Unraveling the role of TGF signaling in thoracic aortic aneurysm and dissection using Fbn1 mutant mouse models

Although abnormal TGF beta 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 TGF beta 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 TGF beta signaling and increased mast cell proteases were associated with microdissection. In contrast, increased abundance of extracellular matrix proteins, which could be reporters for positive TGF beta signaling, were associated with aneurysm. Marked reductions in collagens and fibrillins, and increased TGF beta signaling, were associated with aortic rupture. Our data indicate that TGF beta signaling performs context-dependent roles in the pathogenesis of thoracic aortic disease.