# Manipulating the matrix to improve arteriovenous fistula patency

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $751,004

## Abstract

The preferred vascular access for hemodialysis uses an arteriovenous fistula (AVF) to increase blood
flow through a vein. Successful adaptation of the venous conduit to the arterial-like fistula environment requires
remodeling of the vein wall without excessive wall thickening, enabling mechanical strength to resist
hemodialysis procedures that puncture the AVF wall with large bore needles 3 times a week. 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 fistula environment. This knowledge gap creates an unmet need for novel
approaches to enhance venous remodeling and thereby increase successful clinical use of venous conduits.
 During the funding period, we used an innovative mouse AVF model to show that TGF-β signaling
regulates venous adaptive remodeling to improve AVF patency; activation of both the smad2/3 (canonical) and
tak1 (noncanonical) pathways regulate venous remodeling; and endothelial cell-targeted TGF-β inhibition
regulates both collagen density and smooth muscle cell proliferation to improve AVF patency. We present
exciting new data that: 1) expression of the matricellular protein tenascin-C (TnC) is greatly increased and
colocalizes with the remodeling venous wall; 2) TnC regulates AVF patency and TGF-β signaling during
venous remodeling; 3) TnC expression is not downregulated in failed AVF; and 4) TnC knockout mice have
altered proportions of immune cells in the AVF wall. In addition, we have developed the mouse model further to
incorporate chronic kidney disease (CKD) via 5/6-nephrectomy and these AVF faithfully recapitulate human
AVF maturation. We hypothesize that modulating tenascin-C activity will alter venous remodeling, thereby
improving AVF maturation and patency. We will use our translationally relevant in vivo model, an innovative
tool using nanoparticles for local drug delivery, innovative methodology to analyze the cell composition within
the AVF wall, as well as advanced next-generation analyses using transcriptomics techniques that are
available at Yale, to test our innovative hypothesis with the following specific aims:
Aim I: Determine sex differences in TnC expression during human AVF remodeling in vivo. Aim II: Determine
whether TnC function mediates venous remodeling in mice with CKD. Aim III: Determine whether regulation of
immune cells is a mechanism of TnC-mediated venous remodeling.
 A successful outcome of this investigation will have lasting impact by establishing whether TnC
mediates venous remodeling, and thus whether regulating TnC activity is a valuable strategy for clinical
translation to enhance AVF maturation. We will also determine whether reduced AVF maturation in women is
due to sex differences in TnC function as well as in inflammation and/or immunity. We use an innovative
strategy and novel tools an...

## Key facts

- **NIH application ID:** 10648012
- **Project number:** 2R01HL144476-05A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Alan Dardik
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $751,004
- **Award type:** 2
- **Project period:** 2019-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10648012

## Citation

> US National Institutes of Health, RePORTER application 10648012, Manipulating the matrix to improve arteriovenous fistula patency (2R01HL144476-05A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10648012. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*