Abstract: FR-OR089
Lysyl Oxidase Determines Postoperative Vascular Stiffness and Neointimal Formation after Arteriovenous Fistula Creation
Session Information
- Improving Vascular Access Outcomes
October 26, 2018 | Location: 6B, San Diego Convention Center
Abstract Time: 04:42 PM - 04:54 PM
Category: Dialysis
- 704 Dialysis: Vascular Access
Authors
- Hernandez, Diana Rosa, University of Miami, Miller School of Medicine, Miami, Florida, United States
- Martinez, Laisel, University of Miami, Miller School of Medicine, Miami, Florida, United States
- Tabbara, Marwan, University of Miami, Miller School of Medicine, Miami, Florida, United States
- Duque Ballesteros, Juan Camilo, 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 transformation of a vein to a fistula is one of the most intriguing processes in vascular biology. The desired scenario is that the fistula matures becoming a larger vessel with increased luminal area and a thicker wall. Unfortunately, arteriovenous fistulas (AVFs) frequently fail (~40%) because venous stenosis compromises blood flow. Lysyl oxidase (LOX) is the main enzyme that catalyzes the oxidative deamination of lysine/hydroxylysine residues (ε-amino groups) in proteins to facilitate spontaneous intra/intermolecular covalent crosslinks formation. The most recognized substrate of LOX is collagen. In fact, collagen tensile strength relies upon LOX mediated crosslinking. LOX is critical for vascular and connective tissue formation; however, deregulated LOX increases collagen stiffness and prevents its degradation, thereby contributing to fibrosis.
Methods
Herein, our goal was to demonstrate that upregulated LOX in the venous limb of the AVF mediates improper remodeling, which causes stenosis and failure.
Results
We first demonstrated that immature and mature collagen crosslinks (using UPLC-ESI-MS/MS) were more abundant in failed human AVFs than in fistulas that matured successfully (N=10/group, p< 0.05). Increased crosslinking correlated with vascular accumulation of LOX as determined by immunohistochemistry. Interestingly, LOX appeared in the interstitial space and in the nuclei of smooth muscle cells (SMCs) and neointimal cells, in agreement with prior reports detecting LOX within the nuclei of cultured fibroblasts. The nuclear location of LOX in SMCs was further demonstrated using cell fractioning techniques. The LOX inhibitor β-aminoproprionitrile (BAPN) decreased SMC growth in culture, which suggests a potential role of this enzyme in the postoperative expansion of the intima. Finally, we demonstrated that systemic and local inhibition of LOX with BAPN increases blood flow and elasticity, and prevents medial fibrosis and intimal hyperplasia in a rat model of AVF.
Conclusion
In conclusion, these data indicate, for the first time, the importance of LOX-mediated crosslinking in AVF failure and the potential role of this enzyme not only in vascular stiffness but also in the control of SMC fate and growth.
Funding
- NIDDK Support