Functional blockade of platelet-derived growth factor receptor-beta but not of receptor-alpha prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice

Background-The vascular smooth muscle cell (VSMC) is the central cell compo nent involved in the fibroproliferative response in atherogenesis. As the l esion advances, VSMCs migrate from the media into the subendothelial space, thereby forming fibrous plaque lesions. Platelet-derived growth factor (PD GF) has been known to be a potent chemoattractant and mitogen for SMCs, but the pathophysiological role of the 2 PDGF receptors, receptor-alpha (PDGFR -alpha) and receptor-beta (PDGFR-beta) in atherogenesis is poorly understoo d. To clarify this problem, we prepared antagonistic rat monoclonal antibod ies, APA5 and APB5, against murine PDGFR-alpha and PDGFR-beta, respectively . Methods and Results-Apolipoprotein E-deficient mice were fed a high-fat die t containing 0.3% cholesterol from 6 weeks of age and subjected to injectio n 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 th e number of intimal VSMCs were reduced by 67% and 80%, respectively, compar ed 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 advan ced lesions, APB5 immunolabeled VSMCs, whereas APA5 could detect VSMCs main ly in the media, Conclusions-These results indicate that PDGFR-beta plays a significant role in formation of fibrous atherosclerotic lesions and that regulation of the signal transduction through PDGFR-beta could affect atherogenesis in mice.