Abstract 455: Systemic, But Not Smooth Muscle Cell-Specific, TGF-β Blockade Exacerbates Angiotensin II-Induced Abdominal Aortic Pathology

Abstract

Objectives: The role of TGF-β signaling in adult vascular homeostasis and aortic aneurysm formation is controversial. Some studies report an association between aneurysm formation and evidence of increased TGF-β signaling in the aortic media; other studies report that TGF-β signaling is critical for adult aortic homeostasis and protects against aortic aneurysm growth. Data supporting a protective effect of TGF-β signaling were reported in the mouse model of Ang II-induced abdominal aortic aneurysm (AAA). However, it is unclear whether this protection is conferred by systemic or SMC-specific actions of TGF-β. Based on data that emphasize a salutary role for TGF-β signaling in SMCs, we hypothesized that TGF-β signaling protects the adult aorta from Ang II-induced AAA by actions on medial SMC. Methods: We compared the incidence and severity of AAA among 3 groups of Ang II-infused mice (4 wk infusion of 1000 ng/kg/min; n = 25/group). Groups included: 1) no TGF-β signaling blockade (control); 2) systemic antibody-mediated TGF-β blockade; and 3) SMC-specific blockade of TGF-β signaling (using inducible SMC-specific Cre recombinase). Results: Mice with systemic TGF-β signaling blockade, but not mice with SMC-specific TGF-β blockade, had larger maximal abdominal aortic diameters than control mice [Control = 1.3 ± 0.1 mm, Systemic = 1.8 ± 0.2mm, SMC-specific = 1.2 ± 0.03 mm; p = 0.01 (Systemic vs Control) and p = 0.5 (SMC-specific vs Control)], increased prevalence of aortic pathology [Control = 42%, Systemic = 78%, SMC-specific = 36%; p = 0.02 (Systemic vs Control) and p = 0.9 (SMC-specific vs Control)] and more severe aortic pathology [median severity scores on 0 [[Unable to Display Character: –]] 4 scale: Control = 0, Systemic = 2, SMC-specific = 0; p = 0.06 (Systemic vs Control) and p = 0.5 (SMC-specific vs Control)]. The differences in aortic diameter and pathology could not be attributed to differences in BP, which did not differ among the groups [Control: SBP = 125 ± 4, MAP = 104 ± 4; Systemic: SBP = 128 ± 6, MAP = 105 ± 5, SMC-specific: SBP = 116 ± 6, MAP = 103 ± 8; p = 0.6 (Control vs Systemic) and p = 0.3 (Control vs SMC-specific)]. Conclusions: We confirm a protective effect of TGF-β signaling in the Ang II model of AAA and conclude that TGFβ signaling prevents aortic damage and dilation by actions outside the aortic media.