The role of hypoxia in venous neointimal hyperplasia in hemodialysis grafts

缺氧在血液透析移植物静脉新生内膜增生中的作用

• 批准号: 10400692
• 负责人: Sanjay Misra
• 金额: $ 78.36万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10400692
• 关键词: Address; Adipose tissue; Affect; Allogenic; Angioplasty; Animals; Anti-Inflammatory Agents; Area; Arteriovenous fistula; Autologous; Balloon Angioplasty; Biology; Biopsy; Blinded; Blood Vessels; Cells; Chronic Kidney Failure; Clinical Trials; Control Animal; Data; Development; Dialysis Solutions; Dialysis patients; Dose; End stage renal failure; Experimental Models; Family suidae; Female; Fibroblasts; Funding; Future; Gender; Gene Expression; Genes; Genetic; Goals; Hemodialysis; Histologic; Human; Hyperplasia; Hypoxia; Inflammatory; Inflammatory Response; Investigational Drugs; Kinetics; Knowledge; Label; Light; Mesenchymal Stem Cells; Modeling; Mus; Operative Surgical Procedures; Outcome; PET/CT scan; Patients; Pharmacology; Phase; Physicians; Prevention trial; Primary Prevention; Procedures; Randomized; Renal Replacement Therapy; Research; Role; Safety; Smooth Muscle Myocytes; Source; Stenosis; TNF gene; Testing; Time; Tunica Adventitia; Ultrasonography; Upper Extremity; Veins; Venous; X-Ray Computed Tomography; base; follow-up; genome sequencing; improved; in vivo; macrophage; male; mouse model; necrotic tissue; novel therapeutics; pilot trial; porcine model; response; restenosis; stem cell therapy; ultrasound; whole genome

SUMMARY/ABSTRACT: The long-term goal of this competitive renewal seeks to understand the vascular biology of stenosis formation after percutaneous transluminal angioplasty (PTA) of hemodialysis arteriovenous fistulae (AVF). End-stage renal disease affects >2.3M patients globally. A well-functioning vascular access using an AVF is required for renal replacement therapy using hemodialysis. After a year ~40% of AVFs develop VNH causing venous stenosis—treated using PTA. In >400,000 annual resultant PTA procedures in the US, 40% develop restenosis caused by VNH at 6-12 months. VNH mechanisms after PTA are unknown and likely multifactorial. Understanding the biology of VNH after PTA of hemodialysis AVFs may catalyze the development of new therapies. No experimental models of VNH after PTA of hemodialysis AVF currently exist. We created a neoteric mouse model in which we induced chronic kidney disease (CKD), then placed an AVF, and allowed a venous stenosis to form in the outflow vein. We treated the venous stenosis with angioplasty and performed whole genome sequencing. This model identified an increase in expression of inflammatory genes— including tissue necrosis factor-α (TNF-α) with accumulation of CD68 (+) cells and smooth muscle cells leading to stenosis formation. Experimentally, adipose-derived mesenchymal stem cells (AMSCs) reduce pro-inflammatory gene expression including TNF-α, resulting in a decrease in CD68 (+) expression and venous stenosis formation. This led us to test AMSCs potential in reducing venous stenosis formation after PTA. We observed that, compared to controls, animals treated with AMSCs plus PTA had decreased Tnf-α expression, increased lumen vessel area, better patency, reduced macrophage and smooth muscle cell accumulation as assessed by histologic and ultrasound analyses. We propose to extend these findings and determine the potential of AMSCs in reducing VNH after PTA. Central Hypothesis: Peri-adventitial delivery of AMSCs results in a reduction of VNH after PTA by decreasing Tnf- α gene expression and subsequent macrophage and smooth muscle cell expression. In light of our progress, trial results, preliminary data, and significance of our research, we propose the following three aims: Aim 1: Determine if AMSCs can reduce VNH after PTA using a murine model. Aim 2: Examine inhibitory role of TNF-α in abrogating VNH after PTA. Aim 3: Investigate the efficacy of AMSCs in retarding VNH after PTA using a porcine model.

摘要/摘要： 这一竞争性更新的长期目标是试图了解狭窄形成的血管生物学。 经皮腔内血管成形术(PTA)治疗血液透析动静脉瘘(AVF)终末期肾病 全球有230万患者受到影响。使用动静脉动静脉瘘进行肾脏置换需要功能良好的血管通路。 使用血液透析进行治疗。一年后，约40%的动静脉瘘发展为VNH，导致静脉狭窄-使用 家长会。在美国每年进行的40万例PTA手术中，40%的人在6-12岁时发生由VNH引起的再狭窄 月份。PTA术后的VNH机制尚不清楚，可能是多因素的。了解VNH的生物学后 血液透析动静脉曲张的PTA可能促进新疗法的发展。之后没有实验性的VNH模型 维持性血液透析的PTA目前存在。 我们建立了一个新生的小鼠模型，在其中我们诱导了慢性肾脏疾病(CKD)，然后放置了AVF，并且 使流出静脉形成静脉狭窄。我们对静脉狭窄进行了血管成形术和 进行全基因组测序。这一模型发现炎症基因的表达增加- 包括组织坏死因子-α(肿瘤坏死因子-α)，并积聚CD68(+)细胞和平滑肌细胞导致 狭窄形成。实验上，脂肪来源的间充质干细胞(AMSCs)可减少促炎作用 基因表达包括肿瘤坏死因子-α，导致CD68(+)表达减少，静脉狭窄形成。 这导致我们测试了AMSCs在减少PTA术后静脉狭窄形成方面的潜力。我们观察到，与 与对照组相比，AMSCs+PTA组动物肿瘤坏死因子-α表达降低，管腔血管面积增加， 更好的通畅性，减少巨噬细胞和平滑肌细胞聚集，通过组织学和 超声波分析。我们建议扩展这些发现，并确定AMSCs在减少VNH方面的潜力 在PTA之后。 中心假说：血管外膜周围注射AMSCs可通过降低肿瘤坏死因子减少PTA术后的VNH。 α基因的表达以及随后巨噬细胞和平滑肌细胞的表达。鉴于我们的进展，审判 我们的研究结果、初步数据和意义，我们提出了以下三个目标： 目的1：通过建立小鼠PTA模型，确定AMSCs能否减少PTA后的VNH。 目的2：检测肿瘤坏死因子-α对PTA术后vnH的抑制作用。 目的：利用猪PTA模型，观察AMSCs对PTA术后VNH的延缓作用。