Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids
Phenotypic modulation of vascular smooth muscle cells induced by unsaturated lysophosphatidic acids
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DOI：
10.1161/hh1501.094265
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发表时间：
2001-08-03
影响因子：
20.1
通讯作者：
Sobue, K
中科院分区：
文献类型：
--
作者：
Hayashi, K;Takahashi, M;Sobue, K
血管平滑肌细胞（VSMC）从分化状态到去分化状态的表型调节在动脉粥样硬化的发生和进展中至关重要。尽管许多细胞因子和生长因子已被报道为致动脉粥样硬化因子，但诱发动脉粥样硬化的关键病原体仍然未知，很大程度上是因为尚未开发出适当的检测系统。我们最近建立了内脏 SMC 和 VSMC 的原代培养系统，其中两种 SMC 在含有胰岛素样生长因子-I 的层粘连蛋白上培养时，均显示出分化的表型，如纺锤状形状、配体诱导的收缩性和高水平的 SMC 分化标记基因表达所示。在这项研究中，我们使用我们的培养系统寻找这些 SMC 的关键去分化因子。我们发现从人血清中提取的极性脂质显着诱导 VSMC 去分化，并且这种活性仅存在于溶血磷脂酸 (LPA) 部分中。在人血清脂质中检测到的几种 LPA 种类中，不饱和 LPA 被确定为诱导 VSMC 去分化的主要贡献者。信号传导和表型分析表明，不饱和 LPA 诱导的 VSMC 去分化是通过细胞外信号调节激酶和 p38 丝裂原激活蛋白激酶的协调激活来介导的。因此，本报告首次发现不饱和 LPA（而非饱和 LPA）特异性诱导 VSMC 表型调节，表明这些分子可以充当致动脉粥样硬化因子。
The phenotypic modulation of vascular smooth muscle cells (VSMCs) from the differentiated state to the dedifferentiated one is critically involved in the development and progression of atherosclerosis. Although many cytokines and growth factors have been reported as atherogenic factors, the critical pathogens for inducing atherosclerosis remain unknown, largely because proper examining systems of them have not been developed. We recently established primary culture systems for visceral SMCs and VSMCs in which both SMCs, when cultured on laminin with insulin-like growth factor-I, show a differentiated phenotype, as indicated by a spindle-like shape, ligand-induced contractility, and a high level of SMC differentiation marker gene expression. In this study, we searched for critical dedifferentiation factors for these SMCs using our culture system. We found that polar lipids extracted from human serum markedly induced VSMC 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 to the induction of VSMC dedifferentiation. Signaling and phenotype analyses revealed that unsaturated LPA-induced VSMC dedifferentiation is mediated through the coordinated activation of extracellular signal-regulated kinase and p38 mitogen-activated protein kinase. Thus, this report demonstrates the first finding that unsaturated LPAs, but not saturated LPAs, specifically induce VSMC phenotypic modulation, suggesting that these molecules could function as atherogenic factors.