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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:930.)
© 2001 American Heart Association, Inc.

Vascular Biology

C-Type Natriuretic Peptide Induces Redifferentiation of Vascular Smooth Muscle Cells With Accelerated Reendothelialization

Kentaro Doi¹; Tadashi Ikeda¹; Hiroshi Itoh; Koji Ueyama; Kiminori Hosoda; Yoshihiro Ogawa; Jun Yamashita; Tae-Hwa Chun; Mayumi Inoue; Ken Masatsugu; Naoki Sawada; Yasutomo Fukunaga; Takatoshi Saito; Masakatsu Sone; Kenichi Yamahara; Hyun Kook; Masashi Komeda; Makiko Ueda; Kazuwa Nakao

From the Department of Medicine and Clinical Science (K.D., H.I., K.H., Y.O., J.Y., T-H.C., M.I., K.M., N.S., Y.F., T.S., M.S., K.Y., K.N.) and the Department of Cardiovascular Surgery (T.I., K.U., M.K.), Kyoto University Graduate School of Medicine, Kyoto, Japan; the Department of Pathology (M.U.), Osaka City University Medical School, Osaka, Japan; and the Department of Pharmacology (H.K.), Chonnam University Medical School, Kwang-ju, Korea.

Correspondence to Hiroshi Itoh, MD, PhD, Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail hiito{at}kuhp.kyoto-u.ac.jp

Abstract—We recently reported that C-type natriuretic peptide (CNP) occurs in vascular endothelial cells and acts as a vascular-type natriuretic peptide. In the present study, we stimulated the cGMP cascade in proliferating smooth muscle cells (SMCs), in which particulate guanylate cyclase-B, the specific receptor for CNP, is predominantly expressed, by use of an adenovirus encoding rat CNP cDNA (Ad.CNP). In the Ad.CNP-treated cultured SMCs, CNP caused the growth inhibition of SMCs at G₁ phase with an early increase of p21^CIP1/WAF1 expression and subsequent upregulation of p16^INK4a. The expression of smooth muscle myosin heavy chain-2, which is the molecular marker of highly differentiated SMCs, was reinduced in the Ad.CNP-treated SMCs. The Ad.CNP-treated SMCs also reexpressed particulate guanylate cyclase-A, which shows high affinity to atrial and brain natriuretic peptide and is exclusively expressed in well-differentiated SMCs. CNP, which was overexpressed in rabbit femoral arteries in vivo at the time of balloon injury, significantly suppressed neointimal formation. Furthermore, an enhancement of the expression of smooth muscle myosin heavy chain-2 occurred in the residual neointima. In addition, early regeneration of endothelial cells was observed in the Ad.CNP-infected group. Thus, stimulation of cGMP cascade in proliferating dedifferentiated SMCs can induce growth inhibition and redifferentiation of SMCs with accelerated reendothelialization.

Key Words: adenovirus • C-type natriuretic peptide • gene therapy • vascular smooth muscle cells • endothelial cells

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