内皮细胞microRNA在介导血流剪切力对血管平滑肌功能调控中的作用及机制

项目名称： 内皮细胞microRNA在介导血流剪切力对血管平滑肌功能调控中的作用及机制

项目编号： No.91539116

项目类型： 重大研究计划

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 周菁

作者单位： 北京大学

项目金额： 80万元

中文摘要： 施加于内皮细胞（EC）的血流剪切力可调控平滑肌（SMC）的表型，对血管稳态维持和动脉粥样硬化发生有重要影响。但这一力学信号由EC向SMC的传递机制待阐明。我们发现，microRNA（miRNA）可作为信号分子介导EC与SMC的交互作用：EC分泌的miR-126可促进SMC增殖和去分化表型；保护血管的层流和损伤血管的扰流对miR-126分泌分别有抑制或促进效应。我们推测：作用于EC的剪切力通过诱导流场特异性的miRNA分泌，调控SMC基因表达和表型转换以及血管功能。本研究重点探讨：1、受扰流或层流调控的endo-miRNA的分泌组学及剪切力调控miRNA分泌的机制。2、endo-miRNA 在SMC中的基因和功能调控网络。3、利用动物模型验证干扰endo-miRNA向SMC的转运在血管功能调控中的作用。研究结果将确认胞外miRNA在血管病理生理过程中的作用，增进关于动脉硬化发生机制的了解。

中文关键词： 内皮功能；血管稳态；平滑肌细胞可塑性；；血流剪切力；胞外微小RNA

英文摘要： Shear stress, the tangential component of the hemodynamic forces acting on the vascular endothelium, has been shown to play crucial roles in the regulation of vascular smooth muscle function, vascular homeostasis, as well as the formation and progression of atherosclerosis. However, it remains elusive that how the mechanical stimuli are transmitted into biochemical signals and how the signals are transduced from endothelial cells to smooth muscle cells. Our previous studies have made contributions to the understanding of the mechanisms by which shear stress influences molecular signaling, gene expression, epigenetic regulation, and functions of endothelial cells in health and disease. We have demonstrated that microRNAs originated from endothelial cells not only regulate intracellular gene expression, but also mediate extracellular communication via transportation to smooth muscle cells. Our recent study revealed that shear-modulated microRNAs (e.g., miR-126) in endothelial cells are bound by protein carriers (e.g. Argonaute 2) and then transferred to recipient smooth muscle cells, where they target smooth muscle genes to alter their phenotype and function relevant to atherogenesis. Therefore, in this proposed study, we expand the scope and introduce new directions to elucidate the mechanisms by which distinct flow patterns differentially regulate the endothelial microRNA secretome to affect distinct functional outcomes. We hypothesize that atheroprotective and atheroprone flow patterns modulate distinct endothelial-microRNA-secretome to result in beneficial or detrimental outcomes for the smooth muscle as well as the vasculature. We will use systems biology approaches to elucidate the shear-regulation of diverse endothelial-microRNA-secretome and the consequent modulations of smooth muscle gene expression and functions, and hence vascular homeostasis. We will validate our in vitro and in silico results by using animal models. The results from this study will help to elucidate the mechanotransduction networks in response to hemodynamic shear stress in vasculature and to discover new target biomarkers highly associated with vascular pathophysiology, thereby facilitating the development of new diagnostic and therapeutic strategies for atherosclerosis and other vascular diseases.

英文关键词： endothelial function;vascular homeostasis;smooth muscle plasticity;fluid shear stress;extracellular microRNA