Aortic aneurysms are life-threatening conditions with effective treatments mainly limited to emergency surgery or trans-arterial endovascular stent grafts, thus calling for the identification of specific molecular targets. Genetic studies have highlighted controversial roles of transforming growth factor β (TGF-β) signaling in aneurysm development. Here, we report on aneurysms developing in adult mice after smooth muscle cell (SMC)-specific inactivation of Smad4, an intracellular transducer of TGF-β. The results revealed that Smad4 inhibition activated interleukin-1β (IL-1β) in SMCs. This danger signal later recruited innate immunity in the adventitia through chemokine (C-C motif) ligand 2 (CCL2) and modified the mechanical properties of the aortic wall, thus favoring vessel dilation. SMC-specific Smad4 deletion in Il1r1- or Ccr2-null mice resulted in milder aortic pathology. A chronic treatment with anti-IL-1β antibody effectively hampered aneurysm development. These findings identify a mechanistic target for controlling the progression of aneurysms with compromised TGF-β signaling, such as those driven by SMAD4 mutations.

主动脉瘤是危及生命的疾病，其有效治疗方法主要限于急诊手术或跨动脉血管内支架移植物，因此需要确定特定的分子靶标。遗传研究突出了在动脉瘤形成过程中转化生长因子β（TGF-β）信号转导的争议性作用。在这里，我们报道了成年小鼠在平滑肌细胞（SMC）特异性失活的Smad4（TGF-β的细胞内转导物）后发展成的动脉瘤。结果表明，Smad4抑制激活了SMC中的白介素-1β（IL-1β）。此危险信号随后通过趋化因子（CC基序）配体2（CCL2）在外膜募集了先天免疫力，并改变了主动脉壁的机械性能，从而有利于血管扩张。SMC特定Il1r1-或Ccr2- null小鼠中Smad4缺失导致较轻的主动脉病变。抗IL-1β抗体的长期治疗有效地阻碍了动脉瘤的发展。这些发现确定了用于控制具有受损的TGF-β信号传导的动脉瘤进展的机制靶标，例如由SMAD4突变驱动的那些。