# Mechanisms of imbalanced inward and outward arteriovenous fistula remodeling

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2020 · —

## Abstract

The inability of arteriovenous fistulas (AVFs) to mature sufficiently for adequate dialysis is a major
clinical problem confronting chronic hemodialysis. Up to 60% of newly created AVFs fail to mature, and
currently there is no effective strategy to enhance AVF maturation. AVF maturation failure results from an
imbalance between inward remodeling due to venous neointimal hyperplasia and outward remodeling due to
sustained venous dilation. Although inward remodeling has been intensively studied, the contribution of
outward remodeling to AVF maturation remains largely unexplored. Effective strategies for enhancing AVF
maturation should promote sustained venous dilation while inhibiting hyperplasia. Therefore, it is critically
important to identify therapeutic targets that modulate both processes.
 MicroRNAs (miRs) are crucial modulators in cardiovascular health and diseases, and miR-targeting
strategies have been shown to be promising diagnostics and therapeutics in these diseases. However, the role
of miRs in modulating AVF maturation has not been explored. We have generated novel results suggesting
that microRNA-92a (miR-92a), a key regulator in vascular homeostasis, is a major contributor to pathological
AVF remodeling. Accordingly, this project aims to determine the causal role of increased miR-92a in driving
AVF maturation failure, and to investigate the efficacy of miR-92a inhibition by targeted nanomedicine in
enhancing AVF maturation.
 Our over-arching hypothesis is that upregulation of endothelial miR-92a by chronic kidney disease
(CKD) and AVF-associated aberrant blood flow causes maturation failure through two mechanisms, i.e.,
impairing vasodilation (outward remodeling) and promoting neointimal hyperplasia (inward remodeling). To test
this hypothesis, we propose three Specific Aims. These aims use genetic approaches and targeted
nanotechnology to systematically determine the causal role of miR-92a in AVF maturation failure, advancing
from miR-92a in the whole body to the inflamed endothelium. Specific Aim 1 is to determine the causal role of
miR-92a in pathological AVF development in mice with CKD. We will create AVF in whole-body miR-92a
knockout and wild-type mice with CKD, and determine whether systemic knockout results in greater outward
and less inward AVF remodeling. Specific Aim 2 is to investigate whether AVF development is impaired in
transgenic mice overexpressing endothelial miR-92a. We will create AVF in mice overexpression endothelial
miR-92a and in control mice, and determine whether transgenic mice have impaired outward and exaggerated
inward AVF remodeling. Specific Aim 3 is to investigate the therapeutic potency of miR-92a inhibition by
inflamed-endothelium targeting nanomedicine in enhancing AVF development in rats with CKD. We will
determine whether nanoparticles that target inflamed ECs and contain miR-92a inhibitors can promote outward
and inhibit inward AVF remodeling in rats with CKD.
 These studies are expected t...

## Key facts

- **NIH application ID:** 9815359
- **Project number:** 5I01BX004133-02
- **Recipient organization:** VA SALT LAKE CITY HEALTHCARE SYSTEM
- **Principal Investigator:** YAN-TING E. SHIU
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-10-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815359

## Citation

> US National Institutes of Health, RePORTER application 9815359, Mechanisms of imbalanced inward and outward arteriovenous fistula remodeling (5I01BX004133-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9815359. Licensed CC0.

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