ECM and shear stress

项目摘要 动脉生成不良，与动脉阻塞平行的血管不能重塑或恢复 血液流向受影响的组织，是外周和冠状动脉疾病和死亡的主要因素。 疾病。这个项目是基于这样一种假设，即动脉的形成是由高剪应力引起的。 在触发一系列内皮细胞激活、炎症、基质的小血管中 重塑、血管扩张和分辨率，使切变水平恢复正常和恢复 血管功能正常。因此，动脉重塑由流体剪应力设定点控制，从而 当切应力高于或低于最佳范围时，内皮细胞触发反应以更换血管。 直径并向原始值返回剪切力。这笔赠款的总体目标是澄清这些 更详细的机制，并确定在疾病中抑制动脉形成的限制点。我们的 初步和已发表的数据表明细胞外基质重塑和Smad激活是关键 这些流程的组成部分。基于这些结果，我们将：1)阐明基质的作用 动脉形成中的重塑，特别是检查是否阻断纤维连接蛋白和 炎症途径改善了疾病模型中的动脉生成。 2)阐明了控制流体剪应力设定点的信号网络。3)研制抗体- 基于特定改变流对Smad 2/3与Smad 1/5/8激活的影响的工具，以及 测试它们对动脉形成的影响。

Project Summary Poor arteriogenesis, in which blood vessels parallel to an arterial blockage fail to remodel to restore blood flow to the affected tissue, is a major factor in illness and death in peripheral and coronary artery disease. This project is based on the hypothesis that arteriogenesis is initiated by elevated shear stress in small blood vessels that triggers a sequence of endothelial activation, inflammation, matrix remodeling, vessel expansion and resolution, which returns shear levels toward normal and restores normal vessel function. Artery remodeling is thus governed by a fluid shear stress set point such that when shear stress goes above or below the optimal range, ECs trigger a response to change vessel diameter and return shear toward the original value. The overall goal of this grant is to elucidate these mechanisms in more detail and identify restriction points that inhibit arteriogenesis in disease. Our preliminary and published data implicate extracellular matrix remodeling and smad activation as key components of these processes. Based on these results, we will: 1) Elucidate the role of matrix remodeling in arteriogenesis, specifically examining whether blocking a link between fibronectin and inflammatory pathways improve arteriogenesis in disease models. 2) Elucidate the signaling networks that govern the fluid shear stress set point. 3) Develop antibody- based tools that specifically alter the effects of flow on activation of Smad 2/3 vs Smad 1/5/8, and test their effects on arteriogenesis.