Although abnormal TGFβ signaling is observed in several heritable forms of thoracic aortic aneurysms and dissections including Marfan syndrome, its precise role in aortic disease progression is still disputed. Using a mouse genetic approach and quantitative isobaric labeling proteomics, we sought to elucidate the role of TGFβ signaling in three Fbn1 mutant mouse models representing a range of aortic disease from microdissection (without aneurysm) to aneurysm (without rupture) to aneurysm and rupture. Results indicated that reduced TGFβ signaling and increased mast cell proteases were associated with microdissection. In contrast, increased abundance of extracellular matrix proteins, which could be reporters for positive TGFβ signaling, were associated with aneurysm. Marked reductions in collagens and fibrillins, and increased TGFβ signaling, were associated with aortic rupture. Our data indicate that TGFβ signaling performs context-dependent roles in the pathogenesis of thoracic aortic disease.

尽管在包括马凡综合征在内的几种可遗传形式的胸主动脉瘤和夹层中观察到异常的 TGFβ 信号传导，但其在主动脉疾病进展中的确切作用仍然存在争议。使用小鼠遗传方法和定量同量异位标记蛋白质组学，我们试图阐明 TGFβ 信号在三种Fbn1突变小鼠模型中的作用，这些模型代表一系列主动脉疾病，从显微解剖（无动脉瘤）到动脉瘤（无破裂）再到动脉瘤和破裂。结果表明，TGFβ 信号传导减少和肥大细胞蛋白酶增加与显微切割有关。相比之下，细胞外基质蛋白的丰度增加与动脉瘤相关，这些蛋白可能是阳性 TGFβ 信号传导的报告者。胶原蛋白和原纤维蛋白的显着减少以及 TGFβ 信号传导的增加与主动脉破裂有关。我们的数据表明，TGFβ 信号传导在胸主动脉疾病的发病机制中发挥着背景依赖性作用。