title: Docosahexaenoic acid inhibits vascular endothelial growth factor (VEGF)-induced cell migration via the GPR120/PP2A/ERK1/2/eNOS signaling pathway in human umbilical vein endothelial cells.
abstract: Cell migration plays an important role in angiogenesis and wound repair. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific mitogen that is essential for endothelial cell survival, proliferation, and migration. Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, shows both anti-inflammatory and antioxidant activities in vitro and in vivo. This study investigated the molecular mechanism by which DHA down-regulates VEGF-induced cell migration. HUVECs were used as the study model, and the MTT assay, Western blot, wound-healing assay, and phosphatase activity assay were used to explore the effects of DHA on cell migration. GPR120 is the putative receptor for DHA action. The results showed that DHA, PD98059 (an ERK1/2 inhibitor), and GW9508 (a GPR120 agonist) inhibited VEGF-induced cell migration. In contrast, pretreatment with okadaic acid (OA, a PP2A inhibitor) and S-nitroso-N-acetyl-DL-penicillamine (an NO donor) reversed the inhibition of cell migration by DHA. VEGF-induced cell migration was accompanied by phosphorylation of ERK1/2 and eNOS. Treatment of HUVECs with DHA increased PP2A enzyme activity and decreased VEGF-induced phosphorylation of ERK1/2 and eNOS. However, pretreatment with OA significantly decreased DHA-induced PP2A enzyme activity and reversed the DHA inhibition of VEGF-induced ERK1/2 and eNOS phosphorylation. These results suggest that stimulation of PP2A activity and inhibition of the VEGF-induced ERK1/2/eNOS signaling pathway may be involved in the DHA suppression of VEGF-induced cell migration. Thus, the effect of DHA on angiogenesis and wound repair is at least partly by virtue of its attenuation of cell migration.
authors.affiliation: Department of Health and Nutrition Biotechnology, Asia University , Taichung, Taiwan.
authors.forename: Che-Yi
authors.initials: CY
authors.lastname: Chao
authors.forename: Chong-Kuei
authors.initials: CK
authors.lastname: Lii
authors.forename: Siou-Yu
authors.initials: SY
authors.lastname: Ye
authors.forename: Chien-Chun
authors.initials: CC
authors.lastname: Li
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Lu
authors.forename: Ai-Hsuan
authors.initials: AH
authors.lastname: Lin
authors.forename: Kai-Li
authors.initials: KL
authors.lastname: Liu
authors.forename: Haw-Wen
authors.initials: HW
authors.lastname: Chen
mesh_terms: D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: C519853:FFAR4 protein, human; D043562:Receptors, G-Protein-Coupled; D042461:Vascular Endothelial Growth Factor A; D004281:Docosahexaenoic Acids; D052250:Nitric Oxide Synthase Type III; D048052:Mitogen-Activated Protein Kinase 3; D054648:Protein Phosphatase 2
keywords: cell migration; docosahexaenoic acid (DHA); human umbilical vein endothelial cells (HUVECs); nitric oxide (NO); vascular endothelial growth factor (VEGF)