The role of hypoxia in venous neointimal hyperplasia in hemodialysis grafts

Project: Research project

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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-? (TNF-?) 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-?, 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-? 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- ? 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-? in abrogating VNH after PTA. Aim 3: Investigate the efficacy of AMSCs in retarding VNH after PTA using a porcine model.
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