Study for the molecular mechanism of atherosclerosis

血管平滑肌细胞（SMCs）从分化状态向去分化状态的表型调节，导致细胞增殖和迁移，是动脉粥样硬化发生发展的标志。虽然许多细胞因子和生长因子被认为是动脉粥样硬化的诱发因素，但诱导动脉粥样硬化的关键病原体仍然未知，主要是因为它们的适当检查系统尚未开发。我们最近建立了血管SMCs的原代培养系统，当SMCs在含有胰岛素样生长因子-1的层粘连蛋白上培养时，SMCs表现出分化的表型，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。利用体外培养系统，我们研究了影响血管SMC表型的信号通路，发现igf -1刺激的磷酸肌肽3激酶(P13-K)/蛋白激酶B（PKB(Akt)）通路在维持分化表型和细胞外信号调节激酶（ERK）和p38丝裂原活化蛋白激酶（p38MAPK）通路被生长因子和细胞因子协同激活诱导去分化中起着至关重要的作用。因此，P13-K/PKB （Akt）通路与ERK和p38MAPK通路之间平衡的变化将决定血管SMCs的表型。利用我们的血管SMCs培养系统，我们寻找了关键的去分化因子，并发现人血清中的溶血磷脂酸（LPAs）能有效地诱导SMC去分化。在人类血清极性脂质中检测到的几种LPA中，不饱和LPA是诱导血管SMC去分化的主要因素。信号和表型分析显示，不饱和lpa诱导的血管SMC去分化也通过ERK和p38MAPK的协同激活介导。此外，体内自然存在的不饱和而非饱和LPAs强烈诱导大鼠颈动脉内膜形成。我们的研究证明了体内血管重构是由自然发生的不饱和LPAs引发的，并为动脉粥样硬化形成提供了一种新的致病动物模型。少

The phenotypic modulation of vascular smooth muscle cells (SMCs) from the differentiated state to the dedifferentiated one, which results in cell proliferation and migration, is a hallmark of the development and progression of atherosclerosis. Although many cytokines and growth factors have been proposed 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 vascular SMCs in which SMCs, when cultured on laminin with insulin-like growth factor-1, show a differentiated phenotype as indicated by a spindle-like shape, ligand-induced contractility, and high levels of SMC differentiation marker gene expression.Using our culture system, we investigated the signaling pathways affecting the vascular SMC phenotype, and found that the IGF-1-stimulated phosphoinositide 3-kinase (P13-K)/protein kinase B (PKB(Akt)) pathway plays a critical … More role in maintaining a differentiated phenotype and the coordinated activation of the extracellular-signal regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) pathways by growth factors and cytokines induces dedifferentiation. Thus, changes in the balance between the strengths of the P13-K/PKB (Akt) pathway and the ERK and p38MAPK pathways would determine the phenotype of vascular SMCs.Using our culture system of vascular SMCs, we searched for critical dedifferentiation factors and identified that lysophosphatidic acids (LPAs) in human serum potently induce SMC dedifferentiation. Among several LPA species detected in human serum polar lipids, unsaturated LPAs were major contributors to induce vascular SMC dedifferentiation. Signaling and phenotype analyses revealed that unsaturated LPA-induced vascular SMC dedefferentiation also mediates through the coordinated activation of ERK and p38MAPK. Furthermore, naturally occurring unsaturated, but not saturated, LPAs strongly induced neointimal formation in rat carotid arteries in vivo.Our study demonstrates the vascular remodeling in vivo triggered by naturally occurring unsaturated LPAs and provides a novel pathogenic animal model for atherogenesis. Less