The Role of Nitric oxide/cyclic Guanosine Monophosphate (NO/cGMP) Signaling in Arteriovenous Fistula Maturation

项目摘要 目前在美国有超过700，000名终末期肾病（ESRD）患者。 大约70%的ESRD患者接受血液透析作为其主要肾脏 替代疗法动静脉瘘（AVF）是血管通路的首选类型， 血液透析患者然而，近60%的AVF发生AVF成熟失败 由于早期静脉新生内膜增生形成和外向血管受损， 重塑AVF成熟失败的病理机制不明确， 明白因此，该领域中一个主要的未满足的临床需求是缺乏有效的药物组合物。 治疗和预防AVF成熟失败的方法。这项研究的核心假设是 AVF的产生将导致一氧化氮（NO）和cGMP活性的失调， 通过影响AVF重塑和新生内膜增生破坏AVF正常成熟 阵因此，NO/cGMP信号通路是一个重要的治疗靶点， 临床成功AVF成熟。为探讨NO和cGMP在AVF中的作用 我们将1）检验在AVF时局部给予NO治疗的假设 通过抑制新生内膜增生和增强AVF， 重塑，并减少局部炎症; 2）测试选择性PDE 5A 在AVF产生之前和之后施用的防止cGMP降解的抑制剂将 改善AVF外向重塑和抑制新生内膜增生;也将是有益 在慢性肾脏疾病（CKD）的情况下，AVF是在这种临床环境中产生的。 这些目标将使用啮齿动物AVF模型实现，该模型具有（1）相同的解剖结构 配置为人类AVF和（2）重现进行性静脉新生内膜病变 在人类AVF中观察到增生。我们的研究有望阐明 探讨NO/cGMP信号通路在AVF成熟中的意义，并为进一步研究AVF的成熟机制提供依据。 开发治疗和预防血液透析中AVF成熟失败的新治疗策略 患者

PROJECT SUMMARY There are currently over 700,000 end stage renal disease (ESRD) patients in the United States. Approximately 70% of ESRD patients undergo hemodialysis as their primary kidney replacement therapy. An arteriovenous fistula (AVF) is the preferred type of vascular access in hemodialysis patients. However, nearly 60% of AVFs created develop AVF maturation failure due to early venous neointimal hyperplasia formation and impaired outward vascular remodeling. The pathological mechanisms underlying AVF maturation failure is poorly understood. Therefore, a major unmet clinical need in the field is the lack of effective therapies to treat and prevent AVF maturation failure. The central hypothesis of this study is that AVF creation will result in dysregulation of nitric oxide (NO) and cGMP activity that will disrupt proper AVF maturation by influencing AVF remodeling and neointimal hyperplasia formation. Therefore, NO/cGMP signaling pathway is an important therapeutic target for clinically successful AVF maturation. In order to study the role of NO and cGMP on AVF maturation we will 1) test the hypothesis that locally delivered NO therapy at the time of AVF creation will improve AVF maturation by inhibiting neointimal hyperplasia and enhance AVF remodeling, and reduce local inflammation; 2) test the hypothesis that a selective PDE5A inhibitor, which prevents cGMP degradation, administered before and after AVF creation, will improve AVF outward remodeling and inhibit neointimal hyperplasia; and will be also beneficial in the setting of chronic kidney disease (CKD), where AVFs are created in this clinical setting. These aims will be achieved using a rodent AVF model that has (1) an identical anatomic configuration to human AVF and (2) recapitulates the lesion of progressive venous neointimal hyperplasia seen in human AVF. Our studies are expected to elucidate the pathologic significance of NO/cGMP signaling pathway on AVF maturation as well as provide the basis to develop novel therapeutic strategies to treat and prevent AVF maturation failure in hemodialysis patients.