VIP protects human retinal microvascular endothelial cells against high glucose-induced increases in TNF-α and enhances RvD1

• VIP treatment reduces high glucose-induced TNF-α levels in HREC.
• High glucose reduces RvD1 expression by HREC.
• VIP treatment restores RvD1 levels in HREC exposed to high glucose.
• ALX/FPR2 and GPR32 are expressed on HREC.
• VPAC2 is the predominant receptor expressed on HREC.

PurposeThe 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.MethodsPrimary HREC were cultured in normal (5 mM) or high (25 mM) 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.ResultsHigh 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.ConclusionsOur 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.