Application of Laser Speckle Flowmetry to Vascular Remodeling

激光散斑流量计在血管重塑中的应用

• 批准号: 8887112
• 负责人: Richard J. Price
• 金额: $ 7.61万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8887112
• 关键词: Address; Adult; Arteries; Blood; Blood Flow Velocity; Blood Vessels; Blood flow; Chronic; Clinical; Clinical Trials; Data; Dorsal; Endothelial Cells; Erythrocytes; Exhibits; Flowmetry; Foundations; Future; Goals; Growth; Health; Hindlimb; Hypertension; Image; Individual; Knowledge; Lasers; Leukocytes; Light; Link; Measurement; Measures; Methods; Microcirculation; Molecular; Mus; Outcome; Pathology; Pattern; Perfusion; Peripheral arterial disease; Publications; Recording of previous events; Relative (related person); Retinal Diseases; Role; Scientist; Signal Pathway; Signal Transduction; Solid Neoplasm; Structure; Surface; Testing; Therapeutic; Time; Tissues; Transducers; Variant; Vascular remodeling; Velocimetries; arteriole; artery occlusion; base; blood flow measurement; clinically significant; comparative; cost; density; experience; hemodynamics; imaging modality; improved; in vivo; in vivo Model; insight; interest; monocyte; response; shear stress; statistics; tool; tumor growth; venule

DESCRIPTION (provided by applicant): The major goals of this proposal are (1) to develop and validate laser speckle imaging (LSI) for repeated measurements of absolute blood velocity in microvessels and collateral arteries and (2) to provide, through the use of these LSI methods, insight into how shear stress regulates microvascular remodeling and arteriogenesis. LSI utilizes the speckle pattern generated by the interaction of coherent laser light with tissue. As red blood cells in the tissue move, the image exhibits a decrease in speckle contrast and variation, which can be related to blood flow. LSI has been used previously to measure relative flow changes; however, based on preliminary comparative microparticle image velocimetry (�PIV) studies, we believe that absolute blood flow measurements with LSI may be feasible and applicable to in vivo models of both microvascular remodeling and arteriogenesis. Our overall hypothesis is that LSI can be used to measure and track shear stress levels in individual microvessels and collateral arteries as these vessels structurally remodel through time. In Aim 1, we will optimize and utilize LSI to determine shear stress levels in individual microvessels in mouse dorsal skinfold window chamber as they remodel in response to a hemodynamic perturbation, which will be generated by micro-occluding an arcade arteriole or venule. Microvascular remodeling is essentially a "long-term" autoregulatory response that maintains tissue perfusion; however, dysregulated microvascular remodeling can facilitate and/or exacerbate many pathological conditions. Shear stress is a likely regulator of functional microvascular remodeling; however, the "molecular transducers" linking microvascular remodeling to shear stress are essentially unidentified. We contend this is primarily because no low-cost experimental approaches capable of linking absolute shear stress changes to microvascular remodeling in individual vessels over time currently exist. The results from Aim 1 will fill this critical knowledge gap and enable, for the first time, in vivo experimental investigtion into microvascular adaptation. In Aim 2, we will use an optimized LSI approach to determine how arteriogenesis and monocyte recruitment are regulated by alterations in shear stress magnitude and/or direction. In the context of the treatment of peripheral arterial disease (PAD), therapeutic arteriogenesis clinical trials have been unsuccessful. We contend this is due largely to our continued poor understanding of the endogenous response. Intriguing new studies from our lab show that collateral segments exposed to shear reversal after upstream arterial occlusion exhibit markedly accelerated arteriogenesis. Uncovering why shear reversal accelerates arteriogenesis could provide important clues for improved therapeutic approaches. The studies in Aim 2 will yield detailed shear-growth histories that can then be used to understand how endothelial cells sense and respond to these precise changes in shear stress magnitude and direction. In essence, this will provide the necessary foundation for mechanistic studies aimed at deciphering which signaling pathways link shear stress to accelerated arteriogenic remodeling.

描述（由申请人提供）：本提案的主要目标是（1）开发和验证激光散斑成像（LSI），用于重复测量微血管和侧支动脉中的绝对血流速度，以及（2）通过使用这些LSI方法，深入了解剪切应力如何调节微血管重塑和动脉生成。 LSI 利用相干激光与组织相互作用产生的散斑图案。当组织中的红细胞移动时，图像表现出散斑对比度和变化的减少，这可能与血流有关。 LSI 以前曾用于测量相对流量变化；然而，基于初步的比较微粒图像测速（PIV）研究，我们相信使用LSI进行绝对血流测量可能是可行的，并且适用于微血管重塑和动脉生成的体内模型。我们的总体假设是，LSI 可用于测量和跟踪单个微血管和侧支动脉中的剪切应力水平，因为这些血管会随着时间的推移进行结构重塑。 在目标 1 中，我们将优化并利用 LSI 来确定小鼠背侧皮褶窗室中各个微血管的剪切应力水平，因为它们会因微闭塞拱形小动脉或小静脉而产生的血流动力学扰动而进行重塑。微血管重塑本质上是一种维持组织灌注的“长期”自动调节反应；然而，失调的微血管重塑会促进和/或加剧许多病理状况。剪切应力可能是功能性微血管重塑的调节因子；然而，将微血管重塑与剪切应力联系起来的“分子传感器”基本上是未知的。我们认为这主要是因为目前不存在能够将绝对剪切应力变化与单个血管随时间的微血管重塑联系起来的低成本实验方法。目标 1 的结果将填补这一关键知识空白，并首次实现微血管适应的体内实验研究。在目标 2 中，我们将使用优化的 LSI 方法来确定如何通过剪切应力大小和/或方向的改变来调节动脉生成和单核细胞募集。在治疗外周动脉疾病（PAD）的背景下，治疗性动脉生成临床试验尚未成功。我们认为这主要是由于我们对内源反应的了解仍然不足。我们实验室有趣的新研究表明，上游动脉闭塞后暴露于剪切逆转的侧支节段表现出明显加速的动脉生成。揭示为什么剪切逆转加速动脉生成可以为改进治疗方法提供重要线索。目标 2 中的研究将产生详细的剪切生长历史，然后可用于了解内皮细胞如何感知和响应剪切应力大小和方向的这些精确变化。从本质上讲，这将为旨在破译哪些信号通路将剪切应力与加速动脉重塑联系起来的机制研究提供必要的基础。