Nirvana Sadaghianloo1, Kota Yamamoto2, Hualong Bai3, Masayuki Tsuneki4, Clinton D Protack5, Michael R Hall5, Serge Declemy6, Réda Hassen-Khodja6, Joseph Madri7, Alan Dardik8. 1. Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Vascular Surgery, University Hospital of Nice-Sophia Antipolis, Nice, France. Electronic address: sadaghianloo.n@chu-nice.fr. 2. Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Surgery, Yale University School of Medicine, New Haven, CT; Division of Vascular Surgery, Department of Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. 3. Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Vascular Surgery, First Affiliated Hospital of Zhengzhou University, Henan, China. 4. National Cancer Center Research Institute, Tokyo, Japan; Department of Pathology, Yale University School of Medicine, New Haven, CT. 5. Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Surgery, Yale University School of Medicine, New Haven, CT. 6. Department of Vascular Surgery, University Hospital of Nice-Sophia Antipolis, Nice, France. 7. Department of Pathology, Yale University School of Medicine, New Haven, CT. 8. Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT; Department of Surgery, Yale University School of Medicine, New Haven, CT; Veterans Affairs Connecticut Healthcare Systems, West Haven, CT.
Abstract
BACKGROUND: The poor clinical results that are frequently reported for arteriovenous fistulae (AVF) for hemodialysis are typically due to failure of AVF maturation. We hypothesized that early AVF maturation is associated with generation of reactive oxygen species and activation of the hypoxia-inducible factor-1 (HIF-1) pathway, potentially promoting neointimal hyperplasia. We tested this hypothesis using a previously reported mouse AVF model that recapitulates human AVF maturation. METHODS: Aortocaval fistulae were created in C57Bl/6 mice and compared with sham-operated mice. AVFs or inferior vena cavas were analyzed using a microarray, Amplex Red for extracellular H2O2, quantitative polymerase chain reaction, immunohistochemistry, and immunoblotting for HIF-1α and immunofluorescence for NOX-2, nitrotyrosine, heme oxygenase-1 (HO-1), and vascular endothelial growth factor (VEGF)-A. RESULTS: Oxidative stress was higher in AVF than that in control veins, with more H2O2 (P = 0.007) and enhanced nitrotyrosine immunostaining (P = 0.005). Immunohistochemistry and immunoblot showed increased HIF-1α immunoreactivity in the AVF endothelium; HIF-1 targets NOX-2, HO-1 and VEGF-A were overexpressed in the AVF (P < 0.01). AVF expressed increased numbers of HIF-1α (P < 0.0001) and HO-1 (P < 0.0001) messenger RNA transcripts. CONCLUSIONS: Oxidative stress increases in mouse AVF during early maturation, with increased expression of HIF-1α and its target genes NOX-2, HO-1, and VEGF-A. These results suggest that clinical strategies to improve AVF maturation could target the HIF-1 pathway. Published by Elsevier Inc.
BACKGROUND: The poor clinical results that are frequently reported for arteriovenous fistulae (AVF) for hemodialysis are typically due to failure of AVF maturation. We hypothesized that early AVF maturation is associated with generation of reactive oxygen species and activation of the hypoxia-inducible factor-1 (HIF-1) pathway, potentially promoting neointimal hyperplasia. We tested this hypothesis using a previously reported mouse AVF model that recapitulates human AVF maturation. METHODS: Aortocaval fistulae were created in C57Bl/6 mice and compared with sham-operated mice. AVFs or inferior vena cavas were analyzed using a microarray, Amplex Red for extracellular H2O2, quantitative polymerase chain reaction, immunohistochemistry, and immunoblotting for HIF-1α and immunofluorescence for NOX-2, nitrotyrosine, heme oxygenase-1 (HO-1), and vascular endothelial growth factor (VEGF)-A. RESULTS: Oxidative stress was higher in AVF than that in control veins, with more H2O2 (P = 0.007) and enhanced nitrotyrosine immunostaining (P = 0.005). Immunohistochemistry and immunoblot showed increased HIF-1α immunoreactivity in the AVF endothelium; HIF-1 targets NOX-2, HO-1 and VEGF-A were overexpressed in the AVF (P < 0.01). AVF expressed increased numbers of HIF-1α (P < 0.0001) and HO-1 (P < 0.0001) messenger RNA transcripts. CONCLUSIONS: Oxidative stress increases in mouse AVF during early maturation, with increased expression of HIF-1α and its target genes NOX-2, HO-1, and VEGF-A. These results suggest that clinical strategies to improve AVF maturation could target the HIF-1 pathway. Published by Elsevier Inc.
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