Shear stress and the regulation of vascular function and structure

剪切应力与血管功能和结构的调节

• 批准号: RGPIN-2014-05270
• 负责人: Pyke, Kyra
• 金额: $ 2.48万
• 依托单位: Queen's University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2015
• 资助国家: 加拿大
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=588310
• 关键词: Shear; stress; regulation; vascular; function

Our arteries are lined by a single layer of cells called the vascular endothelium. Due to their position on the inside of the artery, the endothelial cells are constantly exposed to the frictional force created by the flowing blood. Termed shear stress, this frictional force plays a key role in regulating endothelial cell responses that change artery size and stiffness in both the short and the long term. We are interested in understanding the sensitivity of the endothelium to changes in shear stress, the speed of its responses and how these factors may differ in arteries that are in the arms vs. the legs. We will use cutting edge Doppler ultrasound technology to non-invasively measure changes in shear stress and changes in artery function, size, wall thickness and stiffness. In daily living, the most common cause of increases in shear stress is performing exercise. Regular exercise also results in long term changes in artery function and structure, however, we do not know the extent to which these changes are brought about by increases in shear stress per se, or other variables that are altered by exercise. We will isolate the role of shear stress in changes in artery function with a novel technique that allows us to mimic exercise induced changes in large artery shear stress without having to perform contractions. In addition to responding to changes in shear stress, our arteries are controlled by nerves. Similar to the motor neurons that that stimulate our skeletal muscles to contract, the nerves that control our arteries cause the muscle in their walls to contract, making the vessel smaller (constriction). We still do not clearly understand how responses to increases in shear stress, and responses to signals from the nerves interact when they are experienced simultaneously in the same artery. To explore this we will manipulate both variables, and measure changes in artery function and structure and factors that reflect neural activity. In addition to changes in signals from nerves, when we experience something that is acutely stressful, like public speaking, this causes a hormonal response that interacts with vascular function. The proposed research will use a variety of interventions to manipulate aspects of the stress response in order to provide novel insight regarding the interaction of stress response signals and their impact on vascular function. Studies in isolated cells and animal vessels suggest that the pattern of shear stress (e.g. whether it is always in one direction or changing direction) is an important determinant of endothelial cell function. However, we know less about the impact of chronic changes in shear stress pattern in the integrated human system. This is important because several factors including different types of exercise and different levels of neurally mediated constriction can alter the pattern of shear stress in our arteries. The proposed research will use a variety of techniques to chronically expose the arteries of participant’s arms and legs to different shear stress patterns and assess the impact on artery function and structure. As a whole this research will provide important insight into the complex interaction and integration of signals in human arteries. The information gained from these studies will assist in advancing our understanding of basic human cardiovascular function. This research program will also provide a rich training environment for undergraduate and graduate students and research associates allowing them to develop skills that foster the capacity for innovation and critical thinking. This is important to support the development of research leaders and the long term success of research in Canada, which benefits all Canadians.

我们的动脉由一层叫做血管内皮的细胞构成。 由于它们位于动脉内侧，内皮细胞不断暴露于流动血液产生的摩擦力。 这种摩擦力被称为剪切力，在调节内皮细胞反应中起着关键作用，这些反应在短期和长期内改变动脉大小和硬度。 我们有兴趣了解内皮细胞对剪切应力变化的敏感性，其反应速度以及这些因素在手臂与腿部动脉中的差异。 我们将使用最先进的多普勒超声技术来非侵入性地测量剪切应力的变化以及动脉功能、尺寸、壁厚和刚度的变化。 在日常生活中，剪切应力增加的最常见原因是进行运动。 定期运动也会导致动脉功能和结构的长期变化，然而，我们不知道这些变化在多大程度上是由剪切应力本身的增加或运动改变的其他变量引起的。 我们将隔离的作用，动脉功能的变化与一种新的技术，使我们能够模仿运动引起的变化，而不必执行收缩大动脉切应力的剪切应力。 除了对剪切力的变化做出反应外，我们的动脉还受到神经的控制。 与刺激骨骼肌收缩的运动神经元类似，控制动脉的神经导致血管壁的肌肉收缩，使血管变小（收缩）。 我们仍然没有清楚地了解，当在同一动脉中同时经历时，对剪切应力增加的反应和对来自神经的信号的反应如何相互作用。 为了探索这一点，我们将操纵这两个变量，并测量动脉功能和结构的变化以及反映神经活动的因素。 除了神经信号的变化，当我们经历一些急性压力时，比如公开演讲，这会引起与血管功能相互作用的激素反应。 拟议的研究将使用各种干预措施来操纵应激反应的各个方面，以提供有关应激反应信号相互作用及其对血管功能影响的新见解。在离体细胞和动物血管中的研究表明，剪切应力的模式（例如，它是否总是在一个方向或改变方向）是内皮细胞功能的重要决定因素。 然而，我们知道的剪切应力模式的慢性变化的综合人体系统的影响少。 这很重要，因为包括不同类型的运动和不同水平的神经介导的收缩在内的几个因素可以改变我们动脉中的剪切应力模式。拟议的研究将使用各种技术长期暴露参与者手臂和腿部的动脉，以不同的剪切应力模式，并评估对动脉功能和结构的影响。 总的来说，这项研究将为人类动脉中信号的复杂相互作用和整合提供重要的见解。 从这些研究中获得的信息将有助于促进我们对基本人类心血管功能的理解。 该研究计划还将为本科生和研究生以及研究人员提供丰富的培训环境，使他们能够培养创新和批判性思维能力的技能。 这对于支持研究领导者的发展和加拿大研究的长期成功至关重要，这将使所有加拿大人受益。