Abstract 534: Deficiency of Protease-activated Receptor 2 Attenuates Angiotensin II-induced Abdominal Aortic Aneurysm Independent of Vascular Smooth Muscle Cell Tissue Factor

Abstract

Objective: Tissue factor (TF) is constitutively expressed in subendothelial cells, including vascular smooth muscle cells (VSMCs), and maintains hemostasis. The TF/factor VIIa complex as well as factor Xa have been shown to activate protease-activated receptor 2 (PAR-2). We and others have shown that TF/FVIIa-PAR-2 signaling induces migration of VSMCs in vitro and this is reduced in TF and PAR-2 deficient cells. We previously demonstrated C57BL/6 mice with 1% of normal TF levels (Low TF mice) had increased suprarenal abdominal aortic diameter and incidence of abdominal aortic aneurysm (AAA) compared to littermate controls. However, the source of cellular TF and whether signaling occurred through PAR-2 has not been examined. Our objective was to determine the importance of VSMC-specific deletion of TF and PAR-2 deficiency on the etiology of AAA. Methods and Results: VSMC-specific TF deficiency was evaluated on a low-density lipoprotein receptor deficient (Ldlr -/- ) background. Male mice were fed a fat-enriched diet (21% milk fat) and infused with angiotensin II (AngII; 1,000 ng/kg/min) for 28 days. Ldlr -/- /TF flox/flox SM22αCre + mice had increased abdominal aortic luminal diameters (Cre + : 1.92 ± 0.16 (n = 12); Cre - : 1.22 ± 0.03 mm (n = 10); P = 0.001) and incidence of AAA (100% vs. 50%; P = 0.01) compared to Cre - littermates. Next, we determined the effects of PAR-2 deficiency in AAA. Ldlr -/- /PAR-2 +/+ (n = 12) and Ldlr -/- /PAR-2 -/- (n = 15) male mice were fed a fat-enriched diet and infused with AngII for 28 days. PAR-2 deficiency attenuated abdominal aortic luminal diameters (PAR-2 +/+ : 1.78 ± 0.06 mm; PAR2 -/- : 1.17 ± 0.03 mm; P = 0.001) and incidence of AAA (84% versus 40%; P = 0.048) when compared to littermate controls. Total plasma cholesterol concentrations, lipoprotein cholesterol distributions, or increased systolic blood pressure was not different between groups. Conclusion: These results suggest that TF limits AAA growth and incidence via VSMCs in a PAR-2-independent manner. To verify this hypothesis, studies are currently underway to determine the effect of Factor Xa (FXa) inhibitors in PAR-2 deficient mice.