Simvastatin reduces venous stenosis formation in a murine hemodialysis vascular access model

Rajiv Janardhanan, Binxia Yang, Pawan Vohra, Bhaskar Roy, Sarah Withers, Santanu Bhattacharya, Jayawant Mandrekar, Hyunjoon Kong, Edward B Leof, Debabrata Mukhopadhyay, Sanjay Misra

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)338-352
Number of pages15
JournalKidney International
Volume84
Issue number2
DOIs
StatePublished - Aug 2013

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Simvastatin
Matrix Metalloproteinase 9
Hyperplasia
Blood Vessels
Renal Dialysis
Pathologic Constriction
Vascular Endothelial Growth Factor A
Myofibroblasts
Fibroblasts
Fistula
Cell Proliferation
Staining and Labeling
Gene Expression
Adventitia
DNA Nucleotidylexotransferase
Matrix Metalloproteinase 2
Jugular Veins
Arteriovenous Fistula
Carotid Arteries
Caspase 3

Keywords

  • Arteriovenous fistula
  • Chronic kidney disease
  • Murine model
  • Restenosis
  • Veins

ASJC Scopus subject areas

  • Nephrology

Cite this

Simvastatin reduces venous stenosis formation in a murine hemodialysis vascular access model. / Janardhanan, Rajiv; Yang, Binxia; Vohra, Pawan; Roy, Bhaskar; Withers, Sarah; Bhattacharya, Santanu; Mandrekar, Jayawant; Kong, Hyunjoon; Leof, Edward B; Mukhopadhyay, Debabrata; Misra, Sanjay.

In: Kidney International, Vol. 84, No. 2, 08.2013, p. 338-352.

Research output: Contribution to journalArticle

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