Altered transforming growth factor-beta signaling in a murine model of thoracic aortic aneurysm.

Objective: Thoracic aortic aneurysms (TAAs) develop by a multifactorial process involving maladaptive signaling pathways that alter the aortic vascular environment. Transforming growth factor-beta (TGF-beta) has been implicated in regulating the structure and composition of the extracellular matrix by differential activation of various intracellular signaling pathways. However, whether and to what degree TGF-beta signaling contributes to TAA development remains unclear. Accordingly, the hypothesis that alterations in TGF-beta signaling occur during aneurysm formation was tested in a murine model of TAA.

Methods: TAAs were surgically induced in mice (C57BL/6J) and aortas were analyzed at predetermined time points (1, 2, and 4 weeks post-TAA induction). Quantitative real-time PCR (QPCR) was performed to evaluate the expression of 84 relevant TGF-beta superfamily genes, and the protein levels of key signaling intermediates were measured by immunoblotting. Results were compared to unoperated reference control mice.

Results: QPCR revealed increased expression of TGF-beta superfamily ligands (Gdf-2, -6, -7, Inhba), ligand inhibitors (Bmper, Chrd, Gsc), and transcriptional regulators (Dlx2, Evi1), among other genes (Cdkn2b, Igf1, IL-6). Protein levels of TGF-beta receptor(II), Smad2, Smad1/5/8, phospho-Smad1/5/8, and Smurf1 were increased from control values post-TAA induction. Both TGF-beta receptor(I) and Smad4 were decreased from control values, while ALK-1 levels remained unchanged.

Conclusions: These alterations in the TGF-beta pathway suggest a mechanism by which primary signaling is switched from a TGF-betaR(I)/Smad2-dependent response, to an ALK-1/Smad1/5/8 response, representing a significant change in signaling outcome, which may enhance matrix degradation.