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

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. Comparative gene expression profiling analysis of RNA-seq data for WT and Mmp19-/- mice aorta tissues.

背景：胸主动脉瘤与夹层（Thoracic aortic aneurysm and dissection, TAAD）是一类致死率极高的危及生命的心血管事件。既往研究表明，基质金属蛋白酶19（matrix metalloproteinases 19, MMP19）参与了TAAD的发生发展，但MMP19在TAAD发病机制中的具体作用及潜在分子机制仍未明确。
方法：为探究MMP19在TAAD进展中的作用，本研究构建了全身Mmp19敲除小鼠，以及血管平滑肌细胞（vascular smooth muscle cells, VSMCs）特异性Mmp19敲低小鼠，并建立了BAPN诱导的TAAD模型。为阐明聚集蛋白聚糖（Aggrecan, Acan）调控的信号通路，本研究使用血清型9腺相关病毒（adeno-associated virus serotype 9, AAV9）载体编码Acan短发夹RNA（short hairpin RNA, shRNA），实现VSMCs特异性的Acan敲低。最终，将编码VSMCs特异性Mmp19的AAV载体注射至BAPN诱导的TAAD小鼠体内，以评估MMP19是否可缓解TAAD的发生发展。
结果：本研究发现，TAAD小鼠及患者的主动脉组织中，MMP19的mRNA与蛋白水平均显著升高。全身敲除Mmp19，或VSMCs特异性敲低Mmp19，均会显著加重BAPN诱导的进行性TAAD及TAAD相关心血管重构。Mmp19缺陷会导致主动脉内聚集蛋白聚糖（Acan）而非Vcan积累，并通过激活Wnt/β-连环蛋白（Wnt/β-catenin）信号通路，驱动血管平滑肌细胞从收缩表型向合成表型转化。Wnt/β-连环蛋白信号通路的选择性抑制剂MASB可有效逆转聚集蛋白聚糖积累诱导的血管平滑肌细胞去分化。值得注意的是，在VSMCs中特异性敲低Acan，可恢复血管平滑肌细胞的收缩表型并抑制Wnt/β-连环蛋白信号通路，从而缓解Mmp19敲除小鼠中的BAPN诱导的TAAD。此外，对Mmp19敲除小鼠的VSMCs进行MMP19特异性补充，同样可减轻其进行性TAAD表型。
结论：本研究证实，Mmp19缺陷通过促进主动脉内Acan聚集，并通过激活Wnt/β-连环蛋白信号通路破坏血管平滑肌细胞稳态，进而加重TAAD。上述结果表明，MMP19有望成为TAAD干预的新型潜在治疗靶点。
本研究对野生型（WT）与Mmp19敲除（Mmp19-/-）小鼠的主动脉组织开展了RNA测序（RNA-seq）数据的比较基因表达谱分析。