Abstract 460: Adventitial Delivery of Nanoparticle Hydrogel-calcitriol Attenuates Restenosis in a Murine Angioplasty Model

Abstract

Background: Percutaneous transluminal angioplasty (PTA) is the first-line treatment for arteriovenous fistula (AVF) failure and immaturation. High rate of restenosis occurs post PTA procedure caused by venous neointimal hyperplasia (VNH), and decrease the durability of it. Failed AVF showed increased gene expression of Ier3. Poly lactic- co -glycolic acid nanoparticles (PLGA) loaded with 1,25-dihydroxyvitamin D 3 (1,25 NP) can inhibit Ier3 gene expression. Hypothesis: Adventitial delivery of 1,25 NP in hydrogel will reduce venous stenosis in a murine PTA model. Methods: Male C57BL/6J mice underwent partial nephrectomy at day -42 and arteriovenous fistula (AVF) creation at day -14. At day 0, mice were randomized to vehicle group (PTA + PLGA hydrogel) or treatment group (PTA + 1,25 NP hydrogel). Mice were euthanized at day 3 for gene expression analysis and at day 21 for histopathological analysis. Doppler ultrasound was performed weekly to evaluate AVF patency and function. Results: At day 3, PTA + 1,25 NP treated vessels had a significant decrease in the gene expression of Ier3 compared to controls. At day 21, 1,25 NP treated outflow veins had increased lumen vessel area, apoptosis, and higher peak systolic velocity, but decrease in neointimal area/media area ratio, fibroblasts, pro-inflammatory macrophages (M1), fibrosis (picrosirius red staining) and cellular proliferation. Conclusion: Adventitial delivery of 1,25 NP plus PTA has the ability to reduce restenosis and VNH formation. This protective effect is related to inhibition of Ier3 gene expression which modulates vascular inflammation and fibrosis post PTA.