Structural and functional analysis of phenotypic modulation of vascular smooth muscle cell

本研究的目的是探讨血管平滑肌细胞表型改变的机制，这与动脉粥样硬化的发展有关。这项研究是由我们先前观察到的，内膜平滑肌细胞表现出放大的生长能力和迁移活性，并且它们有效地结合变性的脂蛋白成为像巨噬细胞一样的泡沫细胞。在本研究中，我们发现对内皮细胞的IV型胶原处理可抑制血管细胞黏附分子-1的表达，提示血管平滑肌细胞可通过分泌细胞外基质改变内皮细胞的表型，这种现象在动脉粥样硬化的发展过程中起一定作用。接下来，我们发现应用转化生长因子-β1可促进球囊导管损伤兔动脉内膜增厚，提示动脉粥样硬化血管内皮细胞产生的转化生长因子-β可能通过促进血管平滑肌细胞分泌细胞外基质而加速动脉粥样硬化的进展。最后，我们还发现粘着斑激酶在磷脂酰肌醇3-激酶下游的血小板衍生生长因子刺激的趋化作用的细胞内信号转导中发挥重要作用。这一发现将揭示细胞内趋化信号响应各种细胞外刺激的分子机制。

The purpose of this study is to investigate the mechanisms for the phenotypic modulation of vascular smooth muscle cells, which is implicated in the development of atherosclerosis. The study was initiated by our previous observation that the intimal smooth muscle cells show amplified growth potential as well as migratory activity, and they efficiently incorporate the denatured lipoprotein to become foam cells like macrophages. In the present study, we have found that type IV collagen treatment of endothelial cells suppresses the expression of vascular cell adhesion molecule-1, suggesting that vascular smooth muscle cells can change the phenotype of the endothelial cells by secretion of extracellular matrices and such phenomenon plays some role in the developmental process of atherosclerosis. Next, we found that TGF-beta1 administration enhances intimal thickening of the legions made by ballon catheter injury in rabbits, indicating that TGF-beta produced by various cells in atherosclerotic legions accelerates the progression of atherosclerosis possible by promoting the secretion of extracellular matrices from the vascular smooth muscle cells. Finally, we also found that focal adhesion kinase plays an important role in the intracellular signal transduction for chemotaxis stimulated by platelet-derived growth factor downstream of phosphatidylinositol 3-kinase. The findings will reveal the molecular mechanism of the chemotactic signaling inside the cells in response to various extracellular stimuli.