Abstract 15694: Absence of ECM Remodeling in Smad3 Mutant Mice Leads to Aggressive and Accelerated Aneurysmal Growth Through Distorted Downstream TGF-β Signaling
Aneurysm-osteoarthritis syndrome (AOS), caused by SMAD3 gene mutations, is an autosomal dominant condition characterized by aortic aneurysms and early-onset osteoarthritis. As part of the transcription factor complex Smad2/3/4, Smad3 is essential for TGFβ-activated downstream transcription of CTGF, MMPs, SMAD7 and others. Smad3-/- mice show aneurysmal development at young age, but the underlying mechanism is unknown. To better understand the processes involved, we performed thorough phenotypic and molecular analyses of aneurysmal growth in Smad3-/- mice. First, echocardiograms of cross-sectional studies in Smad3-/- mice showed a significant increase in diameter of root and ascending aorta (18-20%), and significant increased aortic length (16-20%) already at 6 weeks of age, but no difference in aortic distensibility. Importantly, 50% of Smad3-/- mice died suddenly between age 6-24 weeks. Successive macroscopic analysis showed up to a 5-fold increase in aortic diameter of the ascending aorta. Next, longitudinal studies showed a steep increase of aneurysmal growth within only 6 weeks. As the aneurysmatic aortic wall remained translucent, this was indicative for the absence of large scale extracellular matrix remodeling or collagen deposition. Indeed, immunohistochemistry showed a disturbed vascular wall and major sites without elastin or collagen. In accordance, in vivo molecular imaging showed increased aortic neutrophil elastase activity. Remarkably, CT-scans showed dilatations of the arterial tree at different sites of the body, as in AOS patients. In absence of Smad3, we still observed increased nuclear translocation of its co-transcription factor (p)Smad2, and upregulated pERK signaling, inferring increased upstream TGFβ signaling. Hence we reasoned that Smad3 deficiency results in activated TGFβ signaling due to inability to activate downstream Smad7 transcription, a potent inhibitor of TGFβ signaling. Indeed, downstream TGFβ signaling seemed abolished as derived from the absence of MMP activation in Smad3-/- mouse aortas. Identifying the underlying molecular mechanism due to Smad3 mutations is crucial to provide the correct ‘personalized’ treatment for aneurysmal disease.
Author Disclosures: I. van der Pluijm: None. N. van Vliet: None. L. Buijs-Offerman: None. A. Bertoli-Avella: None. J. Essers: None.
- © 2014 by American Heart Association, Inc.