Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia

Xudong Shi*, Lian Wang Guo, Stephen Seedial, Toshio Takayama, Bowen Wang, Mengxue Zhang, Sarah R. Franco, Yi Si, Mirnal A. Chaudhary, Bo Liu, K. Craig Kent

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

CXCR4 is a stem/progenitor cell surface receptor specific for the cytokine stromal cell-derived factor-1 (SDF-1α). There is evidence that bone marrow-derived CXCR4-expressing cells contribute to intimal hyperplasia (IH) by homing to the arterial subintima which is enriched with SDF-1α. We have previously found that transforming growth factor-β (TGFβ) and its signaling protein Smad3 are both upregulated following arterial injury and that TGFβ/Smad3 enhances the expression of CXCR4 in vascular smooth muscle cells (SMCs). It remains unknown, however, whether locally induced CXCR4 expression in SM22 expressing vascular SMCs plays a role in neointima formation. Here, we investigated whether elevated TGFβ/Smad3 signaling leads to the induction of CXCR4 expression locally in the injured arterial wall, thereby contributing to IH. We found prominent CXCR4 upregulation (mRNA, 60-fold; protein, 4-fold) in TGFβ-treated, Smad3-expressing SMCs. Chromatin immunoprecipitation assays revealed a specific association of the transcription factor Smad3 with the CXCR4 promoter. TGFβ/Smad3 treatment also markedly enhanced SDF-1α-induced ERK1/2 phosphorylation as well as SMC migration in a CXCR4-dependent manner. Adenoviral expression of Smad3 in balloon-injured rat carotid arteries increased local CXCR4 levels and enhanced IH, whereas SMC-specific depletion of CXCR4 in the wire-injured mouse femoral arterial wall produced a 60% reduction in IH. Our results provide the first evidence that upregulation of TGFβ/Smad3 in injured arteries induces local SMC CXCR4 expression and cell migration, and consequently IH. The Smad3/CXCR4 pathway may provide a potential target for therapeutic interventions to prevent restenosis. Stem Cells 2016;34:2744–2757.

Original languageEnglish
Pages (from-to)2744-2757
Number of pages14
JournalStem Cells
Volume34
Issue number11
DOIs
StatePublished - 1 Nov 2016
Externally publishedYes

Keywords

  • CXCR4/SDF-1α
  • TGFβ/Smad3
  • intimal hyperplasia
  • smooth muscle cell migration
  • smooth muscle cell specific CXCR4 knockout

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