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

血管平滑肌细胞从分化状态到去分化状态的表型调节是动脉粥样硬化发生发展的关键事件。然而，关键的动脉粥样硬化因素仍不清楚。我们建立了内脏和血管SMCs的原代培养系统，其中两种SMCs都能保持分化表型，这表明它们具有纺锤状形状、配体诱导的收缩性和SMC分化标志物的高水平表达。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著诱导SMC去分化，这种活性仅存在于溶血磷脂酸（LPA）部分。在人血脂中检测到的几种LPA中，不饱和LPA被认为是SMC去分化的主要贡献者。不饱和（18:1）LPA，而非饱和（18:0）LPA，在培养中强烈诱导血管SMC去分化，并在体内诱导大鼠颈动脉新生内膜血管重构。18:1 lpa诱导的血管SMC去分化和体内血管重构是通过ERK和p38 MAPK的协同激活介导的。新生内膜主要来源于去分化的内侧血管SMCs。在18:1 lpa诱导的血管重塑过程中，内侧血管SMCs的表型调节先于巨噬细胞浸润。因此，本研究首次发现不饱和LPAs而非饱和LPAs特异性诱导血管SMC表型调节，表明这些分子可能是动脉粥样硬化因子。

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.