PUBLICATION
Coral-Derived Compound WA-25 Inhibits Angiogenesis by Attenuating the VEGF/VEGFR2 Signaling Pathway
- Authors
- Lin, S.W., Huang, S.C., Kuo, H.M., Chen, C.H., Ma, Y.L., Chu, T.H., Bee, Y.S., Wang, E.M., Wu, C.Y., Sung, P.J., Wen, Z.H., Wu, D.C., Sheu, J.H., Tai, M.H.
- ID
- ZDB-PUB-150211-3
- Date
- 2015
- Source
- Marine drugs 13: 861-878 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Angiogenesis Inhibitors/pharmacology*
- Animals
- Anthozoa/chemistry*
- Butanones/pharmacology*
- Cell Movement/drug effects
- Cell Proliferation/drug effects
- Cells, Cultured
- Human Umbilical Vein Endothelial Cells/drug effects
- Humans
- Male
- Matrix Metalloproteinase Inhibitors/pharmacology
- Neovascularization, Pathologic/prevention & control
- Rats
- Rats, Sprague-Dawley
- Signal Transduction/drug effects
- Sulfones/pharmacology*
- Vascular Endothelial Growth Factor A/drug effects*
- Vascular Endothelial Growth Factor Receptor-2/drug effects*
- Zebrafish
- PubMed
- 25668036 Full text @ Mar. Drugs
Citation
Lin, S.W., Huang, S.C., Kuo, H.M., Chen, C.H., Ma, Y.L., Chu, T.H., Bee, Y.S., Wang, E.M., Wu, C.Y., Sung, P.J., Wen, Z.H., Wu, D.C., Sheu, J.H., Tai, M.H. (2015) Coral-Derived Compound WA-25 Inhibits Angiogenesis by Attenuating the VEGF/VEGFR2 Signaling Pathway. Marine drugs. 13:861-878.
Abstract
Background: WA-25 (dihydroaustrasulfone alcohol, a synthetic derivative of marine compound WE-2) suppresses atherosclerosis in rats by reducing neointima formation. Because angiogenesis plays a critical role in the pathogenesis of atherosclerosis, the present study investigated the angiogenic function and mechanism of WA-25. Methods: The angiogenic effect of WA-25 was evaluated using a rat aortic ring assay and transgenic zebrafish models were established using transgenic Tg(fli-1:EGFP)y1 and Tg(kdrl:mCherryci5-fli1a:negfpy7) zebrafish embryos. In addition, the effect of WA-25 on distinct angiogenic processes, including matrix metalloproteinase (MMP) expression, endothelial cell proliferation and migration, as well as tube formation, was studied using human umbilical vein endothelial cells (HUVECs). The effect of WA-25 on the endothelial vascular endothelial growth factor (VEGF) signaling pathway was elucidated using qRT-PCR, immunoblot analysis, immunofluorescence and flow cytometric analyses. Results: The application of WA-25 perturbed the development of intersegmental vessels in transgenic zebrafish. Moreover, WA-25 potently suppressed microvessel sprouting in organotypic rat aortic rings. Among cultured endothelial cells, WA-25 significantly and dose-dependently inhibited MMP-2/MMP-9 expression, proliferation, migration and tube formation in HUVECs. Mechanistic studies revealed that WA-25 significantly reduced the VEGF release by reducing VEGF expression at the mRNA and protein levels. In addition, WA-25 reduced surface VEGF receptor 2 (VEGFR2/Flk-1) expression by repressing the VEGFR2 mRNA level. Finally, an exogenous VEGF supply partially rescued the WA-25-induced angiogenesis blockage in vitro and in vivo. Conclusions: WA-25 is a potent angiogenesis inhibitor that acts through the down-regulation of VEGF and VEGFR2 in endothelial cells. General Significance: WA-25 may constitute a novel anti-angiogenic drug that acts by targeting endothelial VEGF/VEGFR2 signaling.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping