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Lactic Acid Upregulates VEGF Expression in Macrophages and Facilitates Choroidal Neovascularization

Authors
Song, J; Lee, K; Park, SW; Chung, H; Jung, D; Na, YR; Quan, H; Cho, CS; Che, JH; Kim, JH; Park, JH; Seok, SH
Citation
Investigative ophthalmology & visual science, 59(8):3747-3754, 2018
Journal Title
Investigative ophthalmology & visual science
ISSN
0146-04041552-5783
Abstract
PURPOSE: Lactic acid, the end product of glycolysis, has emerged as an immune-modulating metabolite in various diseases. In this study, we aimed to examine whether lactic acid contributes to the disease pathogenesis of choroidal neovascularization (CNV) and to investigate the role of macrophages in CNV pathogenesis.
METHODS: CNV was induced by laser photocoagulation in C57BL/6J mice. Lactic acid concentration was measured in the RPE-choroid region. Macrophage infiltration and VEGF were quantified by flow cytometry. VEGF-positive areas and CNV lesions were measured by flat-mount immunofluorescence staining. To inhibit lactic acid uptake in vivo, alpha-cyano-4-hydroxycinnamic acid (alpha-CHC), a monocarboxylate transporter (MCT) blocker, was injected intravitreally 1 day after laser. VEGF productions were measured in ARPE-19, THP-1 cells, and human umbilical vein endothelial cells (HUVECs) by quantitative PCR and ELISA. Angiogenic activity of lactic acid-treated macrophages was assessed by HUVEC tube formation assay.
RESULTS: Lactic acid was significantly increased in the RPE-choroid region of CNV-induced mice. Lactic acid upregulated VEGFA mRNA and VEGF protein expressions in THP-1 macrophages, but did not in ARPE-19 or HUVECs. THP-1 macrophages treated with lactic acid increased the angiogenesis of endothelial cells independent of MCT activity. Intravitreal injection of alpha-CHC substantially reduced the VEGF-positive area that colocalized with F4/80-positive macrophages. CNV lesions were also significantly reduced following alpha-CHC injection compared with vehicle-injected controls.
CONCLUSIONS: To our knowledge, these results show for the first time the role of lactic acid in facilitating neovascularization through macrophage-induced angiogenesis. We suggest that targeting macrophage metabolism can be a promising strategy for CNV treatment.
Keywords
lactic acidchoroidal neovascularizationVEGFmacrophagesα-CHC
MeSH terms
AnimalsCells, CulturedChoroid/metabolismChoroid/pathology*Choroidal Neovascularization/drug therapyChoroidal Neovascularization/genetics*Choroidal Neovascularization/metabolismChoroidal Neovascularization/pathologyDisease Models, AnimalEnzyme-Linked Immunosorbent AssayFemaleFlow CytometryGene Expression Regulation*HumansLactic Acid/pharmacology*Macrophages/metabolism*MiceMice, Inbred C57BLPolymerase Chain ReactionRNA/geneticsUp-Regulation*Vascular Endothelial Growth Factor A/biosynthesisVascular Endothelial Growth Factor A/genetics*
DOI
10.1167/iovs.18-23892
PMID
30046816
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Journal Papers > School of Medicine / Graduate School of Medicine > Ophthalmology
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