Hemodynamic Adaptation and Vascular Remodeling in Fistula Development

项目总结和摘要 血管通路是血液透析患者的生命线。血管通路最常见的病因 血液透析患者的功能障碍是动静脉内瘘（AVF）未能成功成熟， 透析使用（AVF成熟失败）。目前，AVF成熟失败率仍然很高， 美国和没有有效的治疗方法，以提高AVF的成熟。在放射学水平上，AVF 成熟失败最常见的特征是静脉吻合处狭窄， 在组织学水平上，其特征在于结合了侵袭性的新生内膜增生和不良的外 重塑AVF创建后的不良结局反映了我们对该机制的理解有限 导致AVF成熟失败;并且缺乏治疗这种临床问题的疗法代表了未满足的 临床需要这个建议的目的是了解内皮型一氧化氮合酶的作用 （NOS 3）/一氧化氮（NO）系统在AVF形成中的作用从我们的啮齿动物AVF模型的初步工作， 结果显示：（1）内皮依赖性血管舒张功能受损（NOS 3-衍生的NO减少 生物利用度），（2）AVF吻合口的血流动力学适应性和生物学反应较差， NOS 3功能障碍;（3）AVF新生内膜增生和基质金属蛋白酶升高 在慢性肾脏疾病的背景下产生，和（4）减少新生内膜增生和改善 直接应用于AVF吻合口的NO释放生物纳米基质凝胶的血管生物学反应 在AVF创建期间。根据这些初步研究，这一建议的中心假设是， NOS 3/NO系统通过调节局部血管血流动力学在AVF成功成熟中起关键作用 AVF创建后的适应和血管生物学反应;以及局部输送的NO治疗， 动静脉瘘吻合可改善这两个过程。使用我们的小鼠和大鼠AVF模型，我们将测试我们的 中心假设有两个具体目标：（1）确定NOS 3系统如何调节血流动力学 AVF成熟过程中的适应和生物学反应;（2）评价一氧化氮- 在AVF创建期间在AVF吻合处局部施用释放纳米基质凝胶以增强AVF 发展我们相信我们提出的研究是有意义的，因为：（1）它解决了一个非常重要的问题， 血液透析患者的临床问题，AVF成熟失败，目前没有有效的 治疗和（2）检查AVF发展中的一个基本重要系统，NOS 3/NO系统。 成功完成这些目标将确定开发创新疗法的重要目标， 修饰NOS 3/NO系统以促进AVF成熟。我们的结果也将有广泛的 对其他血管疾病的影响，如外周动脉疾病、冠状动脉疾病和 血管成形术后再狭窄

PROJECT SUMMARY AND ABSTRACT The vascular access is the lifeline for the hemodialysis patient. The most common etiology of vascular access dysfunction in hemodialysis patients is failure of an arteriovenous fistula (AVF) to mature successfully for dialysis use (AVF maturation failure). At present, there remains a very high rate of AVF maturation failure in the United States and there are no effective treatments to enhance AVF maturation. On a radiologic level, AVF maturation failure is most commonly characterized by a stenosis at the venous anastomosis, and at a histological level it is characterized by a combination of aggressive neointimal hyperplasia and poor outward remodeling. The poor outcomes following AVF creation reflect our limited understanding of the mechanisms leading to AVF maturation failure; and the lack of therapies to treat this clinical problem represent an unmet clinical need. The objective of this proposal is to understand the role of the endothelial nitric oxide synthase (NOS3)/nitric oxide (NO) system in AVF development. Preliminary work from our rodent AVF models has demonstrated: (1) impaired endothelial-dependent vasorelaxation (decreased NOS3-derived NO bioavailability) at the AVF anastomosis, (2) poor hemodynamic adaptation and biological responses in the setting of NOS3 dysfunction, (3) increased AVF neointimal hyperplasia and matrix metalloproteinase production in the setting of chronic kidney disease, and (4) reduced neointimal hyperplasia and improved vascular biological responses to a NO-releasing bionanomatrix gel applied directly at the AVF anastomosis during AVF creation. Based on these preliminary studies, the central hypothesis of this proposal is that the NOS3/NO system plays a critical role in successful AVF maturation by regulating local vascular hemodynamic adaptation and vascular biological responses after AVF creation; and locally delivered NO therapies applied at the AVF anastomosis can improve these two processes. Using our murine and rat AVF models, we will test our central hypothesis with two specific aims: (1) To determine how the NOS3 system modulates hemodynamic adaptation and biological responses during AVF maturation and (2) To evaluate the effect of a nitric oxide- releasing nanomatrix gel administered locally at the AVF anastomosis during AVF creation on enhancing AVF development. We believe our proposed research is significant because: (1) it addresses a very important clinical problem in hemodialysis patients, AVF maturation failure, where there are presently no effective therapies and (2) examines a fundamentally important system in AVF development, the NOS3/NO system. Successful completion of these aims will identify important targets for developing innovative therapies that aim to modify the NOS3/NO system in order to enhance AVF maturation. Our results will also have broad implications for other vascular conditions such as peripheral arterial disease, coronary artery disease, and postangioplasty restenosis.