Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula
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...
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Wiley
2020-12-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.018418 |
| _version_ | 1818327993459671040 |
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| author | Chenglei Zhao Sean T. Zuckerman Chuanqi Cai Sreenivasulu Kilari Avishek Singh Michael Simeon Horst A. von Recum Julius N. Korley Sanjay Misra |
| author_facet | Chenglei Zhao Sean T. Zuckerman Chuanqi Cai Sreenivasulu Kilari Avishek Singh Michael Simeon Horst A. von Recum Julius N. Korley Sanjay Misra |
| author_sort | Chenglei Zhao |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T12:25:06Z |
| format | Article |
| id | doaj.art-586553ddcce44a8e96400ea754ce26e5 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-13T12:25:06Z |
| publishDate | 2020-12-01 |
| publisher | Wiley |
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| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-586553ddcce44a8e96400ea754ce26e52022-12-21T23:46:22ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-12-0192410.1161/JAHA.120.018418Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous FistulaChenglei Zhao0Sean T. Zuckerman1Chuanqi Cai2Sreenivasulu Kilari3Avishek Singh4Michael Simeon5Horst A. von Recum6Julius N. Korley7Sanjay Misra8Vascular and Interventional Radiology Translational Laboratory Department of Radiology Mayo Clinic Rochester MNAffinity Therapeutics, LLC Cleveland OHVascular and Interventional Radiology Translational Laboratory Department of Radiology Mayo Clinic Rochester MNVascular and Interventional Radiology Translational Laboratory Department of Radiology Mayo Clinic Rochester MNVascular and Interventional Radiology Translational Laboratory Department of Radiology Mayo Clinic Rochester MNVascular and Interventional Radiology Translational Laboratory Department of Radiology Mayo Clinic Rochester MNDepartment of Biomedical Engineering Case Western Reserve University Cleveland OHAffinity Therapeutics, LLC Cleveland OHVascular and Interventional Radiology Translational Laboratory Department of Radiology Mayo Clinic Rochester MNBackground 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.https://www.ahajournals.org/doi/10.1161/JAHA.120.018418arteriovenous fistuladrug deliveryvascular remodeling |
| spellingShingle | Chenglei Zhao Sean T. Zuckerman Chuanqi Cai Sreenivasulu Kilari Avishek Singh Michael Simeon Horst A. von Recum Julius N. Korley Sanjay Misra Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease arteriovenous fistula drug delivery vascular remodeling |
| title | Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula |
| title_full | Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula |
| title_fullStr | Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula |
| title_full_unstemmed | Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula |
| title_short | Periadventitial Delivery of Simvastatin‐Loaded Microparticles Attenuate Venous Neointimal Hyperplasia Associated With Arteriovenous Fistula |
| title_sort | periadventitial delivery of simvastatin loaded microparticles attenuate venous neointimal hyperplasia associated with arteriovenous fistula |
| topic | arteriovenous fistula drug delivery vascular remodeling |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.018418 |
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