Biophysical-based approach for controlling blood vessel structure and function

摘要 血管结构和功能的失调是一系列病理的特征，包括 炎症、心血管疾病和癌症。因此，控制血管生成和血管的能力 重塑具有相当大的治疗效益。血管内衬有一层紧密连接的单层 机械耦合的内皮细胞(ECs)，形成血液和周围组织之间的屏障。 此外，众所周知，流体机械应力，如与血管内和 血管内皮细胞解释跨血管流动，帮助形成和重塑血管。然而，尽管数量众多 提出了一种详细的、定量的、完整的流量传感模型--机械换能器 帮助开发控制血管生成的系统途径的内皮细胞并不存在。因此，在那里 是对精确设计的体外平台的重大需求，以系统地研究和开发 流体应激对血管结构的功能结果的综合模型。基于我们的 初步数据和以前的发现，我们假设血管内切应力和跨血管血流 在控制血管重塑中传递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。通过彻底评估这些参数，我们认为 我们的方法将识别失调的血管结构的生物物理特征 血管疾病的特点。此外，我们的目标是使用这些生物物理签名来帮助设计 控制病理性血管生成和血管通透性的策略。为了实现这一目标，我们将使用 综合战略，其中3D微流控系统允许控制生理压力水平和 血流条件和完整血管的细胞/基质拓扑结构将与高分辨率 利用纳米设备的显微镜和力光谱来确定流体的物理机制 压力控制血管生成和血管通透性。在目标1中，我们将量化血管的变化 响应流体压力的结构和功能。在目标2中，我们将测量EC连接处的张力变化 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结来提高渗透性。这些研究的完成将有助于建立一个新的 利用细胞和亚细胞生物物理学控制血管生成和血管重塑。

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.