title: Quercetin-4'-O-β-D-glucopyranoside (QODG) inhibits angiogenesis by suppressing VEGFR2-mediated signaling in zebrafish and endothelial cells.
abstract: BACKGROUND
  Angiogenesis plays an important role in many physiological and pathological processes. Identification of small molecules that block angiogenesis and are safe and affordable has been a challenge in drug development. Hypericum attenuatum Choisy is a Chinese herb medicine commonly used for treating hemorrhagic diseases. The present study investigates the anti-angiogenic effects of quercetin-4'-O-β-D-glucopyranoside (QODG), a flavonoid isolated from Hypericum attenuatum Choisy, in vivo and in vitro, and clarifies the underlying mechanism of the activity.
  
  
  RESULTS
  Tg(fli1:EGFP) transgenic zebrafish embryos were treated with different concentrations of quercetin-4'-O-β-D-glucopyranoside (QODG) (20, 60, 180 µM) from 6 hours post fertilisation (hpf) to 72 hpf, and adult zebrafish were allowed to recover in different concentrations of QODG (20, 60, 180 µM) for 7 days post amputation (dpa) prior morphological observation and angiogenesis phenotypes assessment. Human umbilical vein endothelial cells (HUVECs) were treated with or without VEGF and different concentrations of QODG (5, 20, 60, 180 µM), then tested for cell viability, cell migration, tube formation and apoptosis. The role of VEGFR2-mediated signaling pathway in QODG-inhibited angiogenesis was evaluated using quantitative real-time PCR (qRT-PCR) and Western blotting.
  
  
  CONCLUSIONS
  Quercetin-4'-O-β-D-glucopyranoside (QODG) was shown to inhibit angiogenesis in human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish in vivo via suppressing VEGF-induced phosphorylation of VEGFR2. Our results further indicate that QODG inhibits angiogenesis via inhibition of VEGFR2-mediated signaling with the involvement of some key kinases such as c-Src, FAK, ERK, AKT, mTOR and S6K and induction of apoptosis. Together, this study reveals, for the first time, that QODG acts as a potent VEGFR2 kinase inhibitor, and exerts the anti-angiogenic activity at least in part through VEGFR2-mediated signaling pathway.
authors.affiliation: Pharmacy School, Wenzhou Medical College, Wenzhou, Zhejiang Province, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Lin
authors.forename: Menghua
authors.initials: M
authors.lastname: Wu
authors.forename: Jianyong
authors.initials: J
authors.lastname: Dong
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D005960:Glucosides / Q000494:pharmacology* / Q000627:therapeutic use; D029001:Herbal Medicine; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects*; D006801:Humans; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D005960:Glucosides; C110310:quercetin 4'-O-glucopyranoside; D011794:Quercetin; D040301:Vascular Endothelial Growth Factor Receptor-2