The role of hypoxia in venous neointimal hyperplasia in hemodialysis grafts

总结/摘要： 这种竞争性更新的长期目标是寻求了解狭窄形成后的血管生物学 血液透析动静脉瘘（AVF）的经皮腔内血管成形术（PTA）。终末期肾病 影响全球超过230万患者。肾脏置换术需要使用AVF建立功能良好的血管通路 使用血液透析治疗。一年后，约40%的AVF发展为VNH，导致静脉狭窄-使用 家庭教师协会在美国每年进行的> 400，000例PTA手术中，40%在6-12岁时发生VNH引起的再狭窄 个月PTA后的VNH机制尚不清楚，可能是多因素的。了解VNH的生物学， 血液透析AVF的PTA可能促进新疗法的开发。无VNH实验模型， 目前存在血液透析AVF的PTA。 我们建立了一个新的小鼠模型，我们诱导慢性肾病（CKD），然后放置AVF， 使得流出静脉形成静脉狭窄。我们用血管成形术治疗了静脉狭窄， 进行了全基因组测序该模型确定了炎症基因表达的增加- 包括组织坏死因子-α（TNF-α），伴随CD 68（+）细胞和平滑肌细胞蓄积，导致 狭窄形成。在实验中，脂肪来源的间充质干细胞（AMSC）可以减少促炎性细胞因子。 基因表达包括TNF-α，导致CD 68（+）表达减少和静脉狭窄形成。 这促使我们测试AMSC在PTA后减少静脉狭窄形成方面的潜力。我们观察到， 与对照组相比，AMSC + PTA治疗的动物TNF-α表达降低，管腔面积增加， 通过组织学和病理学评估， 超声分析。我们建议扩展这些发现，并确定AMSC在降低VNH方面的潜力。 家长教师协会之后 中心假设：AMSC的外膜周围递送通过降低TNF-α导致PTA后VNH降低。 α基因表达和随后的巨噬细胞和平滑肌细胞表达。根据我们的进展，审判 结果，初步数据，和我们的研究意义，我们提出了以下三个目标： 目的1：使用小鼠模型确定AMSC是否可以减少PTA后的VNH。 目的2：探讨TNF-α对PTA后VNH的抑制作用。 目的3：使用猪模型研究AMSC延缓PTA后VNH的功效。

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.