Kidney Week

Abstract: TH-PO748

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

Session Information

• Hemodialysis: Vascular Access - I
  November 02, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Dialysis

• 603 Hemodialysis: Vascular Access

Authors

• Hernandez, Diana Rosa, University of Miami Miller School of Medicine, Miami, Florida, United States

Diana Rosa Hernandez,

• Wei, Yuntao, University of Miami Miller School of Medicine, Miami, Florida, United States

Yuntao Wei,

• Andreopoulos, Fotios M, University of Miami, Miami, Florida, United States

Fotios M Andreopoulos,

• Martinez, Laisel, University of Miami Miller School of Medicine, Miami, Florida, United States

Laisel Martinez,

• Salman, Loay H., Albany Medical College, Albany, New York, United States

Loay H. Salman,

• Vazquez-Padron, Roberto I., University of Miami Miller School of Medicine, Miami, Florida, United States

Roberto I. Vazquez-Padron,

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 37^oC 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 (E_inc) (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