Hemodynamic Adaptation and Vascular Remodeling in Fistula Development

瘘管发展中的血流动力学适应和血管重塑

• 批准号: 10328935
• 负责人: TIMMY C LEE
• 金额: $ 42.09万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328935
• 关键词: Address; Anastomosis - action; Arteriovenous fistula; Biological; Biological Availability; Blood Vessels; Chronic Kidney Failure; Clinical; Coronary Arteriosclerosis; Cyclic GMP; Development; Dialysis procedure; Endothelium; Enzymes; Etiology; Failure; Fistula; Functional disorder; Gel; Gelatinase A; Goals; Guanosine Monophosphate; Hemodialysis; Histologic; Hyperplasia; Impairment; Innovative Therapy; Intervention; Knowledge; Liquid substance; Magnetic Resonance Imaging; Matrix Metalloproteinases; Mission; Modeling; Morbidity - disease rate; Mus; NOS3 gene; Nitric Oxide; Nitric Oxide Synthase; Outcome; Patients; Pattern; Periodicity; Peripheral arterial disease; Phosphorylation; Play; Procedures; Process; Production; Public Health; Radiology Specialty; Rattus; Research; Rodent; Role; Signaling Molecule; Stenosis; System; Testing; United States; United States National Institutes of Health; Vascular Endothelium; Vascular remodeling; Vasodilation; Vasodilator Agents; Venous; Wild Type Mouse; Work; base; effective therapy; hemodynamics; improved; mortality; novel therapeutics; overexpression; response; restenosis; shear stress

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.

项目摘要和摘要 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瘘(AVF)未能成功成熟 透析使用(动静脉瘘成熟失败)。目前AVF成熟度失败率仍然很高。 目前尚无有效的治疗方法促进动静脉瘘的成熟。在放射学水平上，AVF 成熟失败最常见的特征是静脉吻合口狭窄， 组织学特征为侵袭性新生内膜增生和外缘差。 改建。AVF创建后的糟糕结果反映了我们对机制的有限理解 导致动静脉瘘成熟失败；缺乏治疗这一临床问题的方法是一个未解决的问题。 临床需要。这项建议的目的是了解内皮型一氧化氮合酶的作用。 动静脉瘘发生中的(NOS3)/一氧化氮(NO)系统。我们的啮齿动物AVF模型的初步工作 证实：(1)内皮依赖性血管松弛受损(NOS3来源的NO减少 生物利用度)，(2)较差的血流动力学适应和生物反应 NOS3功能障碍的背景，(3)AVF新生内膜增生和基质金属蛋白酶的增加 在慢性肾脏疾病的背景下产生，以及(4)减少新生内膜增生并改善 血管生物支架凝胶直接应用于动静脉瘘吻合口的血管生物学反应 在AVF创建期间。基于这些初步研究，这项提议的中心假设是 NOS3/NO系统通过调节局部血管血流动力学在动静脉瘘成功成熟中起关键作用 动静脉瘘产生后的适应和血管生物学反应； 动静脉动静脉吻合可以改善这两个过程。使用我们的小鼠和大鼠AVF模型，我们将测试我们的 中心假说有两个具体目的：(1)确定NOS3系统如何调节血流动力学 在AVF成熟过程中的适应和生物反应以及(2)评估一氧化氮- 动静脉瘘造影术中动静脉瘘吻合口局部应用纳米基质凝胶增强动静脉瘘 发展。我们认为我们提出的研究具有重要意义，因为：(1)它解决了一个非常重要的问题 临床问题在血液透析患者中，动静脉瘘成熟失败，其中目前尚无有效方法 治疗和(2)检查AVF发展中的一个根本重要的系统，即NOS3/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 对NOS3/NO系统进行改造以促进AVF成熟。我们的成果也将具有广泛的意义 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。

项目成果

Cardiac changes following arteriovenous fistula creation in a mouse model.

• DOI: 10.1177/11297298211026083
• 发表时间: 2023-01
• 期刊: JOURNAL OF VASCULAR ACCESS
• 影响因子: 1.9
• 作者: Ingle, Kevin;Pham, Linh;Lee, Viangkaeo;Guo, Lingling;Isayeva-Waldrop, Tatyana;Somarathna, Maheshika;Lee, Timmy
• 通讯作者: Lee, Timmy

Perspectives in Individualizing Solutions for Dialysis Access.

透析访问个性化解决方案的观点。

• DOI: 10.1053/j.ackd.2020.03.004
• 发表时间: 2020
• 期刊: Advances in chronic kidney disease
• 影响因子: 2.9
• 作者: Shah,Silvi;Chan,MicahR;Lee,Timmy
• 通讯作者: Lee,Timmy