Molecular mechanism of the signaling pathways that induce dedifferentiation of smooth muscle cells

诱导平滑肌细胞去分化的信号通路分子机制

基本信息

批准号：
13670120
负责人：
HAYASHI Kenichiro
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

The phenotypic modulation of vascular smooth muscle cells (SMCs) from the differentiated state to the dedifferentiated one is critical event in the development and progression of atherosclerosis. However, the critical atherogenic factors remain unclear. We established primary culture systems for visceral and vascular SMCs in which both SMCs can maintain a differentiated phenotype, as indicated by a spindle-like shape, ligand-induced contractility, and a high level expression of SMC differentiation markers. In this study, we searched for critical SMC dedifferentiation factors using our culture systems. We found that polar lipids extracted from human serum markedly induced SMC dedifferentiation, and this activity was solely present in the lysophosphatidic acid (LPA) fraction. Among several LPA species detected in human serum lipids, unsaturated LPAs were identified as major contributors for SMC dedifferentiation. Unsaturated (18:1) LPA, but not saturated (18:0) LPA, strongly induced vascular SMC dedifferentiation in culture and vascular remodeling consisted of neointima in rat carotid arteriesin vivo. 18:1 LPA-induced vascular SMC dedifferentiation in culture and vascular remodelingin vivo were mediated through the coordinated activation of both ERK and p38 MAPK. The neointima was mainly derived from dedifferentiated medial vascular SMCs. During 18:1 LPA-induced vascular remodeling, the phenotypic modulation of medial vascular SMCs preceded macrophage infiltration. Thus, this study demonstrates the first finding that unsaturated LPAs, but not saturated LPAs, specifically induce vascular SMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.

血管平滑肌细胞（SMC）从分化状态到去分化的表型调节是动脉粥样硬化的发展和进展中的关键事件。但是，关键的动脉粥样因素尚不清楚。我们建立了用于内脏和血管SMC的原发性培养系统，在这些培养系统中，这两个SMC都可以维持差异化的表型，如纺锤形样形状，配体诱导的收缩力和SMC分化标记的高水平表达所示。在这项研究中，我们使用我们的培养系统搜索了关键的SMC去分化因子。我们发现从人血清中提取的极性脂质显着诱导了SMC去分化，并且该活性仅存在于溶物磷酸酸（LPA）部分中。在人血清脂质中检测到的几种LPA物种中，不饱和的LPA被确定为SMC去分化的主要贡献者。不饱和（18：1）LPA，但不饱和（18：0）LPA，在培养物中强烈诱导的血管SMC去分化和血管重塑，由大鼠颈动脉动脉中的Neintima组成。 18：1通过ERK和p38 MAPK的协调激活介导了LPA诱导的培养物和血管重塑中的血管SMC去分化。新内膜主要源自去分化的内侧血管SMC。在18：1 LPA诱导的血管重塑期间，内侧血管SMC的表型调节先于巨噬细胞浸润。因此，这项研究证明了第一个发现，即不饱和的LPA而不是饱和的LPA，特别诱导了血管SMC表型调节，表明这些分子可以用作动脉粥样硬化因素。