Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia. (17th July 2016)

• Record Type: Journal Article
• Authors: Shi, Xudong; Guo, Lian-Wang; Seedial, Stephen; Takayama, Toshio; Wang, Bowen; Zhang, Mengxue; Franco, Sarah R.; Si, Yi; Chaudhary, Mirnal A; Liu, Bo; Kent, K. Craig
• Is Part Of: Stem cells. Volume 34:Number 11(2016:Nov.)
• Page Start: 2744
• Page End: 2757
• Publication Date: 2016-07-17
• Subjects: CXCR4/SDF-1α -- TGFβ/Smad3 -- smooth muscle cell migration -- smooth muscle cell specific CXCR4 knockout -- intimal hyperplasia; Cloning -- Periodicals; Clone cells -- Periodicals; Stem cells -- Periodicals; Cell Differentiation -- Periodicals; Cell Division -- Periodicals; Clone Cells -- Periodicals; Hematopoietic Stem Cells -- Periodicals; Stem Cells -- Periodicals; 571.84
• DOI: 10.1002/stem.2442
• Languages: English
• ISSNs: 1066-5099

Abstract

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. Abstract : A schematic model showing transforming growth factor-β/Smad3-stimulated CXCR4 expression in the vascular smooth muscle cell and its signaling activated by the stromal cell-derived factor α ligand.