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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2363.)
© 2007 American Heart Association, Inc.

Vascular Biology

Angiotensin II Receptor Blocker Inhibits Neointimal Hyperplasia Through Regulation of Smooth Muscle–Like Progenitor Cells

Takaaki Yamada; Takahisa Kondo; Yasushi Numaguchi; Michitaka Tsuzuki; Tatsuaki Matsubara; Ichiro Manabe; Masataka Sata; Ryozo Nagai; Toyoaki Murohara

From the Department of Cardiology (T.Y., T.K., Y.N., M.T., T. Matsubara, T. Murohara), Nagoya University Graduate School of Medicine, and the Department of Cardiology, Faculty of Medicine (I.M., M.S., R.N.), University of Tokyo, Japan.

Correspondence to Toyoaki Murohara, MD, PhD, FAHA, Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-Ku, Nagoya 466-8550, Japan. E-mail murohara{at}med.nagoya-u.ac.jp

Objectives— Angiotensin II (ATII) type 1 receptor (AT1R) blocker (ARB) has been shown to inhibit neointimal formation. Bone marrow–derived mononuclear cells (BM-MNCs) give rise to smooth muscle (SM)-like cells at injured arterial wall and contribute to neointimal formation. However, role of the renin—angiotensin system in the homing process of SM-like cells during neointimal formation is unknown.

Material and Methods— When human BM-MNCs and peripheral blood MNCs (PB-MNCs) were cultured under treatment with PDGF-BB and bFGF, these cells gave rise to SM-like cells with expression of SMA, SMemb, and SM1 proteins. RT-PCR showed the expression of AT1R, ATII type 2 receptor (AT2R), SMA, and SMemb mRNAs. ATII accelerated the differentiation of SM-like cells, which was inhibited by an ARB CV11974 (P<0.05). We then examined the effects of ATII, CV11974, and AT2R antagonist PD123319 on neointimal formation and BM-derived SM-like cell incorporation at injured arteries in vivo. BM from green fluorescence protein (GFP)-transgenic mice was transplanted to irradiated WT mice. GFP-BM chimera mice were subjected to wire injury on the left femoral artery. ATII (100 ng/kg/min) stimulated whereas CV11974 (1 mg/kg/d) inhibited neointimal formation. Number of GFP⁺SMA⁺ cells at neointima correlated with the intima/media ratio (r=0.69, P<0.05).

Conclusion— BM-derived SM-like progenitor cells contributed to the neointimal formation after arterial injury. ATII accelerated whereas ARB suppressed this process. These are new aspects of the ARB-mediated inhibition of atherosclerotic disease progression.

Bone marrow (BM)-derived cells differentiate into smooth muscle–like cells at injured arteries and contribute to neointimal formation. However, role of angiotensin II (ATII) in this process was unknown. Here we show that ATII accelerated whereas AT1 receptor blocker (ARB) suppressed this process. These are new aspects of ARB-mediated inhibition of atherosclerotic disease.

Key Words: smooth muscle cell • bone marrow • angiotensin II • angiotensin II type1 receptor blocker • neointima

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