Percutaneous transluminal angioplasty (PTA) of stenotic arteriovenous fistulas (AVFs) is performed to maintain optimal function and patency. The one-year patency rate is 60% because of venous neointimal hyperplasia (VNH) and venous stenosis (VS) formation. Immediate early response gene X-1 (Iex-1) also known as Ier3 increases in response to wall shear stress (WSS), and can cause VNH/VS formation in murine AVF. In human stenotic samples from AVFs, we demonstrated increased gene expression of Ier3. We hypothesized that 1α, 25-dihydroxyvitamin D₃, an inhibitor of IER3 delivered as 1α, 25-dihydroxyvitamin D₃ encapsulated in poly lactic-co-glycolic acid (PLGA) nanoparticles loaded in Pluronic F127 hydrogel (1,25 NP) to the adventitia of the stenotic outflow vein after PTA would decrease VNH/VS formation by reducing Ier3 and chemokine (C–C motif) ligand 2 (Ccl2) expression. In our murine model of AVF stenosis treated with PTA, increased expression of Ier3 and Ccl2 was observed. Using this model, PTA was performed and 10-μL of 1,25 NP or control vehicle (PLGA in hydrogel) was administered by adventitial delivery. Animals were sacrificed at day 3 for unbiased whole genome transcriptomic analysis and at day 21 for immunohistochemical analysis. Doppler US was performed weekly after AVF creation. At day 3, significantly lower gene expression of Ier3 and Ccl2 was noted in 1,25 NP treated vessels. Twenty-one days after PTA, 1,25 NP treated vessels had increased lumen vessel area, with decreased neointima area/media area ratio and cell density compared to vehicle controls. There was a significant increase in apoptosis, with a reduction in CD68, F4/80, CD45, pro-inflammatory macrophages, fibroblasts, Picrosirius red, Masson’s trichrome, collagen IV, and proliferation accompanied with higher wall shear stress (WSS) and average peak velocity. IER3 staining was localized to CD68 and FSP-1 (+) cells. After 1,25 NP delivery, there was a decrease in the proliferation of α-SMA (+) and CD68 (+) cells with increase in the apoptosis of FSP-1 (+) and CD68 (+) cells compared to vehicle controls. RNA sequencing revealed a decrease in inflammatory and apoptosis pathways following 1,25 NP delivery. These data suggest that adventitial delivery of 1,25 NP reduces VNH and venous stenosis formation after PTA.

进行狭窄动静脉瘘 (AVF) 的经皮腔内血管成形术 (PTA) 以保持最佳功能和通畅。由于静脉内膜增生 (VNH) 和静脉狭窄 (VS) 形成，一年的通畅率为 60%。即刻早期反应基因 X-1 ( Iex-1 ) 也称为Ier3响应壁剪切应力 (WSS) 增加，并且可导致小鼠 AVF 中的 VNH/VS 形成。在来自 AVF 的人类狭窄样本中，我们证明了Ier3基因表达增加。我们假设 1α, 25-二羟基维生素 D ₃是一种 IER3 抑制剂，以包裹在聚乳酸中的 1α, 25-二羟基维生素 D _{3形式递送。}将 Pluronic F127 水凝胶 (1,25 NP) 中的 -乙醇酸 (PLGA) 纳米颗粒加载到 PTA 后狭窄流出静脉的外膜，将通过减少Ier3和趋化因子 (C-C 基序) 配体 2 ( Ccl2 )来减少 VNH/VS 的形成表达。在我们用 PTA 治疗的 AVF 狭窄小鼠模型中，观察到Ier3和Ccl2的表达增加。使用该模型，进行 PTA，并通过外膜递送施用 10-μL 的 1,25 NP 或对照载体（水凝胶中的 PLGA）。在第 3 天处死动物进行无偏的全基因组转录组分析，并在第 21 天处死动物进行免疫组织化学分析。多普勒超声在 AVF 创建后每周进行一次。在第 3 天， Ier3的基因表达显着降低和Ccl2在 1,25 个 NP 处理的血管中发现。PTA 后 21 天，与载体对照相比，1,25 个 NP 处理的血管管腔血管面积增加，新内膜面积/中膜面积比和细胞密度降低。细胞凋亡显着增加，CD68、F4/80、CD45、促炎巨噬细胞、成纤维细胞、天狼星红、马松三色、胶原蛋白 IV 和增殖伴随着更高的壁剪切应力 (WSS) 和平均峰值减少速度。IER3 染色定位于 CD68 和 FSP-1 (+) 细胞。在 1,25 NP 递送后，与载体对照相比，α-SMA (+) 和 CD68 (+) 细胞的增殖减少，而 FSP-1 (+) 和 CD68 (+) 细胞的凋亡增加。RNA 测序揭示了 1,25 NP 递送后炎症和细胞凋亡途径的减少。