Abstract: TH-PO748

Decreased Collagen Cross-Linking Improves the Biomechanical Performance of Experimental Arteriovenous Fistulas

Session Information

Category: Dialysis

  • 603 Hemodialysis: Vascular Access

Authors

  • Hernandez, Diana Rosa, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Wei, Yuntao, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Andreopoulos, Fotios M, University of Miami, Miami, Florida, United States
  • Martinez, Laisel, University of Miami Miller School of Medicine, Miami, Florida, United States
  • Salman, Loay H., Albany Medical College, Albany, New York, United States
  • Vazquez-Padron, Roberto I., University of Miami Miller School of Medicine, Miami, Florida, United States
Background

The role of lysyl oxidase (LOX) in arteriovenous fistula (AVF) remodeling has never been studied. As the enzyme that catalyzes the cross-linking of collagen and elastin precursors in the vascular wall, a deficiency in LOX activity may impair wall integrity while excessive activity may lead to stiffness and favor occlusive stenosis. This study hypothesizes that local or systemic inhibition of LOX with β-aminopropionitrile (BAPN) prevents excessive cross-linking of collagen and other extracellular matrix (ECM) proteins and improves the biomechanical performance of experimental AVFs.

Methods

Surrogate indicators of vascular remodeling included fibrosis (% area of collagen) by Masson's trichrome staining, and gene expression of ECM proteins by RT-PCR. Biomechanical properties were evaluated by pressure myography.

Results

We first demonstrated that gene expression of LOX, but not of LOX-like enzymes (LOXL1-4), was significantly upregulated in a rat AVF model created by anastomosing the left epigastric vein to the nearby femoral artery. Systemic administration of BAPN (100 mg/kg, ip) decreased collagen deposition in treated versus control AVFs (p=0.013). In addition, BAPN treatment upregulated the elastin and fibronectin genes in the fistula wall. Next, we electro-spun a PLGA/BAPN (15:1.5) scaffold to locally deliver the drug around the juxta-anastomotic area of experimental AVFs for 21 days post-op. In vitro, BAPN release from the scaffold was almost complete within 7 days, while it took 60 days at 37oC for the scaffold to be fully degraded. Local delivery of BAPN to experimental AVFs improved vascular remodeling by decreasing fibrosis, compared to AVFs wrapped with scaffold alone (n=6 per group, p=0.043). Furthermore, local delivery of BAPN increased distensibility and decreased the incremental elastic modulus (Einc) (4.93 ± 0.85 vs. 2.22 ± 0.39 x 106 dynes cm-2, p=0.019) as determined by pressure myography.

Conclusion

In conclusion, we have demonstrated that inhibition of LOX mediated cross-linking with BAPN significantly improved vascular compliance and the biomechanical properties of experimental AVFs.

Funding

  • NIDDK Support