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Mechano-sensing Mechanism and Mechano-Responsive Genes in Vascular Endothelial Cells

血管内皮细胞的机械感应机制和机械响应基因

基本信息

批准号：
15200034
负责人：
ANDO Joji
金额：
$ 32.2万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15200034/
关键词：
Shear Stress Blood Flow Mechanotransduction DNA Microarray Endothelial Cells Blood Vessels P2X4 Receptor Calcium Ion 剪断能力遺伝子血管リモデリング血行力学因子 DNAチップ粥状動脈硬化剪断応力

项目摘要

To elucidate the role of shear stress, a mechanical force generated by flowing blood, in the regulation of circulatory functions, we investigated the mechanism by which vascular endothelial cells sense shear stress and performed a global analysis of shear stress-responsive genes. The present study showed that endothelial cells transduce shear stress intensity into extracellular Ca^<2+> influx via an ATP-operated cation channel P2X4. We produced P2X4-deficient mice and observed that endothelial cells of P2X4-deficient mice did not show shear stress-induced Ca^<2+> influx and subsequent production of nitric oxide. Compared with wild-type mice, P2X4-deficient mice showed impaired vasodilatory responses to an increase in blood flow, and higher values of blood pressure. P2X4-deficient mice also showed impaired blood flow-dependent vascular remodeling. These findings indicate that the P2X4-mediated shear stress-sensing mechanism plays a critical role in blood flow-dependent control of circulatory functions. DNA micro-array analysis revealed that approximately 3% of the total endothelial genes alter their expression in response to an arterial level of shear stress (15 dynes/cm^2), indicating that about 600 genes are shear stress-responsive. Cluster analysis showed multiple temporal profiles of gene responses to shear stress. We also demonstrated that endothelial gene expression is differentially regulated by laminar and turbulent shear stress. Laminar shear stress decreased the gene expression of urokinase-type plasminogen activator (uPA) via down-regulating gene transcription and accelerating mRNA degradation, while turbulent shear stress increased uPA gene expression through mRNA stabilization.

为了阐明切应力(一种由血液流动产生的机械力)在循环功能调节中的作用，我们研究了血管内皮细胞感受切应力的机制，并对切应力反应基因进行了整体分析。目前的研究表明，内皮细胞通过ATP操作的阳离子通道P2X4将切应力强度转化为细胞外钙离子内流。我们建立了P2X4缺陷小鼠，观察到P2X4缺陷小鼠的内皮细胞没有表现出剪应力诱导的钙离子内流和随后的一氧化氮产生。与野生型小鼠相比，P2X4缺陷小鼠对血流量增加和较高的血压表现出血管扩张反应受损。P2X4基因缺陷的小鼠也表现出血流依赖的血管重塑受损。这些发现表明，P2X4介导的切应力传感机制在血流依赖的循环功能控制中起着关键作用。DNA微阵列分析表明，大约3%的血管内皮细胞基因的表达随着动脉切应力水平(15dynes/cm^2)的变化而改变，这表明大约600个基因是切应力响应的。聚类分析显示了基因对剪切力的多时间响应。我们还证明了内皮基因的表达受层流和湍流剪应力的不同调节。层流切应力通过下调基因转录和加速mRNA降解来降低尿激酶型纤溶酶原激活物(UPA)的基因表达，而湍动切应力通过稳定mRNA来增加uPA基因的表达。