Angiotensin II induces histomorphologic features of unstable plaque in a murine model of accelerated atherosclerosis

• Published in: Journal of vascular surgery Vol. 44; no. 2; pp. 364 - 371
• Main Authors: da Cunha, Valdeci, Martin-McNulty, Baby, Vincelette, Jon, Choy, David F., Li, We-Wei, Schroeder, Miriam, Mahmoudi, Mithra, Halks-Miller, Meredith, Wilson, Dennis W., Vergona, Ronald, Sullivan, Mark E., Wang, Yi-Xin (Jim)
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.08.2006; Elsevier
• Subjects: Angiotensin II; Animals; Apolipoproteins E - deficiency; Apolipoproteins E - genetics; Atherosclerosis - etiology; Atherosclerosis - metabolism; Atherosclerosis - pathology; Biological and medical sciences; Carotid Arteries - drug effects; Carotid Arteries - pathology; Carotid Arteries - surgery; Carotid Artery Diseases - etiology; Carotid Artery Diseases - metabolism; Carotid Artery Diseases - pathology; Chemokine CCL2 - metabolism; Disease Models, Animal; Foam Cells - drug effects; Foam Cells - pathology; Immunohistochemistry; Ligation; Male; Matrix Metalloproteinase 2 - metabolism; Medical sciences; Mice; Mice, Knockout; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Tunica Intima - drug effects; Tunica Intima - metabolism; Tunica Intima - pathology; Vascular Cell Adhesion Molecule-1 - metabolism; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels; Vascular disease; Vertebrata; Mammalia; Mouse; Animal; Surgery; Rodentia; Atherosclerosis; Cardiovascular disease; Angiotensin II
• ISSN: 0741-5214; 1097-6809
• DOI: 10.1016/j.jvs.2006.04.033

We explored the role of angiotensin II in determining the histomorphometric features of plaque stability in apolipoprotein E–deficient mice submitted to ligation of the carotid artery. Six-month-old apolipoprotein E–deficient mice underwent ligation of the common left carotid artery and were immediately assigned to receive either angiotensin II (1.4 mg · kg −1 · d −1 subcutaneously) or vehicle (phosphate-buffered saline; control) via a subcutaneous osmotic minipump for 4 weeks. Ligated arteries from control animals developed intimal lesions composed of macrophage foam cell plaques, which accumulated adjacent to the internal elastic lamina and were surrounded by a fibromuscular layer. Angiotensin II–treated mice had a greater intimal area (threefold), which was accompanied by a fivefold increase in the foam cell area. Lesions from angiotensin II–treated mice also displayed complex morphology characterized by intralesional neovasculature and hemorrhage. The content of active matrix metalloproteinase 2, mainly colocalized with macrophage foam cells, and the production of the inflammatory mediators monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 were also increased by angiotensin II treatment. Although angiotensin II induced vessel expansion and lumen loss to a similar extent, only vessel enlargement correlated with intimal area. Taken together, this study’s results support a role of angiotensin II in plaque vulnerability by promoting intraplaque neovascularization/hemorrhage, inflammation, and expansive remodeling. In this study, we assessed the effect of angiotensin II on histomorphologic features of unstable plaques in the carotid ligation model in mice. We chose an animal model with two important features of human atherosclerosis development: the presence of an intact endothelial layer and an altered hemodynamic environment. Related to these features, macrophage-rich intimal lesions in ligated carotid arteries are associated with outward or expansive remodeling of the vessel, the hallmark of unstable plaques. In addition, to show the effect of angiotensin II on lesion features, our data further strengthen the concept that expansively remodeled plaques represent an unstable phenotype.