SCOPE: We recently reported potent inhibition of VEGF signalling by two flavanols at sub-micromolar concentrations, mediated by direct binding of the flavanols to VEGF. The aim of this study was to quantify the inhibitory potency and binding affinity of a wide range of dietary polyphenols and determine the structural requirements for VEGF inhibition. METHODS AND RESULTS: The concentration of polyphenol required to cause 50% inhibition (IC50 ) of VEGF-dependent VEGFR-2 activation in HUVECS was determined after pretreating VEGF with polyphenols at various concentations. Binding affinities and binding sites on VEGF were predicted using in-silico modelling. Ellagic acid and 15 flavonoids had IC50 values ≤10 μM while 28 other polyhenols were weak/non-inhibitors. Structural features associated with potent inhibition included 3-galloylation, C-ring C2=C3, total OH, B-ring catechol, C-ring 3-OH of flavonoids. Potency was not associated with polyphenol hydrophobicity. There was a strong correlation between potency of inhibition and binding affinities, and all polyphenols were predicted to bind to a region on VEGF involved in VEGFR-2 binding. CONCLUSION: Specific polyphenols bind directly to a discrete region of VEGF and inhibit VEGF signalling, and this potentially explains the associations between consumption of these polyphenols and CVD risk.
SCOPE: We recently reported potent inhibition of VEGF signalling by two flavanols at sub-micromolar concentrations, mediated by direct binding of the flavanols to VEGF. The aim of this study was to quantify the inhibitory potency and binding affinity of a wide range of dietary polyphenols and determine the structural requirements for VEGF inhibition. METHODS AND RESULTS: The concentration of polyphenol required to cause 50% inhibition (IC50 ) of VEGF-dependent VEGFR-2 activation in HUVECS was determined after pretreating VEGF with polyphenols at various concentations. Binding affinities and binding sites on VEGF were predicted using in-silico modelling. Ellagic acid and 15 flavonoids had IC50 values ≤10 μM while 28 other polyhenols were weak/non-inhibitors. Structural features associated with potent inhibition included 3-galloylation, C-ring C2=C3, total OH, B-ring catechol, C-ring 3-OH of flavonoids. Potency was not associated with polyphenol hydrophobicity. There was a strong correlation between potency of inhibition and binding affinities, and all polyphenols were predicted to bind to a region on VEGF involved in VEGFR-2 binding. CONCLUSION: Specific polyphenols bind directly to a discrete region of VEGF and inhibit VEGF signalling, and this potentially explains the associations between consumption of these polyphenols and CVD risk.
Authors: Lee Hooper; Colin Kay; Asmaa Abdelhamid; Paul A Kroon; Jeffrey S Cohn; Eric B Rimm; Aedín Cassidy Journal: Am J Clin Nutr Date: 2012-02-01 Impact factor: 7.045
Authors: Wendy J Hollands; David J Hart; Jack R Dainty; Oliver Hasselwander; Kirsti Tiihonen; Richard Wood; Paul A Kroon Journal: Mol Nutr Food Res Date: 2013-04-23 Impact factor: 5.914
Authors: Andréa Diniz; Laura Escuder-Gilabert; Norberto P Lopes; Rosa María Villanueva-Camañas; Salvador Sagrado; María José Medina-Hernández Journal: Anal Bioanal Chem Date: 2008-04-18 Impact factor: 4.142
Authors: Robert Barrington; Gary Williamson; Richard N Bennett; Barry D Davis; Jennifer S Brodbelt; Paul A Kroon Journal: J Funct Foods Date: 2009-01-01 Impact factor: 4.451
Authors: Ana B Cerezo; María Labrador; Andrés Gutiérrez; Ruth Hornedo-Ortega; Ana M Troncoso; M Carmen Garcia-Parrilla Journal: Nutrients Date: 2019-10-11 Impact factor: 5.717
Authors: Ana B Cerezo; Ruth Hornedo-Ortega; M Antonia Álvarez-Fernández; Ana M Troncoso; M Carmen García-Parrilla Journal: Nutrients Date: 2017-03-08 Impact factor: 5.717