Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia
نویسندگان
چکیده
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.
منابع مشابه
From Genome Wide Association Study to arterial wall protection: homoarginine effect on intimal hyperplasia in balloon-injured rat carotids
متن کامل
Intimal Hyperplasia in Loop-Injured Carotid Arteries Is Attenuated in Transglutaminase 2-Null Mice
Arterial restenosis frequently develops after open or endovascular surgery due to intimal hyperplasia. Since tissue transglutaminase (TG2) is known to involve in fibrosis, wound healing, and extracellular matrix remodeling, we examined the role of TG2 in the process of intimal hyperplasia using TG2-null mice. The neointimal formation was compared between TG2-null and wild-type (C57BL/6) mice by...
متن کاملRole of stromal-derived factor-1<alpha>/CXCR4 in neo-intimal repair
Neo-intimal hyperplasia is one of the major causes of restenosis in which stromal cell-derived factor-1 (SDF-1α) and its receptor CXCR4 play an important role. In a rat common carotid artery balloon injury model, the number of CD34(+)CXCR4(+) cells was significantly increased immediately after injury (p < 0.01), followed by a gradual decrease to baseline seven days after the injury. Furt...
متن کاملArterial enlargement, tortuosity, and intimal thickening in response to sequential exposure to high and low wall shear stress.
We investigated the effects of sequential and prolonged exposure to high and low wall shear stress on arterial remodeling using a rabbit arteriovenous fistula (AVF) model. Blood flow was increased by approximately 17-fold to 20-fold when the AVF was open, and returned to normal when the AVF was occluded. Repeated opening and closing of the AVF resulted in sequential exposure of the artery to hi...
متن کاملCCR2 deficiency decreases intimal hyperplasia after arterial injury.
Monocyte chemoattractant protein (MCP)-1 is upregulated in atherosclerotic plaques and in the media and intima of injured arteries. CC chemokine receptor 2 (CCR2) is the only known functional receptor for MCP-1. Mice deficient in MCP-1 or CCR2 have marked reductions in atherosclerosis. This study examines the effect of CCR2 deficiency in a murine model of femoral arterial injury. Four weeks aft...
متن کامل