Abstract 2135: Altered TGF-beta Signaling in a Murine Model of Thoracic Aortic Aneurysm
Objective: The formation of thoracic aortic aneurysms (TAA) is a multifactorial process involving both cellular and extracellular mechanisms. Transforming growth factor-beta (TGF-beta) stimulates differential intracellular signaling pathways dependent on the specific combination of type I (TGFBRI, ALK1, ALK2) and type II (TGFBRII) receptors. Receptor activation then regulates the activation of specific Smad proteins (TGFBRI = Smad 2/3; ALK1, ALK2 = Smad 1/5/8) which differentially regulate the structure and composition of the extracellular matrix. Alterations in TGF-beta receptor profiles have been identified in Marfan syndrome patients with TAAs, however whether this is an early event in the progression of the TAA process remains unknown. Accordingly, this study tested the hypothesis that alterations in TGF-beta signaling occur during aneurysm formation in a murine model of TAA.
Methods: Thoracic aortas were harvested from mice (C57BL/6J) at various time points [1-wk (n=12), 2-wk (n=12), or 4-wk (n=12)] post-TAA induction (0.5M CaCl2, 15 min). Change in aortic diameter was determined by video micrometry measured at baseline and terminal surgery. TGF-beta signaling components were assessed in aortic tissue homogenates by quantitative immunoblotting. Results (mean ± SEM) are expressed as a percent change from unoperated reference control mice (n=12, set at 100%).
Results: Aortic diameter increased at each time point post-TAA induction consistent with aortic dilatation. TGFBRII levels were increased from control values at 2-wk and 4-wk, while TGFBRI was decreased from control over the same time period. Smad4 decreased at 1-wk post-TAA, but returned to control levels at 2-wk and 4-wk. Additionally, Smad2 and phospho-Smad2 were undetectable at all time points.
Conclusions: These new findings identify specific and relevant targets for the interruption of TGF-beta signaling in the formation and progression of TAAs.