ANG II infusion promotes abdominal aortic aneurysms independent of increased blood pressure in hypercholesterolemic mice

Abstract

Infusion of ANG II in hyperlipidemic mice augments atherosclerosis and causes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define the contribution of ANG II-induced hypertension to these vascular pathologies. Male apolipoprotein E (apoE)- and LDL receptor (LDLr)-deficient mice were infused with ANG II (1,000 ng.kg(-1).min(-1)) or norepinephrine (NE; 5.6 mg.kg(-1).day(-1)) for 28 days. Infusion of ANG II or NE increased mean arterial pressure (MAP; ANG II, 133 +/- 2.8; NE, 129 +/- 13 mmHg) to a similar extent compared with baseline blood pressures (MAP, 107 +/- 2 mmHg). Abdominal aortic width increased in both apoE-deficient (apoE(-/-)) or LDLr-deficient (LDLr(-/-)) mice infused with ANG II (apoE(-/-): 1.4 +/- 0.1; LDLr(-/-): 1.6 +/- 0.2 mm). In contrast, NE did not change diameters of abdominal aortas (apoE(-/-): 0.91 +/- 0.03; LDLr(-/-): 0.87 +/- 0.02 mm). Similarly, atherosclerotic lesions in aortic arches were much greater in mice infused with ANG II compared with NE. At a subpressor infusion rate of ANG II (500 ng.kg(-1).min(-1)), AAAs developed in 50% of apoE(-/-) mice. Alternatively, administration of hydralazine (250 mg/l) to ANG II-infused apoE(-/-) mice (1,000 ng.kg(-1).min(-1)) lowered systolic blood pressure (day 28: ANG II, 157 +/- 6; ANG II/hydralazine, 135 +/- 6 mmHg) but did not prevent AAA formation or atherosclerosis. These results demonstrate that infusion of ANG II to hyperlipidemic mice induces AAAs and augments atherosclerosis independent of increased blood pressure.

Fig. 1.

Infusions of either ANG II or norepinephrine (NE) increase mean arterial pressure (MAP), but only ANG II promotes abdominal aortic aneurysm (AAA) formation. A: MAP was increased to a similar extent by infusions of either ANG II or NE. B: aortic lumen diameters were increased by infusions of ANG II in apoE^−/− or LDLr^−/− mice compared with measurements before infusion. In contrast, infusions of NE did not change baseline aortic lumen diameters. C: external diameter (maximal width) of suprarenal abdominal aortas from apolipoprotein E-deficient (apoE^−/−) or low density lipoprotein receptor-deficient (LDLr^−/−) mice infused with either saline or ANG II. Data are means ± SE from n = 6 mice/group (A) or n = 26 mice/group/treatment (B and C). *Significantly different from baseline (A), from baseline (0) and NE (B), or from NE (C).

Fig. 2.

Atherosclerotic lesions were increased to a greater extent by infusion of ANG II (n = 26/genotype) compared with NE (n = 26/genotype) in both apoE^−/− and LDLr^−/− mice. Lesion areas were greater in LDLr^−/− compared with apoE^−/− mice, regardless of drug infusions. Lesion areas were greater in mice infused with ANG II compared with NE, regardless of genotype. Data are means ± SE on right. *Significantly different from NE, P < 0.05.

Fig. 3.

Infusion of a subpressor rate of ANG II (500 ng·kg⁻¹·min⁻¹) to apoE^−/− mice results in an increased aortic lumen diameter. Aortic diameters of ANG II-infused mice were increased compared with measurements before infusion. Data are means ± SE from n = 5 mice/group. *Significantly different from saline (day 28) and from baseline value, P < 0.05.

Fig. 4.

Administration of hydralazine reduces ANG II-induced increases in systolic blood pressure. Infusion of ANG II increased systolic blood pressure in mice administered either vehicle or hydralazine. However, systolic blood pressures were lower in ANG II-infused mice administered hydralazine compared with vehicle. Data are means ± SE from n = 10 mice/group. *Significantly different from baseline; Δsignificantly different from ANG II, P < 0.05.