Mechanotransduction in Neointimal Hyperplasia Formation in Arteriovenous Grafts

动静脉移植物新内膜增生形成中的机械转导

• 批准号: 9136807
• 负责人: YAN-TING E. SHIU
• 金额: $ 32.41万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-07 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9136807
• 关键词: Activation Analysis; Anastomosis - action; Animals; Architecture; Arteriovenous fistula; Blood; Blood Vessels; Blood flow; Carotid Arteries; Cell Communication; Chronic; Clinical; Complex; DDR1 gene; Data; Development; Dominant-Negative Mutation; Endothelial Growth Factors Receptor; Environment; Event; Failure; Family suidae; Finite Element Analysis; Fistula; Growth; Health; Hemodialysis; Hyperplasia; Image; In Vitro; Injury; Kidney Failure; Knowledge; Liquid substance; Magnetic Resonance Imaging; Mechanical Stress; Mechanics; Mediating; Modeling; Organ Culture Techniques; Pathogenesis; Pathway interactions; Patients; Peptides; Physiologic arteriovenous anastomosis; Platelet-Derived Growth Factor Receptor; Rattus; Receptor Protein-Tyrosine Kinases; Regulation; Research; Research Design; Resistance; Role; Site; Smooth Muscle Myocytes; Stenosis; Stress; System; Tissues; Tyrosine Kinase Inhibitor; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vein graft; Veins; Venous; X-Ray Computed Tomography; base; design; hemodynamics; in vivo; inhibitor/antagonist; innovation; mouse model; novel; pressure; prevent; receptor; research study; shear stress; sound; transcription factor

DESCRIPTION (provided by applicant): Stenosis at the graft-vein anastomosis due to neointimal hyperplasia (NH) is the predominant cause of failure of arteriovenous grafts (AVGs) used for hemodialysis. Currently, there are no clinical therapies that significantly prevent or tret primary AVG NH. Shunting of arterial blood flow directly into the vein greatly alters the hemodynamics in the vein. Consequently, the fluid shear stress (FSS) and wall circumferential stress (WCS) at the NH-susceptible sites of AVGs are markedly altered. We propose that these hemodynamic changes are major contributors to NH development at the venous anastomosis of AVGs. This project aims to understand the hemodynamic regulation of NH development in AVGs. Detailed FSS and WCS in the AVG setting are not yet fully understood. We will use state-of-the-art image-based computational mechanics to characterize these stresses, and apply these data to design experiments to delineate mechanotransduction pathways. We will focus on i) the roles of two receptor tyrosine kinases (RTKs), vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR), as major mechanosensors in the pathogenesis of NH; and ii) the role of the transcription factor E twenty-six-1 (Ets-1) as the primary effector activated by RTK, leading to NH formation. Our proposal is based on our preliminary findings that i) VEGFR, PDGFR and Ets-1 are up-regulated in NH-susceptible sites in a porcine AVG model; ii) the RTK inhibitor sunitinib inhibits Ets-1 expression and NH development in a perfused vein organ culture model; iii) NH formation is reduced by Ets-1 inhibition in a rat model of carotid artery balloon injury and a mouse model of native arteriovenous fistula. Our hypotheses are as follows: i) The activation of RTK and Ets-1 is initiated by increases in FSS and WCS, as a result of increased blood flow and wall distention respectively, at the juxta-anastomotic vein segment of the AVG. ii) VEGFR and PDGFR are the primary mechanosensors in vascular endothelial cells and smooth muscle cells, respectively, that mediate Ets-1 activation by FSS and WCS. iii) RTK activation followed by Ets-1 activation is a critical event in NH formation in the AVG. There are three Specific Aims: i) Understand differences in the mechanical environment between the NH- susceptible and NH-resistant sites of AVG in a porcine model. ii) Determine in a perfused vein culture model whether increased FSS or WCS enhances RTK and Ets-1 activation and subsequently NH formation. iii) Explore whether RTK and Ets-1 mediate NH formation in a porcine AVG model. Delineation of the RTK- and Ets-1-dependent mechanotransduction pathways and exploration of the roles of these pathways in NH formation is novel. The results have the potential for broad applications in other vascular pathological conditions where there is altered blood flow, including AV fistulas. The perfused organ culture system can be used to investigate pharmacological therapies under relevant flow conditions.

描述（由申请人提供）：由于新内膜增生（NH）而引起的移植物静脉吻合术的狭窄是用于血液透析的动静脉移植物（AVGS）失败的主要原因。目前，没有明显预防或TRET原发性AVG NH的临床疗法。动脉血流直接流入静脉，大大改变了静脉中的血液动力学。因此，在AVG的NH敏感位点上的流体剪切应力（FSS）和壁周向应力（WCS）显着改变。我们建议这些血液动力学变化是AVG静脉吻合术中NH发育的主要因素。该项目旨在了解AVG中NH发展的血流动力学调节。 AVG设置中的详细FS和WCS尚未完全理解。我们将使用基于图像的最先进的计算力学来表征这些应力，并将这些数据应用于设计实验来划定机械传输途径。我们将重点介绍I）两种受体酪氨酸激酶（RTK），血管内皮生长因子受体（VEGFR）和血小板衍生的生长因子受体（PDGFR）的作用，作为NH发病机理中的主要机械传感器； ii）转录因子E 26-1（ETS-1）作为RTK激活的主要效应子的作用，导致NH形成。我们的建议是基于我们的初步发现，即I）VEGFR，PDGFR和ETS-1在猪AVG模型中可在NH敏感的位置上上调； ii）RTK抑制剂Sunitinib抑制ETS-1表达 和灌注静脉器官培养模型中的NH发育； iii）在颈动脉球囊损伤的大鼠模型中，通过ETS-1抑制减少了NH的形成和天然动静脉瘘的小鼠模型。我们的假设如下：i）RTK和ETS-1的激活是由于分别增加了FSS和WCS的增加，这是由于血流量增加和壁延伸的增加，在AVG的股骨 - 抗那粒静脉段处。 ii）VEGFR和PDGFR分别是血管内皮细胞和平滑肌细胞中的主要机械传感器，可通过FSS和WCS介导ETS-1激活。 iii）RTK激活，然后进行ETS-1激活是AVG中NH形成的关键事件。有三个具体的目的：i）了解猪模型中AVG的NH易感和NH耐药位点之间的机械环境差异。 ii）在灌注静脉培养模型中确定FSS或WCS是否会增强RTK和ETS-1激活以及随后的NH形成。 iii）探索RTK和ETS-1是否介导猪AVG模型中的NH形成。 RTK和ETS-1依赖性机械转导途径的描述以及这些途径在NH形成中的作用的探索是新颖的。该结果有可能在血液流动改变的其他血管病理状况中进行广泛应用，包括AV瘘。灌注器官培养系统可用于研究相关流条件下的药理学疗法。