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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-1?). 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-1?. We have previously found that transforming growth factor-? (TGF?) and its signaling protein Smad3 are both upregulated following arterial injury and that TGF?/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 TGF?/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 TGF?-treated, Smad3-expressing SMCs. Chromatin immunoprecipitation assays revealed a specific association of the transcription factor Smad3 with the CXCR4 promoter. TGF?/Smad3 treatment also markedly enhanced SDF-1?-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 TGF?/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.

SUBMITTER: Shi X

PROVIDER: S-EPMC5113668 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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

Shi Xudong X Guo Lian-Wang LW Seedial Stephen S Takayama Toshio T Wang Bowen B Zhang Mengxue M Franco Sarah R SR Si Yi Y Chaudhary Mirnal A MA Liu Bo B Kent K Craig KC

Stem cells (Dayton, Ohio) 20160717 11

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 smo ...[more]

PMID: 27340942

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Project description:BACKGROUND AND OBJECTIVES:Preoperative arterial function is associated with arteriovenous fistula (AVF) development. Because arterial pathology may correlate with its function, preexisting arterial intimal hyperplasia may be associated with AVF development. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Vascular specimens obtained from 125 patients (with minimal 2 mm arterial diameter and 2.5 mm venous diameter) undergoing AVF creation were quantified for arterial intimal hyperplasia, arterial medial fibrosis, arterial microcalcification, and venous intimal hyperplasia. A 6-week postoperative ultrasound quantified AVF diameter, blood flow, and stenosis. Clinical AVF maturation was assessed using a predefined protocol. In a prospective cohort study design, we investigated the association of preexisting arterial intimal hyperplasia with the postoperative AVF diameter, blood flow, stenosis, and clinical maturation failure, after controlling for baseline demographics, comorbidities, and preoperative vein diameter. Additional analyses evaluated whether other vascular pathologies interacted with arterial intimal hyperplasia in affecting AVF outcomes. RESULTS:The median intimal thickness of the native artery was 22.0 μm (interquartile range, 14.8-37.1 μm). The median postoperative AVF diameter was 4.8 (interquartile range, 3.7-6.8) mm, blood flow was 796 (interquartile range, 413-1036) ml/min, and stenosis was present in 37 out of 98 patients with ultrasound data (38%). AVF nonmaturation occurred in 37 out of 125 patients (30%). Preexisting arterial intimal thickness was not significantly associated with AVF blood flow (-12 ml/min; 95% confidence interval [95% CI], -55 to 30 ml/min), diameter (-0.04 mm; 95% CI, -0.21 to 0.14 mm), stenosis (odds ratio, 0.93; 95% CI, 0.75 to 1.14), or clinical maturation failure (odds ratio, 1.07; 95% CI, 0.90 to 1.28), all per 10 μm increase. There was no significant interaction of preexisting arterial intimal thickness and postoperative AVF outcomes with arterial medial fibrosis, arterial microcalcification, or venous intimal hyperplasia. CONCLUSIONS:Preexisting arterial intimal hyperplasia is not associated with the 6-week AVF blood flow, diameter or stenosis, or clinical maturation when the preoperative arterial diameter is ≥2 mm.

Dataset Information

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

Publications

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

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