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Mar. Drugs 2015, 13(2), 861-878; doi:10.3390/md13020861

Coral-Derived Compound WA-25 Inhibits Angiogenesis by Attenuating the VEGF/VEGFR2 Signaling Pathway

1
Doctoral Degree Program in Marine Biotechnology, National Sun Yat-Sen University and Academia Sinica, Kaohsiung 804, Taiwan
2
Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung 804, Taiwan
3
Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, Kaohsiung 802, Taiwan
4
Mitochondrial Research Unit, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
5
Division of Nephrology Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
6
Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan
7
Division of Nephrology, Kaohsiung Veterans General Hospital, Kaohsiung 813, Taiwan
8
Department of Ophthalmology, Kaohsiung Veterans General Hospital, Kaohsiung 804, Taiwan
9
National Museum of Marine Biology and Aquarium, Pingtung 944, Taiwan
10
Department of Marine Biotechnology and Resources National Sun Yat-Sen University, Kaohsiung 804, Taiwan
11
Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan
12
Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
13
Department of Medicine, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan
14
Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 404, Taiwan
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Academic Editor: Keith Glaser
Received: 11 August 2014 / Revised: 20 January 2015 / Accepted: 26 January 2015 / Published: 6 February 2015
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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. View Full-Text
Keywords: marine drugs; human umbilical vein endothelial cells (HUVECs); vascular endothelial growth factor (VEGF); VEGF receptor 2 (VEGFR2) marine drugs; human umbilical vein endothelial cells (HUVECs); vascular endothelial growth factor (VEGF); VEGF receptor 2 (VEGFR2)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

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. Coral-Derived Compound WA-25 Inhibits Angiogenesis by Attenuating the VEGF/VEGFR2 Signaling Pathway. Mar. Drugs 2015, 13, 861-878.

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