Angiotensin II infusion promotes ascending aortic aneurysms: attenuation by CCR2 deficiency in apoE−/− mice

Abstract

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.

Local Application of Leptin Antagonist Attenuates Angiotensin II–Induced Ascending Aortic Aneurysm and Cardiac Remodeling

“…Much remains unknown about ATAA pathology, largely because of the wide heterogeneity underlying these abnormalities. Nevertheless, most aortic aneurysms are associated with augmented angiotensin II (AngII) activity,6, 7, 8 and AngII‐infusion murine models have been established for both ATAA and abdominal aortic aneurysm (AAA) 9, 10, 11…”

Insights into ascending aortic aneurysm pathogenesis using in vivo and ex vivo imaging systems in angiotensin II-infused mice

“…Consistent with the human disease, Ang II-induced ascending aortic aneurysms are not associated with hypercholesterolemia (9), whereas hypercholesterolemia augments Ang II-induced abdominal aortic aneurysms (10). This mouse model has provided insights into understanding associations between aortic dissection and ascending aortic aneurysms (9,11,12).…”

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]. Additional inflammatory pathways are also involved in the action of Ang II.…”