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Regulation of smooth muscle cell function and arteriogenesis by glycated collagen and its receptor

糖化胶原及其受体对平滑肌细胞功能和动脉生成的调节

基本信息

批准号：
15590953
负责人：
KOYAMA Hidenori
金额：
$ 2.18万
依托单位：
Osaka City University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590953/
关键词：
Diabetes mellitus arteiogenesis advanced glycation endproduct receptor for AGE (RAGE)smooth muscle cell extracellular matrix collagen type 1 angiogenesis regulatory factors 血管形成、血管新生 AGE 動脈硬化

项目摘要

It has been shown that patients and experimental animal models with diabetes have a lesser ability to develop collateral blood vessels in arterial occlusion. However, the molecular and cellular mechanism underlying impaired arteriogenesis in diabetes is not known. In the present study, we examined the role of advanced glycation endproducts, AGE, and its receptor, RAGE, in diabetes-associated impaired smooth muscle cell (SMC) function and arteriogenesis. On glycolaldehyde-induced glycated form of type 1 fibrillar collagen (AGE-collagen), basal or PDGF-stimulated SMC migration was markedly decreased as compared with SMC cultured on native collagen. Analyses of candidate receptors for type 1 collagen revealed that expression of α2 integrins is suppressed, while levels of αv integrins are upregulated in SMC cultured on AGE-collagen. Culture on AGE collagen suppresses secretion and mRNA expression of vascular endothelial growth factor (VEGF), but enhances mRNA expression of thrombospondin-1, an inhibitor of angiogenesis. To examine arteriogenesis in vivo, we subcutaneously implanted VEGF-containing matrigel to streptozotocin-induced diabetic or control mice. In diabetic mice, numbers of α-actin positive SMC or pericytes migrated into matrigel was decreased by 25% as compared with control mice. Similarly CD31-positive endothelial cells infiltrated less in diabetic mice. Importantly, impaired migration of both SMC and endothelial cells into matrigel in diabetes was completely restored in RAGE-deficient mice. Thus, AGE-RAGE system appears to play fundamental role in impaired arteriogenesis in diabetes.

已经表明，患有糖尿病的患者和实验动物模型在动脉闭塞中具有较低的发展侧支血管的能力。然而，糖尿病动脉生成受损的分子和细胞机制尚不清楚。在本研究中，我们研究了晚期糖基化终产物（AGE）及其受体（AGEs）在糖尿病相关的平滑肌细胞（SMC）功能受损和动脉生成中的作用。在乙醇酸诱导的糖化形式的1型纤维状胶原（AGE-胶原），基础或PDGF刺激的SMC迁移显着减少相比，SMC培养的天然胶原。对1型胶原候选受体的分析显示，在AGE-胶原上培养的SMC中，α2整合素的表达被抑制，而αv整合素的水平上调。AGE胶原蛋白的培养抑制血管内皮生长因子（VEGF）的分泌和mRNA表达，但增强血小板反应蛋白-1（血管生成抑制剂）的mRNA表达。为了研究体内动脉生成，我们将含有VEGF的基质胶皮下植入链脲佐菌素诱导的糖尿病小鼠或对照小鼠。糖尿病小鼠中α-actin阳性的平滑肌细胞和周细胞向基质胶迁移的数量较对照组减少25%。同样，糖尿病小鼠中CD 31阳性内皮细胞浸润较少。重要的是，糖尿病中SMC和内皮细胞向基质胶迁移受损在RAGE缺陷小鼠中完全恢复。因此，AGE-DR系统似乎在糖尿病动脉生成受损中起重要作用。