title: Essential role of angiotensin II type 1a receptors in the host vascular wall, but not the bone marrow, in the pathogenesis of angiotensin II-induced atherosclerosis.
abstract: The angiotensin II (Ang II) type 1a (AT1a) receptor is expressed on multiple cell types in atherosclerotic lesions, including bone marrow-derived cells and vascular wall cells, and mediates inflammatory and proliferative responses. Indeed, Ang II infusion accelerates atherogenesis in hyperlipidemic mice by recruiting monocytes and by activating vascular wall cells. Here, we investigated the relative roles of AT1a receptors in the bone marrow vs. the vascular wall in Ang II-induced atherogenesis. Apolipoprotein E-knockout (ApoE(-/-)) mice with or without bone marrow AT1a receptor were generated by experimental bone marrow transplantation using AT1a(+/+) or AT1a(-/-) recipients. In these mice, 28-d Ang II infusion induced significant atherosclerosis in the aorta, and the severity of plaque formation was not affected by the absence of bone marrow AT1a receptor. We then generated AT1a(-/-)ApoE(-/-) mice with or without bone marrow AT1a receptor. Ang II-induced plaque formation was blunted irrespective of the presence of bone marrow AT1a receptor. Host AT1a receptor deficiency was found to suppress Ang II-induced reactive oxygen species production. In addition, AT1a receptor deficiency also impaired monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in the arterial wall 7 d after Ang II initiation. These molecules normally initiate later macrophage-mediated inflammation in the vascular wall. By contrast, AT1a receptor deficiency in the bone marrow did not affect MCP-1-induced monocyte chemotaxis in vitro. In conclusion, AT1a receptors in the host vascular wall, but not in the bone marrow, are essential in Ang II-induced atherogenesis.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, Japan.
authors.forename: Jun-ichiro
authors.initials: J
authors.lastname: Koga
authors.forename: Kensuke
authors.initials: K
authors.lastname: Egashira
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Matoba
authors.forename: Mitsuki
authors.initials: M
authors.lastname: Kubo
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ihara
authors.forename: Masaru
authors.initials: M
authors.lastname: Iwai
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Horiuchi
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001158:Arteries / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D050197:Atherosclerosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D016026:Bone Marrow Transplantation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology; D002678:Chimera; D008264:Macrophages / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics; D014662:Vasoconstrictor Agents / Q000494:pharmacology
chemical_list: D001057:Apolipoproteins E; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D044140:Receptor, Angiotensin, Type 1; D054390:Receptors, CCR2; D014662:Vasoconstrictor Agents; D000804:Angiotensin II