title: Simvastatin reduces venous stenosis formation in a murine hemodialysis vascular access model.
abstract: Venous neointimal hyperplasia (VNH) is responsible for hemodialysis vascular access malfunction. Here we tested whether VNH formation occurs, in part, due to vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase (MMP)-9 gene expression causing adventitial fibroblast transdifferentiation to myofibroblasts (α-SMA-positive cells). These cells have increased proliferative and migratory capacity leading to VNH formation. Simvastatin was used to decrease VEGF-A and MMP-9 gene expression in our murine arteriovenous fistula model created by connecting the right carotid artery to the ipsilateral jugular vein. Compared to fistulae of vehicle-treated mice, the fistulae of simvastatin-treated mice had the expected decrease in VEGF-A and MMP-9 but also showed a significant reduction in MMP-2 expression with a significant decrease in VNH and a significant increase in the mean lumen vessel area. There was an increase in terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, and decreases in α-SMA density, cell proliferation, and HIF-1α and hypoxyprobe staining. This latter result prompted us to determine the effect of simvastatin on fibroblasts subjected to hypoxia in vitro. Simvastatin-treated fibroblasts had a significant decrease in myofibroblast production along with decreased cellular proliferation, migration, and MMP-9 activity but increased caspase 3 activity suggesting increased apoptosis. Thus, simvastatin results in a significant reduction in VNH, with increase in mean lumen vessel area by decreasing VEGF-A/MMP-9 pathway activity.
authors: Department of Radiology, Vascular and Interventional Radiology Translational Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors: Rajiv
authors: R
authors: Janardhanan
authors: Binxia
authors: B
authors: Yang
authors: Pawan
authors: P
authors: Vohra
authors: Bhaskar
authors: B
authors: Roy
authors: Sarah
authors: S
authors: Withers
authors: Santanu
authors: S
authors: Bhattacharya
authors: Jaywant
authors: J
authors: Mandrekar
authors: Hyunjoon
authors: H
authors: Kong
authors: Edward B
authors: EB
authors: Leof
authors: Debabrata
authors: D
authors: Mukhopadhyay
authors: Sanjay
authors: S
authors: Misra
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001166:Arteriovenous Shunt, Surgical / Q000009:adverse effects*; D002339:Carotid Arteries / Q000601:surgery; D053148:Caspase 3 / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054338:Cell Transdifferentiation / Q000187:drug effects; D003251:Constriction, Pathologic; D004195:Disease Models, Animal; D006083:Graft Occlusion, Vascular / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006965:Hyperplasia; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007601:Jugular Veins / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D058628:Myofibroblasts / Q000187:drug effects / Q000378:metabolism; D041681:NIH 3T3 Cells; D058426:Neointima; D006435:Renal Dialysis; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D000199:Actins; C497443:Hif1a protein, mouse; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; C544013:alpha-smooth muscle actin, mouse; C467480:vascular endothelial growth factor A, mouse; D019821:Simvastatin; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
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