Abstract 17395: Deficiency of Tissue Factor in Vascular Smooth Muscle Cells is Associated With Increased Development of Angiotensin II-induced Abdominal Aortic Aneurysms
Objective: Tissue factor (TF) is constitutively expressed in subendothelial cells, including vascular smooth muscle cells (VSMCs), and maintains hemostasis. Its expression is increased in medial VSMCS in response to vascular injury in vivo and following angiotensin II (AngII) incubation in vitro. The complex of factor VIIa (FVIIa) bound to TF activates 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-deficient cells. However, the importance of TF in the etiology of abdominal aortic aneurysm (AAA) has not been examined. Therefore, we examined the effect of whole body deficiency or VSMC-specific deletion of TF on AngII-induced abdominal aortic aneurysm (AAA) development.
Methods and Results: TF+/+ (n=15) or low TF (n=28; 1% of normal TF levels) mice, on a C57BL/6J background, were infused with AngII (1,000 ng/kg/min) for 28 days. Low TF mice had increased luminal diameters of the suprarenal aortic region (+/+: 0.94 ± 0.05; low TF: 1.58 ± 0.09 mm; P=0.002) as measured in vivo by ultrasound. Low TF mice had a 92% incidence of AAA compared to a 20% incidence in TF+/+ mice (P<0.03). To determine the effects of SMC deficiency in vivo, TFflox/floxSM22αCre (TF-SM22αCre)+ (n=8) or Cre- (n=10) mice on a C57BL/6J background were infused with AngII. TF-SM22αCre+ mice had increased abdominal aortic luminal diameters (Cre+: 1.48 ± 0.13; Cre-: 1.06 ± 0.08 mm; P<0.007) and incidence of AAA (75% vs. 20%; P=0.054) compared to Cre- littermates. VSMC-specific TF deficiency was further evaluated on a low-density lipoprotein receptor deficient (Ldlr-/-) background. Mice were fed a fat-enriched diet (21% milk fat) and infused with AngII for 28 days; Ldlr-/-/TF-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. VSMCs deficient in TF exhibited a significantly reduced migration in response to factor VIIa compared to TF-wild type cells.
Conclusion: These results indicate that VSMC TF, most likely via PAR-2 signaling, limits AAA formation.
- © 2013 by American Heart Association, Inc.