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All-trans retinoic acid antagonizes UV-induced VEGF production and angiogenesis via the inhibition of ERK activation in human skin keratinocytes

Cited 42 time in Web of Science Cited 42 time in Scopus
Authors
Kim, Mi-Sun; Kim, Yeon K; Eun, Hee C; Cho, Kwang H; Chung, Jin H
Issue Date
2006-07-01
Publisher
Nature Publishing Group
Citation
J Invest Dermatol. 2006 Dec;126(12):2697-706. Epub 2006 Jun 29.
Keywords
AdultCell LineEnzyme Activation/drug effectsEpidermis/metabolism/radiation effectsExtracellular Signal-Regulated MAP Kinases/metabolismFemaleHumansKeratinocytes/drug effects/enzymology/*metabolism/*radiation effectsMAP Kinase Signaling System/physiologyMaleNeovascularization, Physiologic/drug effectsSkin/blood supply/drug effectsTretinoin/*pharmacology*Ultraviolet RaysUp-RegulationVascular Endothelial Growth Factor A/*antagonists &inhibitors/*biosynthesis
Abstract
Incident UV radiation leads to the upregulation of vascular endothelial growth factor (VEGF), a potent angiogenic factor, in human skin. However, the molecular basis of UV-induced angiogenesis in skin remains to be elucidated. In this study, we investigated the roles of UV exposure on cutaneous angiogenesis, its associated signaling mechanisms, and the effect of all-trans retinoic acid (tRA) on UV-induced vascularization, and VEGF expression. Using a human epidermal cell line, HaCaT, we found that UV induces VEGF mRNA and protein expression via the MAPK/ERK kinase-ERK1/2 (extracellular signal-regulated kinase 1/2) pathway but not via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and that tRA pretreatment significantly inhibits UV-induced VEGF overexpression and ERK1/2 activation. In human skin in vivo, we confirmed that skin vascularization significantly increased after a single exposure to UV, as was evidenced by a prominent increase in vessel size, vascular density, and in the cutaneous area occupied by vessels, and we found that these events are associated with VEGF upregulation. Topical pretreatment with tRA under occlusion inhibited not only UV-induced VEGF upregulation and angiogenesis with a significant reduction of vessel density but also UV-induced ERK1/2 activation in human skin. Collectively, our data demonstrate that tRA inhibits the UV-induced angiogenic switch via downmodulation of ERK1/2 activation and consecutive VEGF overexpression. These findings may help us understand the molecular mechanisms that regulate skin angiogenesis due to UV exposure, and provide evidence of the potential of tRA in terms of preventing angiogenesis-associated skin damage following exposure to UV irradiation.
ISSN
1523-1747 (Electronic)
Language
English
URI
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16810296

https://hdl.handle.net/10371/42980
DOI
https://doi.org/10.1038/sj.jid.5700463
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College of Medicine/School of Medicine (의과대학/대학원)Molecular and Genomic Medicine (분자유전체의학전공)Journal Papers (저널논문_분자유전체의학전공)
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