| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
Vascular smooth muscle cell (VSMC) is the central cell component involved in fibroproliferative response in atherogenesis. Platelet-derived growth factor (PDGF) has been known as potent chemoattractant and mitogen for smooth muscle cells, but the pathophysiological role of the two PDGF receptors, receptor-α (PDGFR-α) and receptor-β (PDGFR-β) in atherogenesis is poorly understood. To clarify this problem, we prepared antagonistic rat monoclonal antibodies, APA5 and APB5 against murine PDGFR-α and PDGFR-β, respectively. Apolipoprotein E-deficient mice were fed high-fat diet and subjected to intraperitoneal injection with 1 mg/day 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, as 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, while APA5 could mainly detect VSMCs in the media. These results indicate that PDGFR-β plays a significant role in formation of fibrous atherosclerotic lesions and that regulation of the signal transduction through PDGFR-β could affect atherogenesis in mice. To further elucidate the cellular origin of atheroma-associated cells, we examined the effect of hypercholesterolemia on cuff-induced vascular remodeling lesion formation. Double-transgenic mice which lack apolipoprotein (apo) E gene and express ubiquitously green fluorescent protein (GFP) transgene were obtained. We found that bone marrow (BM)-derived cells played significant roles in vascular remodeling process in mice.
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