title: VIP protects human retinal microvascular endothelial cells against high glucose-induced increases in TNF-α and enhances RvD1.
abstract: The purpose of our study was to evaluate the therapeutic effect of VIP on human retinal endothelial cells (HREC) under high glucose conditions. Diabetes affects almost 250 million people worldwide. Over 40% of diabetics are expected to develop diabetic retinopathy, which remains the leading cause of visual impairment/blindness. Currently, treatment is limited to late stages of retinopathy with no options available for early stages. To this end, the purpose of the current study is to evaluate the therapeutic effect of vasoactive intestinal peptide (VIP) on HREC under high glucose conditions.
  
  
  
  Primary HREC were cultured in normal (5mM) or high (25mM) glucose medium +/- VIP treatment. Protein levels of TNF-α, resolvin D1 (RvD1), formyl peptide receptor 2 (FPR2), G protein-coupled receptor 32 (GPR32), VEGF, and VIP receptors, VPAC1 and VPAC2 were measured.
  
  
  
  High glucose-induced changes in TNF-α and RvD1 were restored to control levels with VIP treatment. RvD1 receptors, ALX/FPR2 and GPR32, were partially rescued with VIP treatment. VPAC2 expression appeared to be the major receptor involved in VIP signaling in HREC, as VPAC1 receptor was not detected. In addition, VIP did not induce HREC secretion of VEGF under high glucose conditions.
  
  
  
  Our results demonstrate that VIP's therapeutic effect on HREC, occurs in part, through the balance between the pro-inflammatory cytokine, TNF-α, and the pro-resolving mediator, RvD1. Although VPAC1 is considered the major VIP receptor, VPAC2 is predominantly expressed on HREC under both normal and high glucose conditions.
authors.affiliation: Department of Anatomy & Cell Biology, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, 48201 MI, USA. Electronic address: hshi@med.wayne.edu.
authors.forename: Haoshen
authors.initials: H
authors.lastname: Shi
authors.affiliation: Department of Anatomy & Cell Biology, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, 48201 MI, USA. Electronic address: tcarion@med.wayne.edu.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Carion
authors.affiliation: Department of Anatomy & Cell Biology, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, 48201 MI, USA. Electronic address: youdejiang55@gmail.com.
authors.forename: Youde
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Anatomy & Cell Biology, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, 48201 MI, USA; Department of Ophthalmology, Kresge Eye Institute, 4717 St. Antoine St., Detroit, 48201 MI, USA. Electronic address: jsteinle@med.wayne.edu.
authors.forename: Jena J
authors.initials: JJ
authors.lastname: Steinle
authors.affiliation: Department of Anatomy & Cell Biology, Wayne State University School of Medicine, 540 E. Canfield Ave., Detroit, 48201 MI, USA; Department of Ophthalmology, Kresge Eye Institute, 4717 St. Antoine St., Detroit, 48201 MI, USA. Electronic address: eberger@med.wayne.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Berger
mesh_terms: D004281:Docosahexaenoic Acids / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000037:antagonists & inhibitors* / Q000633:toxicity; D006801:Humans; D061251:Primary Cell Culture; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism; D051239:Receptors, Vasoactive Intestinal Peptide, Type II / Q000235:genetics / Q000378:metabolism; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I / Q000235:genetics / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology*
chemical_list: C105101:FPR2 protein, human; C114479:GPR32 protein, human; D044042:Receptors, Formyl Peptide; D043562:Receptors, G-Protein-Coupled; D044067:Receptors, Lipoxin; D051239:Receptors, Vasoactive Intestinal Peptide, Type II; D051238:Receptors, Vasoactive Intestinal Polypeptide, Type I; D014409:Tumor Necrosis Factor-alpha; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C518399:resolvin D1; D004281:Docosahexaenoic Acids; D014660:Vasoactive Intestinal Peptide; D005947:Glucose
keywords: Diabetic retinopathy; Neuropeptide; Resolvins; Treatment