Diabetic retinopathy (DR) is the most frequent microvascular complications of diabetes and the leading cause of blindness in adults worldwide. Non-proliferative DR (NPDR) is the first stage of DR but currently has few recommended intervention. Eicosanoids play important roles in maintaining vessel homeostasis. However, the functions of eicosanoids in NPDR are still unknown. In this study, we investigated the eicosanoids profile difference in plasma between type 2 diabetes with NPDR or not. A total of 50 patients with type 2 diabetes were recruited and divided into non-DR (NDR) group and NPDR group based on fundus photographs. The eicosanoids profiles in plasma were determined by LC-MS/MS. Adhesion and transwell assay were used to detect the adhesion and migration effects of metabolites on primary bovine retinal pericyte cells (BRPC), respectively. Streptomycin (STZ)-induced diabetic mouse model was used to test the protective effects of selected metabolites according to retinal immunofluorescence staining and fluorescence confocal microscopy. Prostaglandin 2 alpha (PGF2 alpha) was decreased significantly in NPDR group compared to NDR group and negatively correlated with NPDR. In vitro, PGF2 alpha was found to accelerate adhesion and migration by activating prostaglandin F receptor (FP receptor) and subsequent increasing RhoA activity in primary bovine retinal pericyte. Administration of PGF2 alpha analogue diminished the damage on retinal capillary in an STZ-induced diabetic mouse model. Our results suggested that PGF2 alpha may be a protective factor in the progression of NPDR in T2D patients. The protective mechanism of PGF2 alpha was to increase pericyte mobility through FP receptor/RhoA pathway. (C) 2018 Elsevier Inc. All rights reserved.