Angiotensin-induced abdominal aortic aneurysms in hypercholesterolemic mice: role of serum cholesterol and temporal effects of exposure.

OBJECTIVE: Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E(-/-) mice. APPROACH: A cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time. RESULTS: The overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (-0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Δ) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86). CONCLUSIONS: These are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size.

Benzo[a]pyrene potentiates the pathogenesis of abdominal aortic aneurysms in apolipoprotein E knockout mice.

The objective of this study was to determine the effect of benzo[a]pyrene (BaP), an abundant environmental polycyclic aromatic hydrocarbon compound, on the pathogenesis of abdominal aortic aneurysms (AAA). Earlier studies have shown that BaP promotes vasculopathy, including atherosclerosis, a predisposing factor for AAA development. In two experimental arms, 203 apolipoprotein E knockout (ApoE-/-) mice were evaluated in 4 groups: BaP, angiotensin II (AngII), BaP+AngII and control. Mice in the first arm were exposed to 5mg/kg/week of BaP for 42 days, and in the second arm to 0.71mg/kg daily for 60 days. In arm one, AAA incidence was higher in the BaP+AngII (14/28) versus AngII (8/27) group (p < 0.05), rupture (n=3) was observed only in BaP+AngII treated mice (p < 0.05). In the second arm, AAA incidence did not differ between AngII (17/30) and BaP+AngII (16/29) groups. However, intact AAA diameter was larger in the BaP+AngII (2.3 ± 0.1mm) versus AngII (1.9 ± 0.1mm) group (p < 0.05), but AAA rupture did not differ (p=NS). In both experimental arms, BaP+AngII mice showed increased expression of tumor necrosis factor alpha (TNF-α), cyclophilin A (Cyp A), and matrix metalloproteinase-9 (MMP9) (p < 0.05). No AAA occurred in control or BaP groups. These findings suggest the role of BaP exposure in potentiating AAA pathogenesis, which may have potential public health significance.

Quantitative estimates of the variability of in vivo sonographic measurements of the mouse aorta for studies of abdominal aortic aneurysms and related arterial diseases.

OBJECTIVES: Burgeoning interest in reducing the morbidity and mortality associated with abdominal aortic aneurysms (AAAs) has led to experimental strategies to elucidate the disease process and attain pharmacologic regression using the apolipoprotein E(-/-) (ApoE(-/-)) mouse model of angiotensin-induced AAAs and in vivo sonography. However, the variability of in vivo sonographic measurements of the mouse aorta has not been established. Thus, our purpose was to determine quantitative estimates of the variability of in vivo sonographic measurements of the mouse aorta as a guide for the design and assessment of studies focused on regression of AAAs and related arterial diseases. METHODS: We used Bland-Altman, locally weighted scatterplot-smoothing regression, and resampling (bootstrapping) methods for variability analyses of multiple in vivo short- and long-axis sonographic measurements of ApoE(-/-) mouse aortas. We measured distinct aortic sites in vivo at the baseline and after angiotensin-induced AAAs and ex vivo using digital calipers. RESULTS: We analyzed 236 data points from 10 male mice (14 weeks old; mean weight ± SD, 29.7 ± 1.6 g). Overall intramouse differences between short- and long-axis and in vivo and ex vivo measurements were 0.038 (95% confidence interval [CI], 0.031-0.046) and 0.085 (95% CI, 0.062-0.109) mm, respectively. Intermouse differences in short-axis measurements were 0.047 (95% CI, 0.042-0.053), 0.049 (95% CI, 0.044-0.055), and 0.039 (95% CI, 0.036-0.042) mm for infrarenal, suprarenal, and thoracic measurements, respectively; differences in long-axis measurements were 0.054 (95% CI, 0.044-0.064), 0.029 (95% CI, 0.024-0.034), and 0.046 (95% CI, 0.037-0.054) mm. Bland-Altman and locally weighted scatterplot-smoothing analyses showed excellent agreement between measures with no variation in discrepancies vis-à-vis the target measurement. CONCLUSIONS: These data establish previously undefined estimates of measurement variability relevant for in vivo sonographic studies of AAA regression in a commonly studied mouse model.