology
• Extracellular Matrix Biology
• Molecular Medicine

Background:

• Thoracic aortic aneurysm (TAA) involves dysregulated extracellular matrix remodeling.
• Elevated matrix metalloproteinase (MMP) activity, particularly membrane type-1 MMP (MT1-MMP), is implicated in TAA.
• Aortic fibroblasts are a suspected key source of MT1-MMP in TAA.

Purpose of the Study:

• To investigate the specific role of MT1-MMP, especially from fibroblasts, in TAA development.
• To elucidate the molecular mechanisms linking MT1-MMP to TAA pathogenesis.
• To evaluate therapeutic strategies targeting MT1-MMP and TGF-β signaling.

Main Methods:

• Utilized various MT1-MMP transgenic mouse strains, including MT1-MMP deficient and fibroblast-specific knockout models.
• Analyzed TAA induction, aortic diameter changes, and collagen fiber composition.
• Assessed MT1-MMP abundance, activity, and TGF-β activation in isolated aortic fibroblasts.
• Administered MT1-MMP and TGF-β neutralizing antibodies.

Main Results:

• MT1-MMP deficiency reduced TAA development, aortic dilatation, and altered collagen structure.
• Fibroblast-specific MT1-MMP knockout attenuated TAA-induced changes.
• A positive correlation was found between MT1-MMP levels and TGF-β activation in fibroblasts.
• Neutralizing antibodies against MT1-MMP or TGF-β mitigated aortic dilatation.

Conclusions:

• Fibroblast-derived MT1-MMP is essential for thoracic aortic aneurysm development.
• MT1-MMP contributes to TAA pathogenesis by promoting TGF-β signaling.
• Targeting fibroblast MT1-MMP or TGF-β represents a potential therapeutic approach for TAA.