Angiotensin II promotes atherosclerotic lesions and aneurysms in apolipoprotein E-deficient mice.
Increased plasma concentrations of angiotension II (Ang II) have been implicated in atherogenesis. To examine this relationship directly, we infused Ang II or vehicle for 1 month via osmotic minipumps into mature apoE(-/-) mice. These doses of Ang II did not alter arterial blood pressure, body weight, serum cholesterol concentrations, or distribution of lipoprotein cholesterol. However, Ang II infusions promoted an increased severity of aortic atherosclerotic lesions. These Ang II-induced lesions were predominantly lipid-laden macrophages and lymphocytes; moreover, Ang II promoted a marked increase in the number of macrophages present in the adventitial tissue underlying lesions. Unexpectedly, pronounced abdominal aortic aneurysms were present in apoE(-/-) mice infused with Ang II. Sequential sectioning of aneurysmal abdominal aorta revealed two major characteristics: an intact artery that is surrounded by a large remodeled adventitia, and a medial break with pronounced dilation and more modestly remodeled adventitial tissue. Although no atherosclerotic lesions were visible at the medial break point, the presence of hyperlipidemia was required because infusions of Ang II into apoE(+/+) mice failed to generate aneurysms. These results demonstrate that increased plasma concentrations of Ang II have profound and rapid effects on vascular pathology when combined with hyperlipidemia, in the absence of hemodynamic influences.
Daugherty
A
A
Division of Cardiovascular Medicine, Gill Heart Institute, Department of Physiology, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, USA. adaugh@pop.uky.edu
Manning
M W
MW
Cassis
L A
LA
D000804:Angiotensin II / Q000633:toxicity*; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced*; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology*; D001161:Arteriosclerosis / Q000139:chemically induced*; D005260:Female; D008214:Lymphocytes / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL
D001057:Apolipoproteins E; D000804:Angiotensin II