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.

Cytochrome P450 1B1 Contributes to the Development of Angiotensin II–Induced Aortic Aneurysm in Male Apoe−/− Mice

“…Although we have previously shown that CYP1B1 mediates Ang IIeinduced hypertension in male mice, 12 it has already been established that in Apoe À/À male mice the development of Ang IIe induced aneurysm is independent of increased blood pressure. 40 Therefore, we believe that protection against Ang IIeinduced AAA mediated by CYP1B1 is independent of hypertension.…”

“…40 Thoracic aortic aneurysms were observed in only approximately 20% of animals. The administration of the selective CYP1B1 inhibitor TMS 14 or Cyp1b1 gene disruption (Apoe À/À /Cyp1b1 À/À ) minimized Ang IIe induced aortic aneurysms in these mice, suggesting that CYP1B1 is crucial for the development of AAA.…”

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

“…Interestingly, Ang II provokes dissecting AAA in hypercholesterolemic mice, independent of increases in blood pressure [37]. In the early stage of dissecting AAA development, Ang II has been shown to contribute to infiltration and accumulation of macrophages in the sub intima, mainly by stimulating CCL2 (also known as MCP-1) secretion from endothelial and vascular smooth muscle cells [38][39][40].…”

Extracellular Matrix Remodelling and Abdominal Aortic Aneurysm

“…Three most common experimental models of AAA include transient intraluminal infusion of elastase (a pancreatic extract) [45], adventitial exposure of a high concentration CaCl 2 solution [46], or chronic subcutaneous infusion of a hypertensive dose of Angiotensin II (Ang II) in a hypercholestremic [47] or normocholestremic background [48]. Hypercholestremia in mice is achieved by deficiency of apolipoprotein-E (ApoE) or low density lipoprotein receptor (LDLR) combined with high fat or high cholesterol diet [49][50][51]. The Ang II infusion model allows for detection of aneurysm throughout the aorta while the elastase infusion and CaCl 2 exposure models provide information about regional aortic susceptibility.…”