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Angiogenic Remodeling in Pediatric EoE Is Associated With Increased Levels of VEGF-A, Angiogenin, IL-8, and Activation of the TNF-α–NFκB Pathway

Persad, Rabindranath*; Huynh, Hien Q.*; Hao, Li*; Ha, Jacqueline R.*; Sergi, Consolato; Srivastava, Rahul*; Persad, Sujata*

Journal of Pediatric Gastroenterology & Nutrition: September 2012 - Volume 55 - Issue 3 - p 251–260
doi: 10.1097/MPG.0b013e31824b6391

Objectives: Eosinophilic esophagitis (EoE) is a clinicopathologic diagnosis characterized by inflammation and infiltration of eosinophils at the esophageal mucosa. The underlying etiology of EoE remains elusive. Inflammatory diseases, such as asthma, are associated with structural remodeling of the airways, which includes angiogenesis. The aims of this study were to determine the angiogenic profile of esophageal mucosa in children presenting with EoE and to evaluate the putative mechanism(s) underlying the early inflammatory angiogenic response observed in EoE.

Methods: Endoscopically obtained biopsy samples from 18 EoE and 18 control pediatric patients were analyzed for angiogenic markers (CD31, von Willebrand factor, vascular cell adhesion molecule-1) and tissue levels of angiogenic factors (vascular endothelial growth factor [VEGF]-A, VEGF-R2, angiogenin and interleukin [IL]-8). Expression levels of angiogenic factors and markers in EoE and control samples were characterized by immunofluorescence analysis and quantitative reverse transcriptase-polymerase chain reaction. Vascular density of biopsy samples was evaluated by immunofluorescence analysis.

Results: Samples from patients with EoE exhibited higher levels of von Willebrand factor, CD31, and vascular cell adhesion molecule-1, which is suggestive of neovascularization and an activated endothelium. Moreover, EoE biopsies showed greater levels of the angiogenesis promoters VEGFA, angiogenin, and IL-8. Interestingly, there were greater cellular levels of tumor necrosis factor-α in EoE samples compared with controls. Furthermore, there were higher nuclear levels of p50 and p65 subunits of NFκB and lower cellular levels of the inhibitor of NFκB, IκB-α, in EoE samples compared with controls.

Conclusions: We demonstrate increased angiogenesis in the esophageal mucosa of pediatric patients with EoE. The data also provided evidence that the angiogenic factors VEGF-A, angiogenin, and IL-8 were prominently involved in promoting angiogenic remodeling.

*Department of Paediatrics

Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.

Address correspondence and reprint requests to Dr Sujata Persad, Department of Paediatrics, University of Alberta, 3020 KATZ Group Centre for Pharmacy and Health Research, Edmonton, AB, Canada T6G 2E1 (e-mail:

Received 22 February, 2011

Accepted 1 August, 2011

Drs Persad and Huynh are co-first authors.

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This project was funded by the Stollery Children's Hospital Research Foundation, Edmonton.

The authors report no conflicts of interest.

Copyright 2012 by ESPGHAN and NASPGHAN