Singh Avishek K, Cai Chuanqi, Kilari Sreenivasulu, Zhao Chenglei, Simeon Michael L, Takahashi Edwin, Edelman Elazer R, Kong Hyunjoon Joon, Macedo Thanila, Singh Ravinder J, Urban Matthew W, Kumar Rajiv, Misra Sanjay
Department of Radiology, Vascular and Interventional Translational Laboratory, Mayo Clinic, Rochester, Minnesota.
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, Massachusetts.
J Am Soc Nephrol. 2021 Apr;32(4):866-885. doi: 10.1681/ASN.2020060832. Epub 2021 Feb 24.
Few therapies prevent venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation in arteriovenous fistulas (AVF). Expression of the immediate early response gene X-1 (), also known as is associated with VNH and stenosis in murine AVFs. The study aimed to determine if local release of long-acting inhibitor 1α,25(OH)D from poly(lactic-co-glycolic acid) (PLGA) nanoparticles embedded in a thermosensitive Pluronic F127 hydrogel (1,25 NP) could affect VNH/VS formation in a large animal model.
Immediately after AVF creation in a porcine model of renal failure, 1,25 NP or vehicle control was injected into the adventitia space of AVF outflow veins. Scanning electron microscopy and dynamic light scattering characterized drug and control nanoparticles. Animals were sacrificed 3 and 28 days later for gene expression, immunohistologic, magnetic resonance imaging and angiography, and ultrasound analyses. Whole transcriptome RNA sequencing with differential gene expression analysis was performed on outflow veins of AVF.
Encapsulation of 1α,25(OH)D in PLGA nanoparticles formed nanoparticles of uniform size that were similar to nanoparticles without 1α,25(OH)D. The 1,25 NP-treated AVFs exhibited lower VNH/VS, gene expression, and IER-3, MCP-1, CD68, HIF-1α, and VEGF-A immunostaining, fibrosis, and proliferation. Blood flow and lumen area increased significantly, whereas peak systolic velocity and wall shear stress decreased. Treatment increased Young's modulus and correlated with histologic assessment of fibrosis and with no evidence of vascular calcification. RNA sequencing analysis showed changes in the expression of genes associated with inflammatory, TGFβ1, and apoptotic pathways.
Local release of 1,25 NP improves AVF flow and hemodynamics, and reduces stenosis in association with reduction in inflammation, apoptosis, and fibrosis in a porcine model of arteriovenous fistula.
很少有治疗方法能预防动静脉内瘘（AVF）中的静脉内膜增生（VNH）和静脉狭窄（VS）形成。即刻早期反应基因X-1（IER-3），也称为IER3，其表达与小鼠AVF中的VNH和狭窄有关。本研究旨在确定嵌入热敏性泊洛沙姆F127水凝胶（1,25 NP）中的聚乳酸-乙醇酸共聚物（PLGA）纳米颗粒局部释放长效抑制剂1α,25(OH)D是否会影响大型动物模型中的VNH/VS形成。
在猪肾衰竭模型中创建AVF后，立即将1,25 NP或载体对照注入AVF流出静脉的外膜间隙。扫描电子显微镜和动态光散射对药物和对照纳米颗粒进行表征。3天和28天后处死动物，进行基因表达、免疫组织学、磁共振成像和血管造影以及超声分析。对AVF流出静脉进行全转录组RNA测序并进行差异基因表达分析。
1α,25(OH)D封装在PLGA纳米颗粒中形成大小均匀的纳米颗粒，与不含1α,25(OH)D的纳米颗粒相似。接受1,25 NP治疗的AVF表现出较低的VNH/VS、IER-3基因表达以及IER-3、MCP-1、CD68、HIF-1α和VEGF-A免疫染色、纤维化和增殖。血流量和管腔面积显著增加，而收缩期峰值速度和壁面剪应力降低。治疗增加了杨氏模量，并与纤维化的组织学评估相关，且无血管钙化证据。RNA测序分析显示与炎症、TGFβ1和凋亡途径相关的基因表达发生变化。
在猪动静脉内瘘模型中，局部释放1,25 NP可改善AVF血流和血流动力学，并减少狭窄，同时伴有炎症、凋亡和纤维化的减少。
