STUDY ON THE EFFECT OF FUNCTIONAL REGULATION OF VASCULAR SMOOTH MUSCLE CELLS ON ATHEROGENESIS IN MICE

血管平滑肌细胞功能调节对小鼠动脉粥样硬化影响的研究

基本信息

批准号：
12671111
负责人：
YOKODE Masayuki
金额：
$ 2.5万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671111/
关键词：
Atherosclerosis Macrophage Vascular smooth muscle cell ApoE knockout mouse PDGF receptor Monoclonal antibody Vascular remodeling progenitor cell 受容体チロシンキナーゼマウス PDGF 受容体平滑筋細胞内皮細胞増殖因子

项目摘要

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.

血管平滑肌细胞（VSMC）是涉及动脉粥样硬化中纤维增生反应的中心细胞成分。血小板衍生的生长因子（PDGF）被称为平滑肌细胞的潜在化学吸引剂和有丝分裂原，但是在动脉生成中，两个PDGF受体，受体-α（PDGFR-α）和受体-α）和受体-α）和受体-α（PDGFR-α）的病理生理作用尚不理解。为了澄清这个问题，我们分别针对鼠PDGFR-α和PDGFR-β制备了拮抗大鼠单克隆抗体，APA5和APB5。载脂蛋白E缺陷型小鼠喂养高脂饮食，并每隔一天的12至18周进行1 mg/天的腹膜内注射。在注射APB5的小鼠中，与注入无关的大鼠IgG的对照小鼠相比，分别将主动脉粥样硬化病变的大小和内膜VSMC的数量分别减少了67％和80％。相比之下，接受APA5的小鼠仅显示病变大小的最小降低，并且在内膜中观察到大量VSMC。在晚期病变的内膜中，APB5免疫标记的VSMC，而APA5可以主要检测介质中的VSMC。这些结果表明，PDGFR-β在形成纤维动脉粥样硬化病变中起着重要作用，并且通过PDGFR-β对信号转导的调节可能会影响小鼠的动脉粥样硬化。为了进一步阐明与动脉瘤相关细胞的细胞起源，我们检查了高胆固醇血症对袖口诱导的血管重塑病变形成的影响。获得了缺乏载脂蛋白（APO）E基因和表达普遍存在的绿色荧光蛋白（GFP）转基因的双转基因小鼠。我们发现，骨髓（BM）衍生的细胞在小鼠的血管重塑过程中起着重要作用。