Abstract
15-Deoxy-Delta(12,14)-prostaglandin-J(2) (15d-PGJ(2)) upregulates expression of vascular endothelial growth factor (VEGF), but may inhibit angiogenesis. We found that 15d-PGJ(2) (1-10muM) attenuated all VEGF-induced angiogenic activities in human umbilical vein endothelial cells (HUVEC). It blocked almost completely cell proliferation, potently reduced migration, assembly into tube-like network on matrigel, and growth of capillaries into collagen gel. 15d-PGJ(2) inhibited expression of VEGFR-1 and VEGFR-2 receptors both at mRNA and protein levels. This inhibition, however, was transient (observed after 6-12h, but not after 24h) and weak (20-30%), and could not fully explain inhibition of response to VEGF. Accordingly, proliferation was inhibited when 15d-PGJ(2) was added 24h after VEGF or in cells stimulated with basic fibroblast growth factor. Interestingly, 15d-PGJ(2) decreased activities of c-jun and c-myc in HUVEC and overexpression of c-myc attenuated its antiproliferative effects. This suggests that inhibition of this transcription factor by 15d-PGJ(2) contributes to decrease in angiogenic response.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiogenesis Inducing Agents / antagonists & inhibitors*
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Angiogenesis Inhibitors / pharmacology*
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cells, Cultured
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Dose-Response Relationship, Drug
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Down-Regulation
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Endothelial Cells / cytology
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Endothelial Cells / drug effects
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Endothelial Cells / metabolism*
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Humans
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Morphogenesis / drug effects
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Prostaglandin D2 / analogs & derivatives*
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Prostaglandin D2 / metabolism
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Prostaglandin D2 / pharmacology
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Proto-Oncogene Proteins c-myc / metabolism
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RNA, Messenger / metabolism
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Receptors, Vascular Endothelial Growth Factor / metabolism*
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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Time Factors
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Transcription Factors / metabolism
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Umbilical Veins / cytology
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Vascular Endothelial Growth Factor A / antagonists & inhibitors*
Substances
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15-deoxyprostaglandin J2
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Angiogenesis Inducing Agents
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Angiogenesis Inhibitors
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MYC protein, human
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Proto-Oncogene Proteins c-myc
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RNA, Messenger
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Recombinant Proteins
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Transcription Factors
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Vascular Endothelial Growth Factor A
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Receptors, Vascular Endothelial Growth Factor
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Extracellular Signal-Regulated MAP Kinases
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Prostaglandin D2