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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）从分化状态向去分化状态的表型转变是动脉粥样硬化发生发展的关键事件。然而，致动脉粥样硬化的关键因素仍不清楚。我们建立了内脏和血管平滑肌细胞的原代培养系统，其中两种平滑肌细胞都可以保持分化的表型，如梭形形状，配体诱导的收缩性和高水平表达的平滑肌细胞分化标志物所示。在这项研究中，我们使用我们的培养系统寻找关键的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SMC去分化，这种活动是唯一存在于溶血磷脂酸（LPA）馏分。在人血清脂质中检测到的几种LPA物质中，不饱和LPA被鉴定为SMC去分化的主要贡献者。不饱和（18：1）LPA（18：0）LPA（18：1）可明显诱导培养的大鼠颈动脉平滑肌细胞脱分化，并诱导由新生内膜组成的血管重构。18：1 LPA诱导的血管平滑肌细胞去分化和血管重塑是通过ERK和p38 MAPK协同激活介导的。新生内膜主要来源于去分化的中膜血管平滑肌细胞。在18：1 LPA诱导的血管重塑过程中，中膜血管平滑肌细胞的表型调节先于巨噬细胞浸润。因此，这项研究表明，第一个发现，不饱和的LPAs，而不是饱和的LPAs，特异性诱导血管SMC表型调制，这表明这些分子可以作为致动脉粥样硬化因子。