p53在剪切应力微环境决定EPCs定向分化成内皮或平滑肌细胞中的 “开关”机制

The repair process of the endothelial injury is closely related to the occurrence and development of vascular remodeling. In the last two decades, accumulating evidence suggests endothelial progenitor cells (EPCs) play a fundamental role in tissue regeneration and vascular repair by differentiating into endothelial cells. However, more recently, the studies show that EPCs have also the potential to differentiate into other types of cells, eg, smooth muscle cells. Those evidences suggest that EPCs could be a double-edged sword for vascular repair and remodeling. Previous studies show that the blood biomechanical stress plays a key role in EPCs differentiation. Our and other researchers have shown that laminar shear stress can promote the differentiation of EPCs into endothelial cells. In the meantime, our preliminary data have demonstrated unstable shear conditions, such as disturbed shear stress, induce EPCs transdifferentiation into smooth muscle cells. Moreover, p53 might act as a molecular switch during EPCs differention under different types of shear stress. Therefore, it would be interesting to establish the role of p53 in different types of shear stress-induced EPCs differentiation. Herein, we will apply a variety of methods, such as molecular biology, cell biology and mechanics biology and so on, to elucidate the underlying mechanisms of p53 regulating the EPCs differention induced by laminar flow or disturbed shear stress both in vivo and in vitro. These studies would have a high probability to understand why shear stress would guide EPCs differentiation fate. Thus, it is possible to develop a specific inhibitor/drug toward the treatment of vascular remodeling associated with cardiovascular diseases.

血管内皮损伤修复过程和血管重塑的发生发展密切相关。一般认为内皮祖细胞（endothelial progenitor cells，EPCs）是血管内皮修复的主要来源细胞，但近年文献显示EPCs兼有向内皮分化和间质平滑肌转分化的潜能，提示EPCs在血管重塑发生发展中很可能是一把“双刃剑”，而血液流体力学环境影响着EPCs的分化及转分化。我们前期研究和预实验结果显示：层流剪切应力促进EPCs向内皮分化，扰动流剪切应力却导致其向平滑肌转分化，而p53可能是力学环境下，决定EPCs分化的“开关”，但具体途径和机制尚待深入阐明。本研究将以p53分子为靶点，采用分子生物学、细胞生物学、力学生物学等多种方法，从体内、外角度阐明p53在层流和扰动流剪切应力决定EPCs分化及转分化可能途径和机制。如若得到验证，这不仅能加深对血管重塑形成的机理认识，还将为治疗血管重塑为基础的相关疾病找到新的药物靶标。

血管内皮损伤修复过程和血管重塑的发生发展密切相关。一般认为内皮祖细胞（endothelial progenitor cells，EPCs）是血管内皮修复的主要来源细胞，但近年文献显示EPCs兼有向内皮分化和间质细胞转分化的潜能，提示EPCs在血管重塑发生发展中很可能是一把“双刃剑”，而血液流体力学环境影响着EPCs的分化及转分化。我们前期研究和预实验结果显示：层流剪切应力促进EPCs向内皮分化，扰动流剪切应力却导致其向间质细胞转分化。而p53可能是力学环境下，决定EPCs分化的“开关”，但具体途径和机制尚待深入阐明。本课题以p53分子为靶点，采用分子生物学、细胞生物学、力学生物学等多种方法，从体内、外角度阐明了p53在层流和扰动流剪切应力决定EPCs分化及转分化可能途径和机制。即：振荡剪切应力通过ROS/PKCζ/p53途径诱导EPCs向间充质细胞转化；层流剪切应力通过RAS/MEK/ERK/p53途径调控内皮祖细胞的分化。这一研究加深了对血管重塑形成的机理认识，还将为治疗血管重塑为基础的相关疾病找到新的药物靶标。