Smooth muscle nitric oxide responsiveness predicts clinical maturation of hemodialysis fistulae

Abstract

The arteriovenous fistula is the preferred type of hemodialysis vascular access for patients with end‐stage renal disease, but 50% of newly created fistulas fail to mature adequately for use. Stenosis due to neointimal hyperplasia is present in a large proportion of fistulae with maturation failure suggesting that local mechanisms controlling vascular smooth muscle cell (SMC) migration are important contributors to maturation failure. Our objective is to manipulate local factors present in the vein at the time of fistula surgery in order to prevent maturation failure. Using SMC explants from vein tissue obtained at the time of fistula creation from patients enrolled in the NIH Hemodialysis Fistula Maturation Study, we find that among patients with subsequent fistula maturation failure, •NO inhibits SMC migration significantly less. Using strategies initially developed in animal models, we find that impaired •NO inhibition is associated with oxidation of the calcium regulatory protein, sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), and can be reversed by overexpressing SERCA or by down‐regulating Nox4 NADPH oxidase. Our data suggest that SMC •NO responsiveness may be predictive of fistula maturation outcome and that therapeutic restoration of •NO responsiveness through manipulation of local factors may prevent fistula maturation failure.Funding: R21DK084390 and R01 HL31607