Biophysical-based approach for controlling blood vessel structure and function

基于生物物理学的控制血管结构和功能的方法

• 批准号: 10075697
• 负责人: Carlos E. Castro
• 金额: $ 6.86万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10075697
• 关键词: 3-Dimensional; Actins; Address; Angiogenesis Inhibitors; Architecture; Benchmarking; Biophysics; Blood; Blood Vessels; Blood flow; CD31 Antigens; Cardiovascular Diseases; Cell Communication; Cell Line; Cell membrane; Cells; Characteristics; Confocal Microscopy; Coupled; DNA; DNA Binding; Data; Devices; Electron Microscopy; Endothelial Cells; Endothelium; Engineering; Extravasation; Fluorescence Resonance Energy Transfer; Goals; In Vitro; Inflammation; Intercellular Junctions; Knowledge; Lead; Length; Liquid substance; Malignant Neoplasms; Measurement; Measures; Mechanical Stimulation; Mechanical Stress; Mechanics; Mediating; Microfluidics; Microscopy; Modeling; Monitor; Morphology; Optics; Pathologic Neovascularization; Pathology; Pathway interactions; Pharmacology; Physiological; Plasma; Proteins; Reporting; Research; Resolution; Role; Rupture; Side; Site; Spectrum Analysis; Stress; Structure; System; Techniques; Testing; Therapeutic; Time; Tissues; Vascular Diseases; Vascular Permeabilities; Vascular remodeling; Water; angiogenesis; base; cadherin 5; design; experimental study; fluid flow; functional outcomes; microsystems; monolayer; nanodevice; nanoscale; novel; pressure; response; sensor; shear stress; solute

ABSTRACT Dysregulation of vascular architecture and function is characteristic of a broad spectrum of pathologies, including inflammation, cardiovascular diseases, and cancer. Therefore, the ability to control angiogenesis and vessel remodeling has considerable therapeutic benefit. Blood vessels are lined with a monolayer of tightly joined and mechanically coupled endothelial cells (ECs) that form the barrier between blood and the surrounding tissue. In addition, it is well established that fluid mechanical stresses, such as ones associated with intravascular and transvascular flow, are interpreted by ECs to help form and remodel blood vessels. However, while numerous mechanotransducers in ECs have been proposed, a detailed, quantitative, and complete model of flow sensing by ECs that assists in developing a systematic pathway to controlling angiogenesis does not exist. Thus, there is a significant need for accurately engineered in vitro platforms to systematically study and develop a comprehensive model of the functional outcomes of fluid stresses on blood vessel architecture. Based on our preliminary data and previous discoveries, we hypothesize that intravascular shear stress and transvascular flow impart competing effects in controlling blood vessel remodeling leading to quantifiable changes in angiogenesis vascular permeability, and interendothelial ultrastructure. By thoroughly assessing these parameters, we believe that our approach will identify the biophysical signatures of dysregulated vessel architecture that are characteristic of vascular diseases. Moreover, our goal is to use these biophysical signatures to help design strategies for controlling pathological angiogenesis and vascular permeability. To meet this goal, we will use an integrated strategy in which 3-D microfluidic systems that allow control of physiological levels of pressure and flow conditions and the cell/matrix topology of intact blood vessels will be used in conjunction with high-resolution microscopy and force spectroscopy with nanoscale devices to determine the physical mechanisms by which fluid stresses control angiogenesis and vascular permeability. In Aim 1, we will quantify changes in blood vessel structure and function in response to fluid stresses. In Aim 2, we will measure changes in tension at EC junctions in response to fluid stresses. In Aim 3, we will develop approaches for suppressing angiogenesis and vascular permeability by stabilizing EC junctions. Completion of these studies will help establish a new paradigm for using cellular and subcellular biophysics for controlling angiogenesis and blood vessel remodeling.

摘要 血管结构和功能的失调是多种病理学的特征，包括 炎症、心血管疾病和癌症。因此，控制血管生成和血管生成的能力是非常重要的。 重塑具有相当大的治疗益处。血管由单层紧密连接的 在血液和周围组织之间形成屏障的机械偶联内皮细胞（EC）。 此外，已经确定，流体机械应力，例如与血管内和血管外压力相关的应力， 经血管流动，由EC解释，以帮助形成和重塑血管。然而，虽然许多 提出了一种详细的、定量的、完整的流量传感模型 不存在通过内皮细胞帮助发展控制血管生成的系统途径。因此 是对精确工程化的体外平台的重要需求，以系统地研究和开发一种 流体应力对血管结构的功能结果的综合模型。基于我们 初步数据和以前的发现，我们假设血管内剪切应力和经血管血流 在控制血管重塑中赋予竞争效应，导致血管生成的可量化变化 血管通透性和内皮细胞间超微结构。通过全面评估这些参数，我们认为 我们的方法将确定失调的血管结构的生物物理特征， 以血管疾病为特征。此外，我们的目标是利用这些生物物理特征来帮助设计 控制病理性血管生成和血管通透性的策略。为了实现这个目标，我们将使用 集成策略，其中允许控制生理压力水平的3-D微流体系统， 完整血管的流动条件和细胞/基质拓扑结构将与高分辨率 显微镜和力谱与纳米级设备，以确定物理机制，流体 应激控制血管生成和血管渗透性。在目标1中，我们将量化血管 响应流体应力的结构和功能。在目标2中，我们将测量EC结处的张力变化 以应对流体压力。在目标3中，我们将开发抑制血管生成和血管生成的方法。 通过稳定EC连接的渗透性。完成这些研究将有助于建立一个新的模式， 使用细胞和亚细胞生物物理学来控制血管生成和血管重塑。