Abstract
Hemodialysis vascular access can develop venous neointimal hyperplasia (VNH) causing stenosis. Recent clinical and experimental data has demonstrated that there is increased expression of a disintegrin and metalloproteinase thrombospondin motifs-1 (ADAMTS-1) at site of VNH. The experiments outlined in the present paper were designed to test the hypothesis that targeting of the adventitia of the outflow vein of murine arteriovenous fistula (AVF) using a small hairpin RNA that inhibits ADAMTS-1 expression (LV-shRNA-ADAMTS-1) at the time of fistula creation will decrease VNH. At early time points, ADAMTS-1 expression was significantly decreased associated with a reduction in vascular endothelial growth factor-A (VEGF-A) and matrix metalloproteinase-9 (MMP-9) (LV-shRNA-ADAMTS-1 transduced vessels vs. controls). These changes in gene and protein expression resulted in favorable vascular remodeling with a significant increase in mean lumen vessel area, decrease in media/adventitia area, with a significant increase in TUNEL staining accompanied with a decrease in cellular proliferation accompanied with a reduction in CD68 staining. Collectively, these results demonstrate that ADAMTS-1 transduced vessels of the outflow vein of AVF have positive vascular remodeling.
Highlights
There are more than 400,000 patients in the United States who require hemodialysis because of end-stage renal disease (ESRD) [1]
In a murine model of arteriovenous fistula (AVF) with CKD, a significant increase in ADAMTS-1 expression was demonstrated at the outflow vein when compared to controls [7]
ADAMTS-1 expression was reduced using a LV-small hairpin RNA (shRNA)-ADAMTS-1 administered to the adventitia of the outflow vein at the time of AVF placement
Summary
There are more than 400,000 patients in the United States who require hemodialysis because of end-stage renal disease (ESRD) [1]. A well-functioning vascular access is required for optimal hemodialysis to occur. Current recommendations by National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) for hemodialysis vascular access are that patients whom require long-term dialysis have an arteriovenous fistula (AVF). It is estimated that at one year patency of AVF’s is 62%. AVFs fail because of venous stenosis formation which is caused by venous neointimal hyperplasia (VNH) [4]. Treatment of stenosis to maintain the function of hemodialysis AVFs and grafts costs over one billion dollars annually [1]. Developing therapies that could be used to reduce AVF stenosis would be advantageous to ESRD patients
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