# Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure

> **NIH NIH R01** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2023 · $362,106

## Abstract

The failure of hemodialysis arteriovenous (A-V) fistulas, which are surgically created by 
anastomosing a vein to a nearby artery, remains an unmet medical problem in the field of vascular 
surgery. In fact, approximately four out of 10 newly created fistulas will require a surgical or 
intravascular salvage procedure to reach maturation and become suitable for hemodialysis. 
Arteriovenous fistulas fail because stenosis (vascular narrowing) prevents high blood 
flows through the venous limb and increases the risk for thrombosis. We recently 
discovered that stenosis occurs due to excessive medial fibrosis and increased 
extracellular protein crosslinking, and is aggravated by intimal hyperplasia (IH) in a human 
cohort of 165 patients. Therefore, our overall goals are, first, to establish the 
cause-and-effect relationship between LOX, the most important enzyme responsible for 
crosslinking, and A-V fistula failure and, second, to design new therapeutics to facilitate A-V 
fistula maturation through perivascular delivery of LOX inhibitors. Our proposal is built on strong 
scientific premises (manuscripts and unique preliminary data) that suggest a mechanistic 
relationship between postoperative upregulation of LOX in native fistulas and the improper 
wall remodeling that causes fistula failure. Specifically, our overarching hypothesis is 
that LOX activity is a major contributor in A-V fistula maturation failure. Our primary hypothesis 
is that postsurgical upregulation of nuclear LOX deaminates lysine residues in histones to disrupt 
the epigenetic landscape that secures contractile gene expression in SMCs, thereby facilitating 
their maladaptive phenotypic switch, neointima formation, and fibrosis of newly created A-V 
 fistulas. Our secondary hypothesis is that inhibition of LOX prevents inward remodeling 
in a preclinical A-V fistula model in swine. We will test our hypothesis in three 
specific aims that will: 1) identify the cellular source of LOX after A-V fistula creation, 2) 
demonstrate the impact of LOX mediated histone modifications on the SMC phenotype after fistula 
creation, and
3) demonstrate that LOX inhibitors attenuate inward remodeling, IH, and stenosis in preclinical A-V 
fistulas in swine. We will use fine microsurgical techniques in novel conditional 
knockout mice and in vitro and in situ models to successfully achieve our goals. We 
will also use a preclinical model in swine to demonstrate the efficacy and safety of 
perivascular delivery of LOX inhibitors in preventing A-V fistula failure. In conclusion, with the 
successful accomplishment of this proposal, we are paving the way for the design of new drugs and 
cell type-specific interventions to effectively target A-V fistula fibrosis and reduce vascular 
access complications.

## Key facts

- **NIH application ID:** 10605271
- **Project number:** 5R01DK121227-05
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** YAN-TING E. SHIU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $362,106
- **Award type:** 5
- **Project period:** 2019-09-17 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10605271

## Citation

> US National Institutes of Health, RePORTER application 10605271, Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure (5R01DK121227-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10605271. Licensed CC0.

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