Abstract: SA-OR019
Arteriovenous Fistula Under LOXdown: Halting Fibrotic Remodeling to Prevent Failure
Session Information
- Dialysis Vascular Access: From Basic Discovery to Translational Science
November 08, 2025 | Location: Room 342D, Convention Center
Abstract Time: 04:30 PM - 04:40 PM
Category: Dialysis
- 803 Dialysis: Vascular Access
Authors
- Stoyell-Conti, Filipe F., University of Miami, Miami, Florida, United States
- Martinez, Laisel, University of Miami, Miami, Florida, United States
- Santos, Nieves, University of Miami, Miami, Florida, United States
- Wei, Yuntao, University of Miami, Miami, Florida, United States
- Vazquez-Padron, Roberto I., University of Miami, Miami, Florida, United States
Background
Arteriovenous fistulas (AVFs) remain the preferred vascular access for hemodialysis in end-stage renal disease (ESRD) patients. However, a high rate of maturation failure persists, primarily due to inward (flow-restrictive) remodeling of the vein. This study investigates the cellular and molecular mechanisms underlying this maladaptive remodeling, with a focus on lysyl oxidase (LOX), a pro-fibrotic enzyme that catalyzes collagen and elastin crosslinking.
Methods
We performed bulk RNA sequencing and single-cell transcriptomic profiling of jugular vein-to-carotid AVFs from 5/6 nephrectomized mice. Loss-of-function studies were conducted using conditional Lox knockout mice.
Results
Bulk RNA-seq at day 3 post-anastomosis revealed early upregulation of leukocyte activation genes (Cd44, Itgam) and downregulation of vascular smooth muscle contraction markers (Myh11, Cnn1, Tagln). By days 10 and 21, extracellular matrix (ECM) remodeling genes including Lox, Fn1, and Eln were significantly upregulated. scRNA-seq showed increased infiltration of myeloid cells, particularly pro-fibrotic macrophages expressing Spp1 and Lgals3. Initially, 82% of fibroblasts were quiescent, with only 4.7% showing activation (Fap, Postn, Acta2); by day 7, activated fibroblasts expanded to ~50% of the population and emerged as the principal source of Lox expression. Transcription factor analysis implicated Smad3 as a key regulator of Lox and other matrix-related genes downstream of macrophage-derived TGFβ signaling. Genetic inactivation of Lox in Loxf/f CAG-CreERT2;ApoE−/− mice following tamoxifen administration resulted in significantly larger AVF lumens compared to vehicle-treated controls (Wall-Lumen Ratio, Oil: 2.32±0.17 vs. TAM: 1.78±0.09).
Conclusion
AVF creation triggers robust ECM remodeling mediated by pro-fibrotic macrophages and fibroblast activation through TGFβ/Smad3 signaling. LOX plays a central role in this maladaptive process. Genetic inactivation of LOX improves vascular remodeling and may represent a promising therapeutic strategy to prevent AVF failure.
Funding
- NIDDK Support