# Manipulating the matrix to improve arteriovenous fistula patency

> **NIH NIH R01** · YALE UNIVERSITY · 2020 · $655,201

## Abstract

Project Summary
 A cornerstone of several common therapies for human diseases is the use of a vein as a conduit to
increase blood flow such as the arteriovenous fistula (AVF), the preferred access for hemodialysis. However,
the poor maturation and patency of AVF, especially in women and requiring additional re-do procedures and
surgery, reflects our imperfect understanding of the biology of venous remodeling that leads to successful
venous adaptation to the arterial environment. This knowledge gap creates an unmet need for novel
approaches to enhance venous remodeling and thereby to increase successful clinical use of venous conduits.
 Successful venous remodeling requires deposition of extracellular matrix (ECM), enabling mechanical
strength to resist hemodialysis procedures that puncture the AVF wall with large bore needles 3 times a week.
Transforming growth factor (TGF)-β1 regulates numerous cellular functions, including ECM deposition and
remodeling. We present exciting new data that: 1) our innovative mouse model of AVF faithfully recapitulates
human AVF maturation including an ~1/3 failure rate; 2) female mice with AVF have diminished magnitudes of
shear stress compared to male mice; 3) we can manipulate TGF-β1 function in vivo and TGF-β1 is required for
successful early AVF remodeling; 4) in failed mouse AVF there is increased ECM, late TGF-β1 expression
and smad2/tak1 phosphorylation; 5) there is increased smad2/tak1 phosphorylation in human AVF surgically
removed for failure; 6) we developed an innovative nanoparticle tool to manipulate TGF-β1 signaling in vivo.
 Our data suggest that surgical creation of a fistula stimulates early TGF-β1 activation via smad2/3
and/or tak1 phosphorylation that is critical for successful early venous adaptation and AVF maturation. We
hypothesize that exuberant late TGF-β1 activity results in excessive ECM deposition and neointimal
hyperplasia causing AVF failure. Reducing late TGF-β1 activity should reduce ECM deposition and neointimal
hyperplasia, thereby improving AVF patency. We will use our innovative in vivo model, as well as a novel
bioreactor and molecular tools, to test our hypothesis with the following specific aims:
Aim I: Determine whether there are sex differences in TGF-β signaling in vitro and AVF remodeling in vivo.
Aim II: Determine optimal delivery to reduce late TGF-β1 signaling thereby enhancing venous adaptation and
improving AVF patency.
Aim III: Determine whether smad2 or tak1 function is a mechanism of TGFβ1-mediated AVF remodeling.
 This work will have lasting impact by establishing whether excessive TGF-β activity leads to AVF
failure, and whether reducing late TGF-β activity is a valuable strategy for clinical translation to enhance AVF
patency. We will also determine whether the reduced AVF maturation in women is due to insufficient venous
remodeling or increased neointimal hyperplasia. We use an innovative strategy and novel tools to manipulate
TGF-β signaling to alter vessel ...

## Key facts

- **NIH application ID:** 10001593
- **Project number:** 5R01HL144476-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Alan Dardik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $655,201
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10001593

## Citation

> US National Institutes of Health, RePORTER application 10001593, Manipulating the matrix to improve arteriovenous fistula patency (5R01HL144476-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10001593. Licensed CC0.

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