Functional blockade of platelet-derived growth factor receptor-β but not of receptor-α prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice
Functional blockade of platelet-derived growth factor receptor-β but not of receptor-α prevents vascular smooth muscle cell accumulation in fibrous cap lesions in apolipoprotein E-deficient mice
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DOI：
10.1161/01.cir.103.24.2955
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发表时间：
2001-06-19
期刊：
影响因子：
37.8
通讯作者：
Kita, T
中科院分区：
文献类型：
--
作者：
Sano, H;Sudo, T;Kita, T
背景：血管平滑肌细胞（VSMC）是动脉粥样硬化过程中参与纤维增殖反应的中心细胞成分。随着病变的进展，VSMCs从介质迁移到内皮下空间，从而形成纤维斑块病变。众所周知，血小板衍生生长因子（PDGF）是一种有效的SMCs化学引诱剂和丝裂原，但2种PDGF受体，受体- α (pdgfr - α)和受体- β (pdgfr - β)在动脉粥样硬化中的病理生理作用尚不清楚。为了澄清这一问题，我们分别制备了抗小鼠pdgfr - α和pdgfr - β的大鼠单克隆抗体ap5和APB5。方法与结果：载脂蛋白e缺乏小鼠从6周龄开始饲喂含0.3%胆固醇的高脂饲料，从12 ~ 18周起每隔一天注射1 mg/d的任意一种抗体。与注射不相关大鼠IgG的对照组相比，注射APB5的小鼠主动脉粥样硬化病变大小和内膜VSMCs数量分别减少67%和80%。在晚期病变的内膜中，APB5免疫标记了VSMCs，而ap5主要能检测到介质中的VSMCs。结论-这些结果表明pdgfr - β在纤维性动脉粥样硬化病变的形成中起着重要作用，通过pdgfr - β调节信号转导可影响小鼠动脉粥样硬化的发生。
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-alpha (PDGFR-alpha) and receptor-beta (PDGFR-beta) in atherogenesis is poorly understood. To clarify this problem, we prepared antagonistic rat monoclonal antibodies, APA5 and APB5, against murine PDGFR-alpha and PDGFR-beta, 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-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.