Linking Spatial Variations in Shear Stress with Oxidative Stress

描述（由申请人提供）：动脉粥样硬化是一种全身性疾病;然而，其表现往往是局灶性和偏心性的。已知剪切应力调节NADPH氧化酶活性作为内皮超氧化物产生（O2-）的来源。微机电系统（MEMS）提供了一个空间分辨率相当于单独伸长的内皮细胞和时间分辨率在71 kHz，允许调查的机制，从而空间和时间变化的剪切应力调节氧化应激介导的反应。我们的工作假设是，在动脉分叉处，血流保持单向和轴向对齐的中高剪切应力区域经历相对较少的氧化应力。相比之下，过量生产的活性氧（ROS）的发展主要是在相对低的剪切应力，流动分离，并偏离轴向对齐和单向流动剖面的区域。我们建议，在分叉处的剪切应力的空间变化调节的相对生产的02-。或ROS和一氧化氮或活性氮物质（RNS）的产生。在动脉分叉处，其中振荡剪切应力是普遍的，O2.相对于NO的产生，NO的产生可能通过形成有效的氧化剂过氧亚硝酸盐（ONOO-）而限制NO的生物利用度。为了将MEMS传感器与我们的假设相结合，我们提出了以下三个目标：目标1。证明MEMS传感器提供空间分辨率，以解决三维对称分叉模型中剪切应力的周向变化。目标二。确定剪切应力的空间变化对新西兰白色（NZW）兔腹主动脉特定区域血管氧化应激的影响。目标3。阐明切应力的时空变化对内皮细胞、NO和O2-的调节机制。产生和随后的致动脉粥样硬化LDL修饰。新的剪切应力传感技术可以应用于体内测量，这对于验证迄今为止在细胞系统和体外的发现至关重要。进一步开发和应用MEMS技术在兔子体内的研究将是本项目的主要目标。

DESCRIPTION (provided by applicant): Atherosclerosis is a systemic disease; however, its manifestations tend to be focal and eccentric. Shear stress is known to regulate NADPH oxidase activities as a source of endothelial superoxide production (O2-.). The Micro Electro Mechanical Systems (MEMS) provide a spatial resolution comparable to the individually elongated endothelial cells and temporal resolution at 71 kHz that permits investigation of the mechanisms whereby spatial and temporal variations of shear stress regulate the oxidant stress-mediated responses. Our working hypothesis is that at arterial bifurcations, the regions of moderate to high shear stress where flow remains unidirectional and axially aligned experience relatively little oxidative stress. In contrast, excess production of reactive oxygen species (ROS) develops largely in regions of relative low shear stress, flow separation, and departure from axjally aligned and unidirectional flow profiles. We propose that the spatial variations in shear stress at bifurcations regulate the relative production of 02-. or ROS and nitric oxide or reactive nitrogen species (RNS) production. At arterial bifurcations where oscillatory shear stress is prevalent, the increase in O2.- production relative to NO production likely limits NO bioavailability through formation of the potent oxidant, peroxynitrite (ONOO-). To interface the MEMS sensors with our hypothesis, we propose following three aims: Aim 1. Demonstrate that MEMS sensors provide spatial resolution to resolve circumferential variations in shear stress in a 3-D symmetric bifurcation model. Aim 2. Determine the effects of spatial variations in shear stress on specific regions of vascular oxidative stress in the aortas of New Zealand White (NZW) rabbits. Aim 3. Elucidate the mechanism(s) by which spatial and temporal variations in shear stress regulate endothelial .NO and O2-. production and subsequent atherogenic LDL modifications. The new shear stress sensing technology can be applied to in vivo measurements that are critical to validating the findings so far in cell systems and in vitro. Further development and application of MEMS technology to in vivo studies in rabbits will be a major goal of this project.