Osteopontin mediation of disturbed flow–induced endothelial mesenchymal transition through CD44 is a novel mechanism of neointimal hyperplasia in arteriovenous fistulae for hemodialysis access

Chi Jen Chang, Ying Ju Lai, Ying Chang Tung, Lung Sheng Wu, Lung An Hsu, Chi Nan Tseng, Gwo Jyh Chang, Kai Chien Yang, Yung Hsin Yeh*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

11 Scopus citations

Abstract

In dysfunctional arteriovenous fistulae (AVF) for hemodialysis access, neointimal hyperplasia (NH) is prone to occur in the region exposed to disturbed flow. We hypothesized that disturbed flow contributes to NH in AVF by inducing endothelial mesenchymal transition (EndMT) through activation of the osteopontin/CD44 axis. In rats with aortocaval fistula, a rodent model of AVF, we demonstrated development of EndMT and expression of osteopontin and CD44 specifically in the vicinity of the arteriovenous junction using immunostaining. Duplex scan confirmed this region was exposed to a disturbed flow. A mixed ultrastructural phenotype of endothelium and smooth muscle cells was found in luminal endothelial cells of the arteriovenous junction by electron microscopy ascertaining the presence of EndMT. Endothelial lineage tracing using Cdh5-Cre/ERT2;ROSA26-tdTomato transgenic mice showed that EndMT was involved in NH of AVF since the early stage and that the endothelial-derived cells contributed to 24% of neointimal cells. In human umbilical vein endothelial cells (HUVECs) in culture, osteopontin treatment induced EndMT, which was suppressed by CD44 knockdown. Exposure to low oscillatory wall shear stress using a parallel-plate system induced EndMT in HUVECs, also suppressed by osteopontin or CD44 knockdown. In AVF of CD44 knockout mice, EndMT was mitigated and NH decreased by 35% compared to that in wild-type mice. In dysfunctional AVF of patients with uremia, expressions of osteopontin, CD44, and mesenchymal markers in endothelial cells overlying the neointima was also found by immunostaining. Thus, the osteopontin/CD44 axis regulates disturbed flow-induced EndMT, plays an important role in neointimal hyperplasia of AVF, and may act as a potential therapeutic target to prevent AVF dysfunction.

Original languageEnglish
Pages (from-to)702-718
Number of pages17
JournalKidney International
Volume103
Issue number4
DOIs
StatePublished - 04 2023

Bibliographical note

Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Keywords

  • CD44
  • arteriovenous fistula
  • disturbed flow
  • endothelial mesenchymal transition
  • osteopontin
  • Endothelium/metabolism
  • Hyaluronan Receptors/genetics
  • Humans
  • Osteopontin/genetics
  • Hyperplasia/pathology
  • Rats
  • Neointima/pathology
  • Animals
  • Renal Dialysis/adverse effects
  • Human Umbilical Vein Endothelial Cells/metabolism
  • Mice

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