Smooth muscle cell (SMC) proliferation has been thought to limit the progression of thoracic aortic aneurysm and dissection (TAAD) because loss of medial cells associates with advanced disease. We investigated effects of SMC proliferation in the aortic media by conditional disruption of Tsc1, which hyperactivates mTOR complex 1. Consequent SMC hyperplasia led to progressive medial degeneration and TAAD. In addition to diminished contractile and synthetic functions, fate-mapped SMCs displayed increased proteolysis, endocytosis, phagocytosis, and lysosomal clearance of extracellular matrix and apoptotic cells. SMCs acquired a limited repertoire of macrophage markers and functions via biogenesis of degradative organelles through an mTOR/β-catenin/MITF-dependent pathway, but were distinguishable from conventional macrophages by an absence of hematopoietic lineage markers and certain immune effectors even in the context of hyperlipidemia. Similar mTOR activation and induction of a degradative SMC phenotype in a model of mild TAAD due to Fbn1 mutation greatly worsened disease with near-uniform lethality. The finding of increased lysosomal markers in medial SMCs from clinical TAAD specimens with hyperplasia and matrix degradation further supports the concept that proliferation of degradative SMCs within the media causes aortic disease, thus identifying mTOR-dependent phenotypic modulation as a therapeutic target for combating TAAD.

中文翻译：

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慢性 mTOR 激活诱导降解性平滑肌细胞表型。

平滑肌细胞 (SMC) 增殖被认为会限制胸主动脉瘤和夹层 (TAAD) 的进展，因为中层细胞的丧失与晚期疾病相关。我们通过条件性破坏 Tsc1 来研究主动脉中膜中 SMC 增殖的影响，Tsc1 过度激活 mTOR 复合物 1。随之而来的 SMC 增生导致进行性内侧变性和 TAAD。除了收缩和合成功能减弱外，命运映射的 SMC 还显示出蛋白水解、内吞作用、吞噬作用以及细胞外基质和凋亡细胞的溶酶体清除增加。SMCs 通过 mTOR/β-catenin/MITF 依赖性途径通过降解细胞器的生物发生获得了有限的巨噬细胞标志物和功能，但由于缺乏造血谱系标记物和某些免疫效应物，即使在高脂血症的情况下也能与常规巨噬细胞区分开来。由于 Fbn1 突变，轻度 TAAD 模型中类似的 mTOR 激活和降解性 SMC 表型的诱导大大恶化了疾病，具有接近均匀的致死率。来自具有增生和基质降解的临床 TAAD 标本的内侧 SMC 中溶酶体标志物增加的发现进一步支持了这样一个概念，即培养基内降解性 SMC 的增殖会导致主动脉疾病，从而将 mTOR 依赖性表型调节确定为对抗 TAAD 的治疗靶点。由于 Fbn1 突变，轻度 TAAD 模型中类似的 mTOR 激活和降解性 SMC 表型的诱导大大恶化了疾病，具有接近均匀的致死率。来自具有增生和基质降解的临床 TAAD 标本的内侧 SMC 中溶酶体标志物增加的发现进一步支持了这样一个概念，即培养基内降解性 SMC 的增殖会导致主动脉疾病，从而将 mTOR 依赖性表型调节确定为对抗 TAAD 的治疗靶点。由于 Fbn1 突变，轻度 TAAD 模型中类似的 mTOR 激活和降解性 SMC 表型的诱导大大恶化了疾病，具有接近均匀的致死率。来自具有增生和基质降解的临床 TAAD 标本的内侧 SMC 中溶酶体标志物增加的发现进一步支持了这样一个概念，即培养基内降解性 SMC 的增殖会导致主动脉疾病，从而将 mTOR 依赖性表型调节确定为对抗 TAAD 的治疗靶点。