Piceatannol, a Natural Analog of Resveratrol, Exerts Anti-angiogenic Efficiencies by Blockage of Vascular Endothelial Growth Factor Binding to Its Receptor.

Wei-Hui Hu,Karl Wah-Keung Tsim,Ran Duan,Tina Ting-Xia Dong,Diana Kun Dai,Brody Zhong-Yu Zheng,Qi-Wei Qin

doi:10.3390/molecules25173769

Abstract

Piceatannol is also named as trans-3,4,3′,5′-tetrahydroxy-stilbene, which is a natural analog of resveratrol and a polyphenol existing in red wine, grape and sugar cane. Piceatannol has been proved to possess activities of immunomodulatory, anti-inflammatory, antiproliferative and anticancer. However, the effect of piceatannol on VEGF-mediated angiogenesis is not known. Here, the inhibitory effects of piceatannol on VEGF-induced angiogenesis were tested both in vitro and in vivo models of angiogenesis. In human umbilical vein endothelial cells (HUVECs), piceatannol markedly reduced the VEGF-induced cell proliferation, migration, invasion, as well as tube formation without affecting cell viability. Furthermore, piceatannol significantly inhibited the formation of subintestinal vessel in zebrafish embryos in vivo. In addition, we identified the underlying mechanism of piceatannol in triggering the anti-angiogenic functions. Piceatannol was proposed to bind with VEGF, thus attenuating VEGF in activating VEGF receptor and blocking VEGF-mediated downstream signaling, including expressions of phosphorylated eNOS, Erk and Akt. Furthermore, piceatannol visibly suppressed ROS formation, as triggered by VEGF. Moreover, we further determined the outcome of piceatannol binding to VEGF in cancer cells: piceatannol significantly suppressed VEGF-induced colon cancer proliferation and migration. Thus, these lines of evidence supported the conclusion that piceatannol could down regulate the VEGF-mediated angiogenic functions with no cytotoxicity via decreasing the amount of VEGF binding to its receptors, thus affecting the related downstream signaling. Piceatannol may be developed into therapeutic agents or health products to reduce the high incidence of angiogenesis-related diseases.

Highlights

It was firstly proposed in the early 1970s that the new formation of blood vessels was a prerequisite for a tumor to grow larger than a few mm3 in size, providing with oxygen and nutrition to support the exponential growth of tumor [1]
VEGFR2 is required for vascular development of endothelial cells, and the affinity value of vascular endothelial growth factor A (VEGF) binding to VEGFR2 is much higher than that to VEGFR1 [11,12]
We found that piceatannol application strongly suppressed VEGF-induced VEGFR2 phosphorylation in time- and dose-dependent manners in response to VEGF (Figure 4A, Supplementary Figure S5); but which exerted few effects on the phosphorylation of VEGFR1, as stimulated by VEGF (Figure 5, Supplementary Figure S6), giving support to the notion that the binding sites of piceatannol to VEGF may be located at the binding site of VEGF with VEGFR2, but not at that of VEGFR1

Summary

Introduction

It was firstly proposed in the early 1970s that the new formation of blood vessels was a prerequisite for a tumor to grow larger than a few mm in size, providing with oxygen and nutrition to support the exponential growth of tumor [1]. The growth of new blood vessel, defined as angiogenesis, Molecules 2020, 25, 3769; doi:10.3390/molecules25173769 www.mdpi.com/journal/molecules. A large number of proteins and its mechanism involved in the regulation of this process have been identified [4,5,6]. Among these proteins related with vessel growth, vascular endothelial growth factor A (VEGF) has been shown to be the most significant angiogenic factor, secreted by tumor [7,8]. After activated by VEGF, both VEGFR1 and VEGFR2 separately experience signal transduction, and VEGFR2 demonstrates stronger ligand-dependent tyrosine phosphorylation, as compared with that of VEGFR1 [13,14]

Methods

Findings

Discussion

Conclusion