Rationale: Although not fully understood, the phenotypic transition of vascular smooth muscle cells exhibits at the early onset of the pathology of aortic aneurysms. Exploring the key regulators that are responsible for maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs) may confer vascular homeostasis and prevent aneurysmal disease. XBP1 (X-box binding protein 1), which exists in a transcriptionally inactive unspliced form (XBP1u) and a spliced active form (XBP1s), is a key component in response to endoplasmic reticular stress. Compared with XBP1s, little is known about the role of XBP1u in vascular homeostasis and disease.

Objective: We aim to investigate the role of XBP1u in VSMC phenotypic switching and the pathogenesis of aortic aneurysms.

Methods and Results: XBP1u, but not XBP1s, was markedly repressed in the aorta during the early onset of aortic aneurysm in both angiotensin II–infused apolipoprotein E knockout (ApoE^−/−) and CaPO₄ (calcium phosphate)-induced C57BL/6J murine models, in parallel with a decrease in smooth muscle cell contractile apparatus proteins. In vivo studies revealed that XBP1 deficiency in smooth muscle cells caused VSMC dedifferentiation, enhanced vascular inflammation and proteolytic activity, and significantly aggravated both thoracic and abdominal aortic aneurysms in mice. XBP1 deficiency, but not an inhibition of XBP1 splicing, induced VSMC switching from the contractile phenotype to a proinflammatory and proteolytic phenotype. Mechanically, in the cytoplasm, XBP1u directly associated with the N terminus of FoxO4 (Forkhead box protein O 4), a recognized repressor of VSMC differentiation via the interaction and inhibition of myocardin. Blocking the XBP1u–FoxO4 interaction facilitated nuclear translocation of FoxO4, repressed smooth muscle cell marker genes expression, promoted proinflammatory and proteolytic phenotypic transitioning in vitro, and stimulated aortic aneurysm formation in vivo.

Conclusions: Our study revealed the pivotal role of the XBP1u–FoxO4–myocardin axis in maintaining the VSMC contractile phenotype and providing protection from aortic aneurysm formation.

理由：虽然尚未完全了解，但血管平滑肌细胞的表型转变在主动脉瘤病理的早期就表现出来。探索负责维持血管平滑肌细胞（VSMC）收缩表型的关键调节因子可能会赋予血管稳态并预防动脉瘤疾病。 XBP1（X-box 结合蛋白 1）以转录失活的未剪接形式 (XBP1u) 和剪接活性形式 (XBP1s) 存在，是响应内质网状应激的关键成分。与 XBP1s 相比，人们对 XBP1u 在血管稳态和疾病中的作用知之甚少。

目的：我们旨在探讨XBP1u在VSMC表型转换中的作用以及主动脉瘤的发病机制。

方法和结果：在血管紧张素 II 输注载脂蛋白 E 敲除 (ApoE ^−/− ) 和 CaPO ₄ （磷酸钙）诱导的 C57BL/6J 中，主动脉瘤早期发病期间，XBP1u（而非 XBP1s）在主动脉中受到显着抑制。小鼠模型中，平滑肌细胞收缩装置蛋白的减少同时发生。体内研究表明，平滑肌细胞中的XBP1缺陷会导致VSMC去分化，增强血管炎症和蛋白水解活性，并显着加重小鼠的胸主动脉瘤和腹​​主动脉瘤。 XBP1 缺乏但不抑制 XBP1 剪接，诱导 VSMC 从收缩表型转变为促炎和蛋白水解表型。从机械角度来看，在细胞质中，XBP1u 直接与 FoxO4（叉头盒蛋白 O 4）的 N 末端相关，FoxO4 是一种公认​​的 VSMC 分化抑制因子，通过与心肌素的相互作用和抑制作用实现。阻断 XBP1u-FoxO4 相互作用可促进 FoxO4 的核转位，抑制平滑肌细胞标记基因表达，在体外促进促炎和蛋白水解表型转变，并在体内刺激主动脉瘤形成。

结论：我们的研究揭示了 XBP1u-FoxO4-心肌素轴在维持 VSMC 收缩表型和防止主动脉瘤形成方面的关键作用。