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.
Jones
Jeffrey A
JA
Department of Surgery, Division of Cardiothoracic Surgery Research, Medical University of South Carolina, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC 29425, USA. jonesja@musc.edu
Barbour
John R
JR
Stroud
Robert E
RE
Bouges
Shenikqua
S
Stephens
Shelly L
SL
Spinale
Francis G
FG
Ikonomidis
John S
JS
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism* / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
D014409:Tumor Necrosis Factor-alpha