The Institute of Cardiovascular Sciences and Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides of Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China.
Cardiology Division, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cardiovasc Res. 2022 May 6;118(6):1564-1582. doi: 10.1093/cvr/cvab109.
Acute aortic dissection (AAD) is a life-threatening disease with high morbidity and mortality. Previous studies have showed that vascular smooth muscle cell (VSMC) phenotype switching modulates vascular function and AAD progression. However, whether an endogenous signalling system that protects AAD progression exists remains unknown. Our aim is to investigate the role of Anxa1 in VSMC phenotype switching and the pathogenesis of AAD.
We first assessed Anxa1 expression levels by immunohistochemical staining in control aorta and AAD tissue from mice. A strong increase of Anxa1 expression was seen in the mouse AAD tissues. In line with these findings, micro-CT scan results indicated that Anxa1 plays a role in the development of AAD in our murine model, with systemic deficiency of Anxa1 markedly progressing AAD. Conversely, administration of Anxa1 mimetic peptide, Ac2-26, rescued the AAD phenotype in Anxa1-/- mice. Transcriptomic studies revealed a novel role for Anxa1 in VSMC phenotype switching, with Anxa1 deficiency triggering the synthetic phenotype of VSMCs via down-regulation of the JunB/MYL9 pathway. The resultant VSMC synthetic phenotype rendered elevated inflammation and enhanced matrix metalloproteinases (MMPs) production, leading to augmented elastin degradation. VSMC-restricted deficiency of Anxa1 in mice phenocopied VSMC phenotype switching and the consequent exacerbation of AAD. Finally, our studies in human AAD aortic specimens recapitulated key findings in murine AAD, specifically that the decrease of Anxa1 is associated with VSMC phenotype switch, heightened inflammation, and enhanced MMP production in human aortas.
Our findings demonstrated that Anxa1 is a novel endogenous defender that prevents AAD by inhibiting VSMC phenotype switching, suggesting that Anxa1 signalling may be a potential target for AAD pharmacological therapy.
急性主动脉夹层（AAD）是一种发病率和死亡率都很高的危及生命的疾病。先前的研究表明，血管平滑肌细胞（VSMC）表型转换调节血管功能和 AAD 进展。然而，是否存在保护 AAD 进展的内源性信号系统尚不清楚。我们的目的是研究 Anxa1 在 VSMC 表型转换和 AAD 发病机制中的作用。
我们首先通过免疫组织化学染色评估了对照主动脉和来自小鼠的 AAD 组织中的 Anxa1 表达水平。在小鼠 AAD 组织中观察到 Anxa1 表达的强烈增加。与这些发现一致，微 CT 扫描结果表明，Anxa1 在我们的小鼠模型中发挥作用，系统性缺乏 Anxa1 明显促进 AAD 的发展。相反，Anxa1 模拟肽 Ac2-26 的给药挽救了 Anxa1-/-小鼠的 AAD 表型。转录组研究揭示了 Anxa1 在 VSMC 表型转换中的新作用，Anxa1 缺乏通过下调 JunB/MYL9 通路触发 VSMC 的合成表型。由此产生的 VSMC 合成表型导致炎症升高和基质金属蛋白酶（MMPs）产生增强，导致弹性蛋白降解增加。在小鼠中 VSMC 特异性缺乏 Anxa1 可模拟 VSMC 表型转换和随后的 AAD 加重。最后，我们在人类 AAD 主动脉标本中的研究重现了小鼠 AAD 中的关键发现，特别是 Anxa1 的减少与 VSMC 表型转换、人类主动脉中的炎症加剧和 MMP 产生增强相关。
我们的研究结果表明，Anxa1 是一种新型的内源性保护因子，通过抑制 VSMC 表型转换来预防 AAD，表明 Anxa1 信号可能是 AAD 药理学治疗的潜在靶点。
