Binding of Resveratrol to Vascular Endothelial Growth Factor Suppresses Angiogenesis by Inhibiting the Receptor Signaling

Abstract

Resveratrol is a polyphenol commonly found in plants and food health products, such as grape and red wine, and was identified for its binding to vascular endothelial growth factor (VEGF) by using HerboChips screening. The binding, therefore, resulted in alterations of VEGF binding to its receptor and revealed the roles of VEGF in angiogenesis. Several lines of evidence gave support to the inhibitory activities of resveratrol in VEGF-triggered angiogenesis. In human umbilical vein endothelial cells (HUVECs), compared with a VEGF-induced group, resveratrol, at a high concentration, suppressed VEGF-mediated endothelial cell proliferation, cell migration, cell invasion, and tube formation by 80 ± 9.01%, 140 ± 3.78%, 110 ± 7.51%, and 120 ± 10.26%, respectively. Moreover, resveratrol inhibited the subintestinal vessel formation in zebrafish embryo. In signaling cascades, application of resveratrol in HUVECs reduced the VEGF-triggered VEGF receptor 2 phosphorylation and c-Jun N-terminal kinase phosphorylation. Moreover, the VEGF-mediated phosphorylations of endothelial nitric oxide synthase, protein kinase B, and extracellular signal-regulated kinase were obviously decreased by (3 ± 0.37)-, (2 ± 0.27)- and (6 ± 0.23)-fold, respectively, in the presence of resveratrol at high concentration. Parallelly, the VEGF-induced reactive oxygen species formation was significantly decreased by 50 ± 7.88% to 120 ± 14.82% under resveratrol treatment. Thus, our results provided support to the antiangiogenic roles of resveratrol, as well as its related signaling mechanisms, in attenuating the VEGF-mediated responses. The present results supported possible development of resveratrol, which should be considered as a therapeutic agent in terms of prevention and clinical treatment of diseases related to angiogenesis.

Synergy of Ginkgetin and Resveratrol in Suppressing VEGF-Induced Angiogenesis: A Therapy in Treating Colorectal Cancer

“…In cultured HUVECs, the treatment of ginkgetin inhibited VEGF-mediated expressions of MMP-2 and MMP-9 proteins at~2-fold and~4-fold, respectively ( Figure 3B). On the other hand, resveratrol, another popular phytochemical, has been previously shown to suppress VEGF-mediated angiogenesis, similar to that of ginkgetin as described here; however, the binding site was proposed to be different to that of ginkgetin [21].…”

“…Resveratrol is a polyphenol commonly found in many natural products, which is able to do the job as that of ginkgetin in VEGF-mediated angiogenesis [21]. Resveratrol has several closely related chemical analogues (i.e., polydatin, pterostilbene, 3,4 ,5-trimethoxy-trans-stilbene, and piceatannol), and these analogues are also commonly found in natural products [43].…”

“…Briefly, 5 × 10 3 endothelial cells in 100 µL of medium were seeded on a sterile 96-well plate (Corning Incorporated, New York, NY, USA). After incubation for 24 h, the medium in each well was changed with 100 µL of fresh medium containing VEGF at 10 ng/mL, or a series of concentrations of ginkgetin/resveratrol, as described previously [21]. After drug treatment for 48 h, 10 µL/well of MTT solution (5 mg/mL) was added.…”

“…After three rounds of washing with PBS, acetonitrile (ACN) was applied to precipitate the VEGF/biotin-labelled VEGF complex. The supernatant was subjected to UPLC analysis to determine the amount of ginkgetin, as described previously [21].…”

“…A wound-healing assay was performed to determine the cell migration in vitro [21,44]. Briefly, 20 × 10 4 endothelial cells in 1 mL of medium were seeded on a sterile 12-well plate.…”