title: Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia.
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.
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Xudong
authors.initials: X
authors.lastname: Shi
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Lian-Wang
authors.initials: LW
authors.lastname: Guo
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Seedial
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Toshio
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Bowen
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Mengxue
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Sarah R
authors.initials: SR
authors.lastname: Franco
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Si
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Mirnal A
authors.initials: MA
authors.lastname: Chaudhary
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
authors.forename: K Craig
authors.initials: KC
authors.lastname: Kent
mesh_terms: D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement; D005786:Gene Expression Regulation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D058426:Neointima / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology; D017539:Tunica Intima / Q000293:injuries / Q000378:metabolism*
chemical_list: C514936:CXCR4 protein, mouse; D008840:Microfilament Proteins; D009124:Muscle Proteins; D019718:Receptors, CXCR4; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C058992:Tagln protein, mouse; D016212:Transforming Growth Factor beta; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: CXCR4/SDF-1α; TGFβ/Smad3; intimal hyperplasia; smooth muscle cell migration; smooth muscle cell specific CXCR4 knockout