(Circulation. 2001;103:2955.)
© 2001 American Heart Association, Inc.
Basic Science Reports |
Functional Blockade of Platelet-Derived Growth Factor Receptor-ß but Not of Receptor-
Prevents Vascular Smooth Muscle Cell Accumulation in Fibrous Cap Lesions in Apolipoprotein E–Deficient Mice
Presented in part at the 72nd Scientific Sessions of the American Heart Association, Atlanta, Ga, November 7–10, 1999, and published in abstract form (Circulation. 1999;100[suppl I]:I-742).
From the Departments of Geriatric Medicine (H.S., M.Y., T.M., H.K., T.K.) and Molecular Genetics (T.S., N.T., S.N., S.-I.N.), Graduate School of Medicine, Kyoto University, Japan.
Correspondence to Masayuki Yokode, MD, Department of Geriatric Medicine, Kyoto University Graduate School of Medicine, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. E-mail yokode{at}kuhp.kyoto-u.ac.jp
Background—The
vascular smooth muscle cell (VSMC) is the central cell component
involved in the fibroproliferative response in atherogenesis. As the
lesion advances, VSMCs migrate from the media into the
subendothelial space, thereby forming fibrous plaque
lesions. Platelet-derived growth factor (PDGF) has been known to be
a potent chemoattractant and mitogen for SMCs, but the
pathophysiological role of the 2 PDGF receptors,
receptor-
(PDGFR-) and receptor-ß (PDGFR-ß) in atherogenesis
is poorly understood. To clarify this problem, we prepared
antagonistic rat monoclonal antibodies, APA5 and APB5,
against murine PDGFR- and PDGFR-ß,
respectively.
Methods and Results—Apolipoprotein E–deficient mice were fed a high-fat diet containing 0.3% cholesterol from 6 weeks of age and subjected to injection with 1 mg/d IP of either antibody from 12 to 18 weeks every other day. In the mice injected with APB5, the aortic atherosclerotic lesion size and the number of intimal VSMCs were reduced by 67% and 80%, respectively, compared with the control mice injected with irrelevant rat IgG. In contrast, the mice that received APA5 showed only minimal reduction of lesion size, and a large number of VSMCs were observed in the intima. In the intima of advanced lesions, APB5 immunolabeled VSMCs, whereas APA5 could detect VSMCs mainly in the media.
Conclusions—These results indicate that PDGFR-ß plays a significant role in formation of fibrous atherosclerotic lesions and that regulation of the signal transduction through PDGFR-ß could affect atherogenesis in mice.
Key Words: platelet-derived factors • aorta • atherosclerosis • plaque • antibodies
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