Chuanqi Cai1,2, Sreenivasulu Kilari2, Chenglei Zhao2,3, Michael L Simeon2, Avanish Misra2, Yiqing Li1, Andre J van Wijnen4,5, Debabrata Mukhopadhyay6, Sanjay Misra7,5,8. 1. Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. 2. Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, Mayo Clinic, Rochester, Minnesota. 3. Department of Vascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China. 4. Department of Orthopedic Surgery, Mayo Clinic, Rochester, Minnesota. 5. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. 6. Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida. 7. Vascular and Interventional Radiology Translational Laboratory, Department of Radiology, Mayo Clinic, Rochester, Minnesota misra.sanjay@mayo.edu. 8. Department of Radiology, Vascular and Interventional Radiology, Mayo Clinic, Rochester, Minnesota.
Abstract
BACKGROUND: Percutaneous transluminal angioplasty (PTA) is the first line of treatment for stenosis in the arteriovenous fistula (AVF) created to provide access for hemodialysis, but resenosis still occurs. Transplants of adipose-derived mesenchymal stem cells (AMSCs) labeled with green fluorescent protein (GFP) to the adventitia could reduce pro-inflammatory gene expression, possibly restoring patency in a murine model of PTA for venous stenosis. METHODS: Partial nephrectomy of male C57BL/6J mice induced CKD. Placement of the AVF was 28 days later and, 14 days after that, PTA of the stenotic outflow vein was performed with delivery of either vehicle control or AMSCs (5×105) to the adventitia of the vein. Mice were euthanized 3 days later and gene expression for interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha TNF-α) analyzed, and histopathologic analysis performed on day 14 and 28. GFP (+) AMSCs were tracked after transplantation for up to 28 days and Doppler ultrasound performed weekly after AVF creation. RESULTS: Gene and protein expression of IL-1β and TNF-α, fibrosis, proliferation, apoptosis and smooth muscle actin decreased, and the proportions of macrophage types (M2/M1) shifted in a manner consistent with less inflammation in AMSC-transplanted vessels compared to controls. After PTA, AMSC-treated vessels had significantly higher wall shear stress, average peak, and mean velocity, with increased lumen vessel area and decreased neointima/media area ratio compared to the control group. At 28 days after delivery, GFP (+) AMSC were present in the adventitia of the outflow vein. CONCLUSIONS: AMSC-treated vessels had improved vascular remodeling with decreased proinflammatory gene expression, inflammation, and fibrotic staining compared to untreated vessels.
BACKGROUND: Percutaneous transluminal angioplasty (PTA) is the first line of treatment for stenosis in the arteriovenous fistula (AVF) created to provide access for hemodialysis, but resenosis still occurs. Transplants of adipose-derived mesenchymal stem cells (AMSCs) labeled with green fluorescent protein (GFP) to the adventitia could reduce pro-inflammatory gene expression, possibly restoring patency in a murine model of PTA for venous stenosis. METHODS: Partial nephrectomy of male C57BL/6J mice induced CKD. Placement of the AVF was 28 days later and, 14 days after that, PTA of the stenotic outflow vein was performed with delivery of either vehicle control or AMSCs (5×105) to the adventitia of the vein. Mice were euthanized 3 days later and gene expression for interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha TNF-α) analyzed, and histopathologic analysis performed on day 14 and 28. GFP (+) AMSCs were tracked after transplantation for up to 28 days and Doppler ultrasound performed weekly after AVF creation. RESULTS: Gene and protein expression of IL-1β and TNF-α, fibrosis, proliferation, apoptosis and smooth muscle actin decreased, and the proportions of macrophage types (M2/M1) shifted in a manner consistent with less inflammation in AMSC-transplanted vessels compared to controls. After PTA, AMSC-treated vessels had significantly higher wall shear stress, average peak, and mean velocity, with increased lumen vessel area and decreased neointima/media area ratio compared to the control group. At 28 days after delivery, GFP (+) AMSC were present in the adventitia of the outflow vein. CONCLUSIONS: AMSC-treated vessels had improved vascular remodeling with decreased proinflammatory gene expression, inflammation, and fibrotic staining compared to untreated vessels.
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Authors: Chenglei Zhao; Sean T Zuckerman; Chuanqi Cai; Sreenivasulu Kilari; Avishek Singh; Michael Simeon; Horst A von Recum; Julius N Korley; Sanjay Misra Journal: J Am Heart Assoc Date: 2020-12-05 Impact factor: 5.501