Nitric oxide releasing nanomatrix gel treatment inhibits venous intimal hyperplasia and improves vascular remodeling in a rodent arteriovenous fistula.

Vascular access is the lifeline for hemodialysis patients and the single most important component of the hemodialysis procedure. Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis patients, but nearly 60% of AVFs created fail to successfully mature due to early intimal hyperplasia development and poor outward remodeling. There are currently no therapies available to prevent AVF maturation failure. First, we showed the important regulatory role of nitric oxide (NO) on AVF development by demonstrating that intimal hyperplasia development was reduced in an overexpressed endothelial nitric oxide synthase (NOS3) mouse AVF model. This supported the rationale for the potential application of NO to the AVF. Thus, we developed a self-assembled NO releasing nanomatrix gel and applied it perivascularly at the arteriovenous anastomosis immediately following rat AVF creation to investigate its therapeutic effect on AVF development. We demonstrated that the NO releasing nanomatrix gel inhibited intimal hyperplasia formation (more than 70% reduction), as well as improved vascular outward remodeling (increased vein diameter) and hemodynamic adaptation (lower wall shear stress approaching the preoperative level and less vorticity). Therefore, direct application of the NO releasing nanomatrix gel to the AVF anastomosis immediately following AVF creation may enhance AVF development, thereby providing long-term and durable vascular access for hemodialysis.

Analysis of Geometric and Hemodynamic Profiles in Rat Arteriovenous Fistula Following PDE5A Inhibition.

Arteriovenous fistula (AVF) is essential for chronic kidney disease (CKD) patients on hemodialysis, but treatment for AVF maturation failure remains an unmet clinical need. Successful AVF remodeling occurs through sufficient lumen expansion to increase AVF blood flow and lumen area. Aberrant blood flow is thought to impair AVF remodeling, but previous literature has largely focused on hemodynamics averaged over the entire AVF or at a single location. We hypothesized that hemodynamics is heterogeneous, and thus any treatment's effect size is heterogeneous in the AVF. To test our hypothesis, we used the PDE5A inhibitor sildenafil to treat AVFs in a rat model and performed magnetic resonance imaging (MRI) based computational fluid dynamics (CFD) to generate a detailed spatial profile of hemodynamics in AVFs. 90 mg/kg of sildenafil was administered to rats in their drinking water for 14 days. On day 14 femoral AVFs were created in rats and sildenafil treatment continued for another 21 days. 21 days post-AVF creation, rats underwent non-contrast MRI for CFD and geometrical analysis. Lumen cross-sectional area (CSA) and flow rate were used to quantify AVF remodeling. Parameters used to describe aberrant blood flow include velocity magnitude, wall shear stress (WSS), oscillatory shear index (OSI), and vorticity. Geometrical parameters include arterial-venous (A-V) distance, anastomosis angle, tortuosity, and nonplanarity angle magnitude. When averaged across the entire AVF, sildenafil treated rats had significantly higher CSA, flow rate, velocity, WSS, OSI, and vorticity than control rats. To analyze heterogeneity, the vein was separated into zones: 0-5, 5-10, 10-15, and 15-20 mm from the anastomosis. In both groups: 1) CSA increased from the 0-5 to 15-20 zone; 2) velocity, WSS, and vorticity were highest in the 0-5 zone and dropped significantly thereafter; and 3) OSI increased at the 5-10 zone and then decreased gradually. Thus, the effect size of sildenafil on AVF remodeling and the relationship between hemodynamics and AVF remodeling depend on location. There was no significant difference between control and sildenafil groups for the other geometric parameters. Rats tolerated sildenafil treatment well, and our results suggest that sildenafil may be a safe and effective therapy for AVF maturation.

The geometry of arteriovenous fistulas using endothelial nitric oxide synthase mouse models.

BACKGROUND: Arteriovenous fistula (AVF) maturation failure is a significant clinical problem in the hemodialysis population. Geometric parameters of human AVFs were associated with AVF development, but causative studies are lacking. We characterized mouse AVF geometry using endothelial nitric oxide synthase (NOS3) mouse models. METHODS: Carotid-jugular AVFs were created in NOS3 overexpression (OE), knockout (KO), and wild type (WT) mice. At 7 and 21 days postcreation, black-blood magnetic resonance images of AVFs were acquired and used to build three-dimensional reconstructions of AVF lumens. We used these reconstructions to calculate the lumen area, lumen centerline, and centerline-derived parameters: anastomosis angle, tortuosity, nonplanarity angle, and location of maximal distance between the feeding artery and AVF vein. Inter- and intrauser variabilities were also determined. RESULTS: When all mice were considered, increased minimum AVF venous lumen area was accompanied by increased venous tortuosity and increased distance between the artery and vein, with both remaining in-plane with the anastomosis. At day 7, the lumen area of AVFs from all strains was 1.5- to 2.5-fold larger than native veins. Furthermore, at day 21, AVF lumen in NOS3 OE (4.04±1.43 mm2) was significantly larger than KO (2.74±1.34 mm2) (P<0.001) and WT (2.94±1.30 mm2) mice (p<0.001). At day 21, the location of maximal artery-vein distance on the vein was further away from the anastomosis in OE (4.49±0.66 mm) than KO (2.87±0.38 mm) (p=0.001). Other geometric parameters were not significantly different between mouse strains or time points. Inter- and intrauser variabilities were small, indicating the reliability and reproducibility of our protocol. CONCLUSIONS: Our study presents a detailed characterization of mouse AVF geometry, and a robust protocol for future mechanistic studies to investigate the role of molecular pathways in AVF geometry. Identifying a geometry related to desired AVF remodeling can help inform surgery to enhance AVF maturation.