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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:380.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Bone Marrow Transplantation Reveals That Recipient AT1a Receptors Are Required to Initiate Angiotensin II–Induced Atherosclerosis and Aneurysms

Lisa A. Cassis; Debra L. Rateri; Hong Lu; Alan Daugherty

From the Graduate Center for Nutritional Sciences (L.A.C., A.D.) and the Cardiovascular Research Center (D.L.R., H.L., A.D.), University of Kentucky, Lexington.

Correspondence to Alan Daugherty or Lisa Cassis, Wethington Building, Room 521, University of Kentucky, Lexington, KY 40536-0200. E-mail Alan.Daugherty{at}uky.edu or cassis@uky.edu

Objective— Angiotensin II (AngII) infusion into hypercholesterolemic mice accelerates atherosclerosis and promotes formation of abdominal aortic aneurysms (AAAs). The purpose of this study was to define whether AngII interacts with receptors on infiltrating versus resident cells in promoting vascular pathologies.

Methods and Results— Male LDL receptor–/– mice, that were either AT1a receptor +/+ or –/–, were fed a fat enriched diet and infused with either saline or AngII. AngII-induced augmentation of atherosclerosis and formation of AAAs was ablated in AT1a receptor–/– mice. Bone marrow transplantation studies were performed to determine the role of AT1a receptors expressed on infiltrating cells. AT1a receptor +/+ and –/– mice were irradiated and repopulated with bone marrow–derived stem cells of either genotype. These 4 groups of chimeric mice were infused with either saline or AngII. Repopulation of irradiated AT1a receptor +/+ mice with –/– bone marrow–derived cells resulted in modest reductions in AngII-induced atherosclerosis. Unexpectedly, AT1a receptor–deficient recipient mice were dramatically protected from AngII-induced vascular pathologies, irrespective of donor genotype.

Conclusion— AngII promotes vascular pathology via AT1a receptors. AT1a receptors expressed on infiltrating cells exert modest regulation of AngII-induced atherosclerosis. However, the presence of this receptor in resident tissue is required for the initiation of AngII-induced atherosclerosis and AAAs.

AngII infusion into hyperlipidemic mice leads to augmentation of atherosclerosis and formation of AAAs. The absence of AT1a receptors ablated the development of both these pathologies. Bone marrow transplantation studies demonstrated that the AT1a receptor genotype of the recipient was required to initiate these vascular diseases.

Key Words: angiotensin receptors • atherosclerosis • aneurysms

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