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.


METHODS
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.
Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, United States of America.
Petra A
PA
Prins
Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, United States of America.
Michael F
MF
Hill
Department of Biostatistics, VUMC, Nashville, Tennessee, United States of America.
David
D
Airey
Department of Biostatistics, VUMC, Nashville, Tennessee, United States of America.
Sam
S
Nwosu
NCI Information Systems, Inc. Nashville Tennessee, United States of America.
Prudhvidhar R
PR
Perati
Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, United States of America.
Hagai
H
Tavori
Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, United States of America.
Macrae
M
F Linton
Department of Pediatrics, VUMC, Nashville, Tennessee, United States of America.
Valentina
V
Kon
Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, United States of America ; Department of Pathology, Microbiology and Immunology, VUMC, Nashville, Tennessee, United States of America.
Sergio
S
Fazio
Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, Tennessee, United States of America ; Department of Pathology, Microbiology and Immunology, VUMC, Nashville, Tennessee, United States of America ; Department of Radiology and Radiological Sciences, VUMC, Nashville, Tennessee, United States of America.
Uchechukwu K
UK
Sampson
D000804:Angiotensin II; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000097:blood* / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000276:immunology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000150:complications* / Q000276:immunology; D002784:Cholesterol / Q000097:blood*; D004549:Elastin / Q000378:metabolism; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications* / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D013997:Time Factors; D014463:Ultrasonography
D001057:Apolipoproteins E; D000804:Angiotensin II; D004549:Elastin; D002784:Cholesterol; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse