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.

New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes

“…They reported that simvastatin reduced neointimal hyperplasia development and increased luminal AVF diameter through mechanisms involving decreased expression of MMP-9, MMP-2, and vascular endothelial growth factor-A (VEGF-A) and reduction in smooth muscle cell activation, proliferation, and migration (20). Thus, simvastatin, if it can be delivered locally at the level of the AVF, could potentially have beneficial effects on outward AVF remodeling and neointimal hyperplasia development.…”

“…In a recent study, Misra and colleagues evaluated the role of simvastatin administered before AVF creation and its effect on AVF remodeling in a mouse AVF model (20). They reported that simvastatin reduced neointimal hyperplasia development and increased luminal AVF diameter through mechanisms involving decreased expression of MMP-9, MMP-2, and vascular endothelial growth factor-A (VEGF-A) and reduction in smooth muscle cell activation, proliferation, and migration (20).…”

Establishment of a rat autogenous arteriovenous fistula model following 5/6 nephrectomy

“…This indicates that acute decompensation may gradually transition to residual renal compensation, indicating an improved simulation of chronic renal insufficiency 28 days after surgery. It is currently considered that the important pathological changes of intimal hyperplasia are the increase of vascular smooth muscle cells and extracellular matrix (13,(25)(26)(27)(28). The present study showed that there was intimal hyperplasia of the fistula in the first week after surgery, and the pathological features included smooth muscle cell proliferation, the accumulation of collagen fibers, extensive polypoidal hyperplasia, and evident stenosis in the fourth week after surgery.…”

Hyperglycemia-Induced Modulation of the Physiognomy and Angiogenic Potential of Fibroblasts Mediated by Matrix Metalloproteinase-2: Implications for Venous Stenosis Formation Associated with Hemodialysis Vascular Access in Diabetic Milieu

“…AVFs have been used for more than 50 years and are prone to venous stenosis formation [2]. Although the exact mechanism for venous stenosis is not yet clear, several major factors have been hypothesized including hypoxia, shear stress, oxidative stress and inflammation [3,4]. As a consequence, these factors lead to an accumulation of macrophages, fibroblasts and smooth-muscle cells in the vessel wall, that lead to stenosis formation [5].…”

“…Previous results from our laboratory indicate that with a hypoxic stimulus, there is an increased expression of matrix metalloproteinase-2 (Mmp-2) accompanied by fibroblast-to-myofibroblast differentiation [10]. Moreover, inhibiting vascular endothelial growth factor-A (Vegf-A) gene expression in this model has been associated with a decrease in the differentiation of fibroblasts to myofibroblasts, which is accompanied by a reduction in the expression of Mmp-2 gene and MMP-2 protein [3]. In line with these results, the implantation of autologous blood outgrowth endothelial cells to the adventitia of the arteriovenous grafts also decreases MMP-2 protein activity, accompanied by a decrease in venous stenosis formation [11].…”