Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula

Abstract

Background Venous neointimal hyperplasia and venous stenosis (VS) formation can result in a decrease in arteriovenous fistula (AVF) patency in patients with end‐stage renal disease. There are limited therapies that prevent VNH/VS. Systemic delivery of simvastatin has been shown to reduce VNH/VS but local delivery may help decrease the side effects associated with statin use. We determined if microparticles (MP) composed of cyclodextrins loaded with simvastatin (MP‐SV) could reduce VS/VNH using a murine arteriovenous fistula model with chronic kidney disease. Methods and Results Male C57BL/6J mice underwent nephrectomy to induce chronic kidney disease. Four weeks later, an arteriovenous fistula was placed and animals were randomized to 3 groups: 20 μL of PBS or 20 μL of PBS with 16.6 mg/mL of either MP or MP‐SV. Animals were euthanized 3 days later and the outflow veins were harvested for quantitative reverse transcriptase–polymerase chain reaction analysis and 28 days later for immunohistochemistical staining with morphometric analysis. Doppler ultrasound was performed weekly. Gene expression of vascular endothelial growth factor‐A ( Vegf‐A ), matrix metalloproteinase‐9 ( Mmp‐9 ), transforming growth factor beta 1 ( Tgf‐β1 ), and monocyte chemoattractant protein‐1 ( Mcp‐1 ) were significantly decreased in MP‐SV treated vessels compared with controls. There was a significant decrease in the neointimal area, cell proliferation, inflammation, and fibrosis, with an increase in apoptosis and peak velocity in MP‐SV treated outflow veins. MP‐SV treated fibroblasts when exposed to hypoxic injury had decreased gene expression of Vegf‐A and Mmp‐9 . Conclusions In experimental arteriovenous fistulas, periadventitial delivery of MP‐SV decreased gene expression of Vegf‐A , Mmp‐9 , Tgf‐β1 and Mcp‐1, VNH/VS, inflammation, and fibrosis.

Localized Perivascular Therapeutic Approaches to Inhibit Venous Neointimal Hyperplasia in Arteriovenous Fistula Access for Hemodialysis Use

“…Although the systemic administration of statins has had promising results, patients may experience adverse effects, such as myopathy and hepatotoxicity, from high-dose therapy [ 53 ]. Localized perivascular delivery is posited to allow the delivery of high-dose treatment on the vascular wall without significantly increasing the risk for systemic toxicity.…”

“…Localized perivascular delivery is posited to allow the delivery of high-dose treatment on the vascular wall without significantly increasing the risk for systemic toxicity. Zhao et al recently implemented periadventitial delivery of simvastatin in a murine AVF model by using cyclodextrin microparticles and found that this strategy reduced the expression of known NIH mediators; the expression of vascular endothelial growth factor-A (VEGF-A), transforming growth factor-beta 1 (TGF-β1), and monocyte chemoattractant protein-1 (MCP-1) significantly decreased by 84% ( p < 0.01), 69% ( p < 0.05), and 79% ( p < 0.05), respectively [ 53 ]. There were also significant decreases in the average neointimal area in the simvastatin-treated group (21,669 ± 8636 μm 2 ) versus the control group (52,910 ± 21,738 μm 2 ; p < 0.05) and in neointimal cell density in the simvastatin-treated group (15,578 ± 3966/mm 2 ) versus the control group (21,622 ± 1911/mm 2 ; p < 0.05) [ 53 ].…”

Effect of local anti-vascular endothelial growth factor therapy to prevent the formation of stenosis in outflow vein in arteriovenous fistula

“…[ 10 ] AFs are the precursor cells of myofibroblasts (α-SMA–positive cells found in specimens removed from patients with failed AVFs), [ 11 ] which promote the formation of venous neointimal hyperplasia (VNH) [ 12 , 13 ] in the subsequent process. This process of injury is orchestrated by a large number of mediators such as the growth factors vascular endothelial growth factor (VEGF), [ 14 , 15 ] platelet-derived growth factor (PDGF), [ 16 ] insulin-like growth factor-1 (IGF-1), [ 17 ] and basic fibroblast growth factor (bFGF). [ 18 ] Therefore, effective treatment must ensure that the concentration of the drug is sufficient to block the cascade reaction of venous stenosis formation effectively.…”

MMP-9 Deletion Attenuates Arteriovenous Fistula Neointima through Reduced Perioperative Vascular Inflammation

“…Janardhanan et al reported simvastatin reduced AVF venous stenosis through decreasing VEGF-A, MMP-9, and MMP-2 expression on CKD mice [ 29 ]. Furthermore, in their recent report, periadventitial local application of simvastatin also had similar effects [ 59 ]. In contrary, the administration of doxycycline did not show beneficial effects on venous injury or patency of AVF despite downregulating MMP-9 in the study by Nath et al [ 30 ].…”

“…CKD has been found to augment MMP-9 expression in AVF [ 31 ], and therefore, the inhibition of MMP-9 could have more impact on AVF in CKD mice. Simvastatin influences multiple targets, such as eNOS, endothelin-1, IL-6, IL-1β, and VEGF-A, other than MMP-9 [ 59 , 60 ]. On the other side, doxycycline is a non-selective MMP inhibitor.…”