Abstract 309: Deletion of a Specific Type-I Transforming Growth Factor-beta Receptor Attenuates Thoracic Aortic Aneurysm Development

Abstract

Introduction: Pathological remodeling with thoracic aortic aneurysms (TAA) occurs as a result of an imbalance between deposition and degradation of the extracellular matrix. TGF-β is a soluble peptide growth factor that signals through a heteromeric receptor complex involving two type-I receptors (either TGF-βR1 or ALK-1) to regulate matrix homeostasis. Alterations in type-1 TGF-β receptor abundance are coincident with TAA formation, suggesting matrix regulation shifts from a TGFβR1 to an ALK-1 mediated pathway. This study tested the hypothesis that ALK-1 signaling is required for TAA development. Methods and Results: TAAs were induced (periadventitial CaCl 2 : 0.5 M, 15 mins) in TGF-βR1- (TGF-βR1 +/- ), and ALK-1 +/- deficient mice, and compared to wild-type littermate controls. Baseline aortic diameters (pre-procedural) were similar in TGF-βR1 +/- (795±42 μm), ALK-1 +/- (712±46 μm), and control animals (744±52 μm TGF-βR1 +/- line; 735±22 ALK-1 +/- line). Mice were randomized for terminal study (biochemistry, histology) at 2, 4, 8, or 16 weeks (7-10 mice/group, M/F) post-TAA induction. The change in aortic diameter was computed for each mouse as a percent increase from its own baseline measurement. Aortic dilatation was observed in all groups at 2 weeks post-TAA induction and continued to increase through 16-weeks. However, the change aortic dilation over time was attenuated in the ALK-1 +/- deficient mice vs. littermate control (Figure). Conclusions: These results demonstrate that signaling through the ALK-1 receptor is necessary for TAA development, and suggest that therapeutic strategies aimed at ALK-1 inhibition may reduce or prevent the clinical progression of TAA.