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(Circulation Research. 2004;94:1203.)
© 2004 American Heart Association, Inc.

Molecular Medicine

Critical Role of Monocyte Chemoattractant Protein-1 Receptor CCR2 on Monocytes in Hypertension-Induced Vascular Inflammation and Remodeling

Minako Ishibashi, Ken-ichi Hiasa, Qingwei Zhao, Shujiro Inoue, Kisho Ohtani, Shiro Kitamoto, Miyuki Tsuchihashi, Takeshi Sugaya, Israel F. Charo, Shinobu Kura, Teruhisa Tsuzuki, Tatsuro Ishibashi, Akira Takeshita, Kensuke Egashira

From the Department of Cardiovascular Medicine (M.I., K.H., Q.Z., S.I., K.O., S. Kitamoto, M.T., A.T., K.E.) and Department of Medical Biophysics and Radiation Biology (S. Kura, T.T.), Department of Ophthalmology (T.I.), Graduate School of Medical Science, Kyushu University, Fukuoka, Japan; Discovery Research Laboratory (T.S.), Tanabe Seiyaku Co, Ltd, Kashima, Osaka, Japan; and Gladstone Institute of Cardiovascular Disease (I.F.C.), San Francisco, Calif.

Correspondence to Kensuke Egashira, MD, PhD, Department of Cardiovascular Medicine, Graduate School of Medical Science, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail egashira{at}cardiol.med.kyushu-u.ac.jp

Activated monocytes are present in the arterial walls of hypertensive patients and animals. Monocyte chemoattractant protein-1 (MCP-1), which controls monocyte function through its receptor (CCR2), is implicated in hypertensive inflammatory changes in the arterial wall. The role of CCR2 expression on monocytes in hypertension-induced vascular remodeling, however, has not been addressed. We hypothesized that CCR2 on monocytes is critical in hypertension-induced vascular inflammation and remodeling. Hypertension was induced by infusion of angiotensin II (Ang II) into wild-type mice, CCR2-deficient (CCR2^–/–) mice, and bone marrow-transferred mice with a leukocyte-selective CCR2 deficiency (BMT-CCR2^–/–). In wild-type mice, Ang II increased CCR2 intensity in circulating monocytes, which was prevented by an Ang II type-1 (AT₁) receptor blocker or blunted in AT₁ receptor-deficient mice. Enhanced CCR2 intensity on monocytes was observed in hypertensive patients and rats, and was reduced by treatment with the Ang II receptor blocker, supporting the clinical relevance of the observation in mice. In CCR2^–/– and BMT-CCR2^–/– mice, Ang II-induced vascular inflammation and vascular remodeling (aortic wall thickening and fibrosis) were blunted as compared with control mice. In contrast, Ang II-induced left ventricular hypertrophy developed in CCR2^–/– and BMT-CCR2^–/– mice. The present study suggests that CCR2 expression in monocytes has a critical role in vascular inflammation and remodeling in Ang II-induced hypertension, and possibly in other forms of hypertension.

Key Words: vascular remodeling • angiotensin II • inflammation • leukocytes

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