期刊
JOURNAL OF VASCULAR RESEARCH
卷 45, 期 6, 页码 457-468出版社
KARGER
DOI: 10.1159/000127437
关键词
TGF-beta; Aneurysm; Signal transduction; Extracellular matrix; Remodeling
资金
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL059165, R01HL102121, R01HL075488] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE ON AGING [R01AG036954] Funding Source: NIH RePORTER
- NHLBI NIH HHS [R01 HL075488-04, R01 HL059165, R01 HL102121, R01 HL075488-05, R01 HL059165-07, R01 HL075488] Funding Source: Medline
- NIA NIH HHS [R01 AG036954] Funding Source: Medline
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(1) 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-beta R-1/Smad2-dependent response, to an ALK-1/Smad1/5/8 response, representing a significant change in signaling outcome, which may enhance matrix degradation. Copyright (C) 2008 S. Karger AG, Basel.
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