Manipulating the matrix to improve arteriovenous fistula patency

血液透析的首选血管通路使用动静脉瘘(AVF)来增加血液 流经静脉。静脉管道成功适应动脉样瘘环境需要 静脉壁的重塑而不会过度增厚，使机械强度能够抵抗 用大口径针刺穿动静脉壁的血液透析术，每周3次。然而， 动静脉瘘的成熟度和通畅性较差，特别是在女性，需要额外的重做手术和 手术，反映了我们对导致成功的静脉重塑生物学的不完全理解 静脉适应瘘管环境。这种知识鸿沟创造了对小说的未得到满足的需求 增强静脉重塑，从而提高静脉导管临床使用成功率的方法。 在资助期间，我们使用了一个创新的小鼠aVF模型来表明转化生长因子-β信号转导 调节静脉适应性重构以改善AVF的通畅性；激活Smad2/3(典型性)和 Tak1(非规范)途径调节静脉重塑；内皮细胞靶向转化生长因子-β抑制 调节胶原密度和平滑肌细胞增殖，改善动静脉瘘的通畅性。我们呈现的是 令人兴奋的新数据：1)基质细胞蛋白TnC(TnC)的表达显著增加，并 与重塑的静脉壁共定位；2)TNC调节aVF通畅和转化生长因子-β信号转导。 静脉重塑；3)TNC表达在失败的AVF中没有下调；4)TNC基因敲除小鼠有 动静脉壁的免疫细胞比例发生改变。此外，我们还进一步开发了小鼠模型以 通过5/6肾切除术合并慢性肾脏疾病(CKD)，这些AVF忠实地概括了人类 AVF成熟。我们假设，调节Tenascin-C活性将改变静脉重构，从而 提高动静脉瘘的成熟度和通畅率。我们将使用我们的体内翻译相关模型，一种创新的 使用纳米颗粒局部给药的工具，创新的方法来分析细胞内的成分 AVF WALL，以及使用转录组学技术的高级下一代分析，这些技术 耶鲁大学提供的，用于测试我们的创新假设，具体目标如下： 目的：研究在体人AVF重塑过程中TNC表达的性别差异。目标二：确定 TNC功能是否参与慢性肾脏病小鼠的静脉重塑。目标三：确定监管是否 免疫细胞是TNC介导的静脉重塑的机制之一。 这项调查的成功结果将产生持久的影响，因为它将确定跨国公司 介导静脉重塑，因此调节TNC活性是否为临床有价值的策略 翻译以促进AVF的成熟。我们还将确定女性AVF成熟度降低是否 由于TNC功能以及炎症和/或免疫方面的性别差异。我们使用一种创新的 战略和新的工具和模型，以改变静脉重构，从而改善AVF成熟度。

The preferred vascular access for hemodialysis uses an arteriovenous fistula (AVF) to increase blood flow through a vein. Successful adaptation of the venous conduit to the arterial-like fistula environment requires remodeling of the vein wall without excessive wall thickening, enabling mechanical strength to resist hemodialysis procedures that puncture the AVF wall with large bore needles 3 times a week. However, the poor maturation and patency of AVF, especially in women and requiring additional re-do procedures and surgery, reflects our imperfect understanding of the biology of venous remodeling that leads to successful venous adaptation to the fistula environment. This knowledge gap creates an unmet need for novel approaches to enhance venous remodeling and thereby increase successful clinical use of venous conduits. During the funding period, we used an innovative mouse AVF model to show that TGF-β signaling regulates venous adaptive remodeling to improve AVF patency; activation of both the smad2/3 (canonical) and tak1 (noncanonical) pathways regulate venous remodeling; and endothelial cell-targeted TGF-β inhibition regulates both collagen density and smooth muscle cell proliferation to improve AVF patency. We present exciting new data that: 1) expression of the matricellular protein tenascin-C (TnC) is greatly increased and colocalizes with the remodeling venous wall; 2) TnC regulates AVF patency and TGF-β signaling during venous remodeling; 3) TnC expression is not downregulated in failed AVF; and 4) TnC knockout mice have altered proportions of immune cells in the AVF wall. In addition, we have developed the mouse model further to incorporate chronic kidney disease (CKD) via 5/6-nephrectomy and these AVF faithfully recapitulate human AVF maturation. We hypothesize that modulating tenascin-C activity will alter venous remodeling, thereby improving AVF maturation and patency. We will use our translationally relevant in vivo model, an innovative tool using nanoparticles for local drug delivery, innovative methodology to analyze the cell composition within the AVF wall, as well as advanced next-generation analyses using transcriptomics techniques that are available at Yale, to test our innovative hypothesis with the following specific aims: Aim I: Determine sex differences in TnC expression during human AVF remodeling in vivo. Aim II: Determine whether TnC function mediates venous remodeling in mice with CKD. Aim III: Determine whether regulation of immune cells is a mechanism of TnC-mediated venous remodeling. A successful outcome of this investigation will have lasting impact by establishing whether TnC mediates venous remodeling, and thus whether regulating TnC activity is a valuable strategy for clinical translation to enhance AVF maturation. We will also determine whether reduced AVF maturation in women is due to sex differences in TnC function as well as in inflammation and/or immunity. We use an innovative strategy and novel tools and models to alter venous remodeling and thereby improve AVF maturation.