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AngII (angiotensin II) induces atherosclerosis and AAAs (abdominal aortic aneurysms) through multiple proposed mechanisms, including chemotaxis. Therefore, we determined the effects of whole-body deficiency of the chemokine receptor CCR2 (CC chemokine receptor 2) on these diseases. To meet this objective, apoE (apolipoprotein E)-/- mice that were either CCR2+/+ or CCR2-/-, were infused with either saline or AngII (1000 ng.kg-1 of body weight.min-1) for 28 days via mini-osmotic pumps. Deficiency of CCR2 markedly attenuated both atherosclerosis and AAAs, unrelated to systolic blood pressure or plasma cholesterol concentrations. During the course of the present study, we also observed that AngII infusion led to large dilatations that were restricted to the ascending aortic region of apoE-/- mice. The aortic media in most of the dilated area was thickened. In regions of medial thickening, distinct elastin layers were discernable. There was an expansion of the distance between elastin layers in a gradient from the intimal to the adventitial aspect of the media. This pathology differed in a circumscribed area of the anterior region of ascending aortas in which elastin breaks were focal and almost transmural. All regions of the ascending aorta of AngII-infused mice had diffuse medial macrophage accumulation. Deficiency of CCR2 greatly attenuated the AngII-induced lumen dilatation in the ascending aorta. This new model of ascending aortic aneurysms has pathology that differs markedly from AngII-induced atherosclerosis or AAAs, but all vascular pathologies were attenuated by CCR2 deficiency.

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 x [kg.sup.-1] x [min.sup.-1]) or norepinephrine (NE; 5.6 mg x [kg.sup.-1] x [day.sup.-1]) for 28 days. Infusion of ANG II or NE increased mean arterial pressure (MAP; ANG II, 133 [+ or -] 2.8; NE, 129 [+ or -] 13 mmHg) to a similar extent compared with baseline blood pressures (MAP, 107 [+ or -] 2 mmHg). Abdominal aortic width increased in both apoE-deficient (apo[E.sup.-/-]) or LDLr-deficient (LD[Lr.sup.-/-]) mice infused with ANG II (apo[E.sup.-/-]: 1.4 [+ or -] 0.1; LD[Lr.sup.-/-]: 1.6 [+ or -] 0.2 mm). In contrast, NE did not change diameters of abdominal aortas (apo[E.sup.-/-]: 0.91 [+ or -] 0.03; LD[Lr.sup.-/-]: 0.87 [+ or -] 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 x [kg.sup.-1] x [min.sup.-1]), AAAs developed in 50% of apo[E.sup.-/-] mice. Alternatively, administration of hydralazine (250 mg/l) to ANG II-infused apo[E.sup.-/-] mice (1,000 ng x [kg.sup.-1] x [min.sup.-1]) lowered systolic blood pressure (day 28: ANG II, 157 [+ or -] 6; ANG II/hydralazine, 135 [+ or -] 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. aneurysms; hypertension; vascular lesions

The role of the renin angiotensin system (RAS) in atherosclerosis is complex because of the involvement of multiple peptides and receptors. Renin is the rate-limiting enzyme in the production of all angiotensin peptides. To determine the effects of renin inhibition on atherosclerosis, we administered the novel renin inhibitor aliskiren over a broad dose range to fat-fed LDL receptor--deficient (Ldlr-/-) mice. Renin inhibition resulted in striking reductions of atherosclerotic lesion size in both the aortic arch and the root. Subsequent studies demonstrated that cultured macrophages expressed all components of the RAS. To determine the role of macrophage-derived angiotensin in the development of atherosclerosis, we transplanted renin-deficient bone marrow to irradiated Ldlr-/- mice and observed a profound decrease in the size of atherosclerotic lesions. In similar experiments, transplantation of bone marrow deficient for angiotensin II type 1a receptors failed to influence lesion development. We conclude that renin-dependent angiotensin production in macrophages does not act in an autocrine/paracrine manner. Furthermore, in vitro studies demonstrated that coculture with renin-expressing macrophages augmented monocyte adhesion to endothelial cells. Therefore, although previous work suggests that angiotensin peptides have conflicting effects on atherogenesis, we found that renin inhibition profoundly decreased lesion development in mice., Introduction There is evolving complexity in the renin angiotensin system (RAS) because of the identification of a spectrum of bioactive angiotensin peptides including AngII, AngIII, AngIV, and Ang1-7 (1-3). There [...]