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 血管通道是血液透析患者的生命线。血管通道最常见的病因 血液透析患者功能障碍是动静脉瘘（AVF）成功成熟的失败 透析使用（AVF成熟失败）。目前，AVF成熟失败的发生率很高 美国，没有有效的治疗方法来增强AVF的成熟。在放射学水平上，AVF 成熟失败的最常见特征是静脉吻合处的狭窄，在 组织学水平的特征是侵略性的新内膜增生和外在差的结合 重塑。 AVF创建后的不良结果反映了我们对机制的有限理解 导致AVF成熟失败；缺乏治疗此临床问题的疗法代表了未定的 临床需求。该建议的目的是了解内皮一氧化氮合酶的作用 （NOS3）/AVF开发中的一氧化氮系统。我们啮齿动物AVF模型的初步工作 证明：（1）内皮依赖性的血管延迟受损（NOS3衍生的NO降低 生物利用度）在AVF吻合术中（2）血液动力学适应不良和生物学反应 NOS3功能障碍的设置，（3）增加AVF新内膜增生和基质金属蛋白酶 在慢性肾脏疾病的情况下的产生，（4）减少新内膜增生并改善 血管生物学对直接施加在AVF吻合术的无释放的bionanomatrix凝胶的血管生物学反应 在AVF创建期间。基于这些初步研究，该提议的核心假设是 NOS3/NO系统通过调节局部血管血流动力学在成功的AVF成熟中起关键作用 AVF创建后的适应和血管生物反应；并在本地交付的任何疗法 AVF吻合可以改善这两个过程。使用我们的鼠和大鼠AVF型号，我们将测试我们的 中央假设具有两个具体的目的：（1）确定NOS3系统如何调节血液动力学 AVF成熟过程中的适应和生物反应以及（2）评估一氧化氮的作用 在AVF创建期间，在AVF创建过程中释放纳米质凝胶，以增强AVF 发展。我们认为我们提出的研究很重要，因为：（1）它解决了一个非常重要的研究 血液透析患者，AVF成熟失败的临床问题，目前没有有效 疗法和（2）研究了AVF开发中的根本重要系统，即NOS3/NO系统。 这些目标的成功完成将确定发展目标的创新疗法的重要目标 修改NOS3/NO系统以增强AVF成熟。我们的结果也将有广泛 对其他血管疾病的影响，例如外周动脉疾病，冠状动脉疾病和 后血管成形术再狭窄。

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