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.
Highlights
In the history of drug discovery, marine-derived extracts or compounds have served as unique pharmaceutical sources and gained increasing attention in recent years for the treatment of intractable diseases [1]
We found that WA-25 supply prominently reduced enhanced green fluorescent protein (EGFP) expression in the intersegmental vessels (ISVs) of zebrafish embryos (Figure 1B)
Because vascular endothelial growth factor (VEGF)-A signaling plays a pivotal role in angiogenesis, we investigated whether WA-25 exerted an antiangiogenic effect through the modulation of VEGF-A expression in endothelial cells
Summary
In the history of drug discovery, marine-derived extracts or compounds have served as unique pharmaceutical sources and gained increasing attention in recent years for the treatment of intractable diseases [1]. Angiogenesis involves a multiple cellular processes including endothelial cell proliferation, migration, and morphological differentiation and is closely regulated by growth factors and intracellular signaling pathways [13,14]. VEGF secreted from tumor and endothelial cells plays critical roles in tumor progression, in tumor angiogenesis and metastasis [18,19,20]. VEGF and VEGF receptors, VEGF receptor 2 (VEGFR2/Flk-1), are considered to constitute the key signaling system regulating endothelial cell proliferation and migration [14,21,22]. The suppression of VEGF signaling pathway is considered a potential strategy for tumor angiogenesis inhibition. Because angiogenesis plays a critical role in the pathogenesis of atherosclerosis, the present study investigated the angiogenic function and mechanism of WA-25
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