MMP19 in vascular smooth muscle cells protects against thoracic aortic aneurysm and dissection via the MMP19/Aggrecan/Wnt/β-catenin axis

Abstract

Background

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular event characterized by high mortality rates. Previous studies have shown that matrix metalloproteinases 19 (MMP19) was involved in TAAD formation, while the detailed role of MMP19 in TAAD pathogenesis and underlying mechanism remain unclear.

Methods

To investigate the role of MMP19 in the progression of TAAD, we generated global Mmp19 knockout mice, as well as VSMCs (vascular smooth muscle cells)-specific Mmp19 knockdown mice, and established a BAPN-induced TAAD model. To elucidate the signaling pathways modulated by Aggrecan, we employed an adeno-associated virus serotype 9 (AAV9) vector encoding Acan short hairpin RNA (shRNA) for VSMC-specific knockdown of Acan. Ultimately, we injected an AAV vector encoding VSMC-specific Mmp19 into BAPN-induced TAAD mice to assess whether MMP19 can mitigate the development of TAAD.

Results

Our findings revealed elevated mRNA and protein levels of MMP19 in the aortas of both TAAD mice and patients. The systemic ablation of Mmp19, as well as VSMC-specific Mmp19 knockdown, significantly exacerbated BAPN-induced progressive TAAD, and TAAD-related cardiovascular remodeling. Mmp19 deficiency resulted in the accumulation of Acan, but not Vcan, within the aorta, driving the phenotypic switch of VSMCs from contractile to synthetic state through activting Wnt/β-catenin signaling pathway. The selective inhibitor of Wnt/β-catenin signaling, MASB, was effective in reversing the dedifferentiation of VSMCs induced by aggrecan accumulation. Notably, the specific knockdown of Acan in VSMCs restored the contractile phenotype of VSMCs and inhibited Wnt/β-catenin signaling, thereby alleviating BAPN-induced TAAD in Mmp19^−/− mice. Additionally, VSMC-specific complementation of MMP19 also alleviated the progressive TAAD phenotype in Mmp19^−/− mice.

Conclusions

The study underscores that MMP19 deficiency exacerbates TAAD by promoting Acan aggregation and destroying the homeostasis of VSMCs by activating Wnt/β-catenin signaling pathway. These results posit MMP19 as a promising novel therapeutic target for TAAD intervention.