TY - JOUR
T1 - Periadventitial delivery of simvastatin-loaded microparticles attenuate venous neointimal hyperplasia associated with arteriovenous fistula
AU - Zhao, Chenglei
AU - Zuckerman, Sean T.
AU - Cai, Chuanqi
AU - Kilari, Sreenivasulu
AU - Singh, Avishek
AU - Simeon, Michael
AU - von Recum, Horst A.
AU - Korley, Julius N.
AU - Misra, Sanjay
N1 - Publisher Copyright:
© 2020 The Authors and Affinity Therapeutics, LLC. Published on behalf of the American Heart Association, Inc., by Wiley.
PY - 2020/12/15
Y1 - 2020/12/15
N2 - BACKGROUND: Venous neointimal hyperplasia and venous stenosis (VS) formation can result in a decrease in arteriovenous fis-tula (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 neoin-timal area, cell proliferation, inflammation, and fibrosis, with an increase in apoptosis and peak velocity in MP-SV treated out-flow 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.
AB - BACKGROUND: Venous neointimal hyperplasia and venous stenosis (VS) formation can result in a decrease in arteriovenous fis-tula (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 neoin-timal area, cell proliferation, inflammation, and fibrosis, with an increase in apoptosis and peak velocity in MP-SV treated out-flow 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.
KW - Arteriovenous fistula
KW - Drug delivery
KW - Vascular remodeling
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U2 - 10.1161/JAHA.120.018418
DO - 10.1161/JAHA.120.018418
M3 - Article
C2 - 33283594
AN - SCOPUS:85098531887
SN - 2047-9980
VL - 9
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 24
M1 - e018418
ER -