Manipulating the matrix to improve arteriovenous fistula patency

操纵基质以改善动静脉内瘘的通畅

• 批准号: 10648012
• 负责人: Alan Dardik
• 金额: $ 75.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10648012
• 关键词: Address; Arteriovenous fistula; Biology; Blood Vessels; Blood flow; Cell Proliferation; Cells; Chronic Kidney Failure; Clinical; Clinical Trials; Collagen; Data; Deposition; End stage renal failure; Endothelial Cells; Environment; Expenditure; Extracellular Matrix; Failure; Female; Fistula; Funding; Goals; Healthcare; Hemodialysis; Human; Hyperplasia; Immune; Immunity; Inflammation; Intervention; Investigation; Knockout Mice; Knowledge; Legal patent; Macrophage; Mechanics; Mediating; Mediator; Methodology; Modeling; Mus; Needles; Nephrectomy; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Procedures; Proteins; Puncture procedure; Resources; Sex Differences; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Specimen; T-Lymphocyte Subsets; Techniques; Tenascin; Testing; Transforming Growth Factor beta; Veins; Venous; Wild Type Mouse; Woman; Work; clinical translation; density; experience; hemodynamics; human disease; immunoregulation; improved; in vivo; in vivo Model; innovation; local drug delivery; male; men; mouse model; nanoparticle; next generation; novel; novel strategies; shear stress; tool; transcriptomics

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.

血液透析的首选血管通路使用动静脉瘘 (AVF) 来增加血液 通过静脉流动。静脉导管成功适应动脉样瘘管环境需要 在不过度增厚静脉壁的情况下重塑静脉壁，从而使机械强度能够抵抗 每周 3 次用大口径针刺破 AVF 壁的血液透析程序。然而， AVF 的成熟度和通畅性较差，尤其是女性，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 静脉对瘘管环境的适应。这种知识差距造成了对小说的未满足的需求 增强静脉重塑的方法，从而增加静脉导管的成功临床使用。 在资助期间，我们使用创新的小鼠 AVF 模型来证明 TGF-β 信号传导 调节静脉适应性重塑以改善 AVF 通畅性； smad2/3（规范）和 tak1（非规范）途径调节静脉重塑；和内皮细胞靶向 TGF-β 抑制 调节胶原蛋白密度和平滑肌细胞增殖，以改善 AVF 通畅性。我们呈现 令人兴奋的新数据：1) 基质细胞蛋白生腱蛋白-C (TnC) 的表达大大增加，并且 与重塑静脉壁共定位； 2) TnC 在 AVF 通畅和 TGF-β 信号传导过程中调节 静脉重塑； 3）失败的AVF中TnC表达没有下调； 4) TnC 敲除小鼠 改变了 AVF 壁中免疫细胞的比例。此外，我们还进一步开发了小鼠模型 通过 5/6 肾切除术纳入慢性肾脏病 (CKD)，这些 AVF 忠实地再现了人类 AVF 成熟。我们假设调节生腱蛋白-C 活性将改变静脉重塑，从而 改善 AVF 的成熟度和通畅性。我们将使用我们的翻译相关体内模型，这是一种创新的 使用纳米颗粒进行局部药物输送的工具，分析内部细胞成分的创新方法 AVF 墙，以及使用转录组学技术的先进下一代分析 耶鲁大学提供，以测试我们的创新假设，其具体目标如下： 目标 I：确定人 AVF 体内重塑过程中 TnC 表达的性别差异。目标二：确定 TnC 功能是否介导 CKD 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。 这项调查的成功结果将通过确定 TnC 是否 介导静脉重塑，因此调节 TnC 活性是否是临床上有价值的策略 翻译以增强 AVF 成熟度。我们还将确定女性 AVF 成熟度降低是否与 由于 TnC 功能以及炎症和/或免疫方面的性别差异。我们使用创新的 改变静脉重塑的策略以及新颖的工具和模型，从而提高 AVF 的成熟度。

项目成果

Sex differences in arterial identity correlate with neointimal hyperplasia after balloon injury.

动脉身份的性别差异与球囊损伤后的新内膜增生相关。

• DOI: 10.1007/s11033-022-07644-2
• 发表时间: 2022-09
• 期刊: MOLECULAR BIOLOGY REPORTS
• 影响因子: 2.8
• 作者: Gao, Mingjie;Gao, Xixiang;Taniguchi, Ryosuke;Brahmandam, Anand;Matsubara, Yutaka;Liu, Jia;Liu, Hao;Zhang, Weichang;Dardik, Alan
• 通讯作者: Dardik, Alan

Hypoxia and hypoxia-inducible factors promote the development of neointimal hyperplasia in arteriovenous fistula.

• DOI: 10.1113/jp281218
• 发表时间: 2021-04
• 期刊: The Journal of physiology
• 作者: Sadaghianloo N;Contenti J;Declemy S;Ambrosetti D;Zdralevic M;Tannour-Louet M;Fabbri L;Pagès G;Bost F;Hassen-Khodja R;Pouysségur J;Jean-Baptiste E;Dardik A;Mazure NM
• 通讯作者: Mazure NM

Endothelial Cell TGF-β (Transforming Growth Factor-Beta) Signaling Regulates Venous Adaptive Remodeling to Improve Arteriovenous Fistula Patency.

• DOI: 10.1161/atvbaha.122.317676
• 发表时间: 2022-07
• 期刊: ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
• 影响因子: 8.7
• 作者: Taniguchi, Ryosuke;Ohashi, Yuichi;Lee, Jung Seok;Hu, Haidi;Gonzalez, Luis;Zhang, Weichang;Langford, John;Matsubara, Yutaka;Yatsula, Bogdan;Tellides, George;Fahmy, Tarek M.;Hoshina, Katsuyuki;Dardik, Alan
• 通讯作者: Dardik, Alan

EphB4 monomer inhibits chronic graft vasculopathy in an aortic transplant model.

• DOI: 10.1016/j.jvssci.2023.100109
• 发表时间: 2023
• 期刊: JVS-vascular science
• 作者: Langford, John T;Gonzalez, Luis;Taniguchi, Ryosuke;Brahmandam, Anand;Zhang, Weichang;Dardik, Alan
• 通讯作者: Dardik, Alan

A central arteriovenous fistula reduces systemic hypertension in a mouse model.

中央动静脉瘘可降低小鼠模型的全身性高血压。

• DOI: 10.1016/j.jvssci.2024.100191
• 发表时间: 2024
• 期刊: JVS-vascular science
• 作者: Brahmandam,Anand;Alves,Rafael;Liu,Hao;Gonzalez,Luis;Aoyagi,Yukihiko;Ohashi,Yuichi;Langford,JohnT;Thaxton,Carly;Taniguchi,Ryosuke;Zhang,Weichang;Bai,Hualong;Yatsula,Bogdan;Dardik,Alan
• 通讯作者: Dardik,Alan