Hostname: page-component-669899f699-7xsfk Total loading time: 0 Render date: 2025-04-27T11:05:06.577Z Has data issue: false hasContentIssue false
  • English
  • Français

Divergent effects of quercetin conjugates on angiogenesis

Published online by Cambridge University Press:  08 March 2007

Sandra Donnini ,
Federica Finetti ,
Lorenzo Lusini ,
Lucia Morbidelli ,
Veronique Cheynier ,
Denis Barron ,
Gary Williamson ,
Johannes Waltenberger  and
Marina Ziche
Sandra Donnini
Affiliation:
Section of Pharmacology, Department of Molecular Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
Federica Finetti
Affiliation:
Section of Pharmacology, Department of Molecular Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
Lorenzo Lusini
Affiliation:
Section of Pharmacology, Department of Molecular Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
Lucia Morbidelli*
Affiliation:
Section of Pharmacology, Department of Molecular Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
Veronique Cheynier
Affiliation:
UnitéMixte de Recherche Sciences pour l'oenologie, Equipe Polyphénols, INRA, 2, Place Viala, 34060 Montpellier Cedex, France
Denis Barron
Affiliation:
Nestle Research Center, Vers-Chez-Les-Blanc, PO Box 44, CH-1000 Lausanne 26, Switzerland
Gary Williamson
Affiliation:
Institute of Food ResearchNorwich Research Park, Colney, Norwich NR4 7UA, UK
Johannes Waltenberger
Affiliation:
Department of Cardiology, University Hospital and Cardiovascular Research Institute (CARIM), 6202 AZ Maastricht, The Netherlands
Marina Ziche
Affiliation:
Section of Pharmacology, Department of Molecular Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy
*
*Corresponding author: Dr Lucia Morbidelli, fax +39 0577 234343, emailmorbidelli@unisi.it
Rights & Permissions [Opens in a new window]

Abstract

Core share and HTML view are not available for this content. However, as you have access to this content, a full PDF is available via the ‘Save PDF’ action button.

The present study reports the activities of quercetin and its main circulating conjugates in man (quercetin-3′-sulphate (Q3′S) and quercetin-3-glucuronide (Q3G)) on in vivo angiogenesis induced by vascular endothelial growth factor (VEGF) and examines the effects of these molecules on cultured endothelial cells. We found opposing effects of quercetin and its metabolites on angiogenesis. While quercetin and Q3G inhibited VEGF-induced endothelial cell functions and angiogenesis, Q3′S per se promoted endothelial cell proliferation and angiogenesis. The inhibitory effect elicited by Q3G was linked to inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) phosphorylation elicited by VEGF. The activation of endothelial cells by Q3′S was associated to stimulation of VEGF receptor-2 and to downstream signalling activation (phosphatidylinositol-3 kinase/Akt and nitric oxide synthase pathways), ultimately responsible for ERK1/2 phosphorylation. These data indicate that the effects of circulating quercetin conjugates on angiogenesis are different depending on the nature of the conjugate. Q3G andQ3′S are the two major conjugates in plasma, but their ratio is dependenton several factors, so thatinhibition or activation of angiogenesis could be subtly shifted as a result of metabolismin vivo.

Keywords

AngiogenesisQuercetinQuercetin conjugatesMicrovascular endothelial cellsProliferationMitogen-activated protein kinase
Type
Research Article
Information
British Journal of Nutrition , Volume 95 , Issue 5 , May 2006 , pp. 1016 - 1023
Copyright
Copyright © The Nutrition Society 2006

References

Bagli, E, Stefaniotou, M, Morbidelli, L, Ziche, M, Psillas, K, Murphy, C & Fotsis, TLuteolin inhibits vascular endothelial growth factor-induced angiogenesis; inhibition of endothelial cell survival and proliferation by targeting phosphatidylinositol 30-kinase activity. Cancer Res 2004 64, 7936–7946.CrossRefGoogle ScholarPubMed
Burchell, B & Coughtrie, MWHGenetic and environmental factors associated with variation of human xenobiotic glucuronidation and sulfation. Environ Health Perspect 1997 105, 739–747.Google ScholarPubMed
Cantara, S, Donnini, S, Morbidelli, L, Giachetti, A, Schulz, R, Memo, M & Ziche, MPhysiological levels of amyloid peptides stimulate the angiogenic response through FGF-2. FASEB J 2004 18, 1943–1945.CrossRefGoogle ScholarPubMed
Cappelli, A, Giuliani, G, La Pericot Mohr, G, et al.. A nonpeptide NK1 receptor agonist showing subpicomolar affinity. J Med Chem 2004 47, 1315–1318.CrossRefGoogle ScholarPubMed
Cheynier, V & Rigaud, JHPLC separation and characterization of flavonols in the skins of Vitis vinifera var Cinsault. Am J Enol Vitic 1986 37, 248–252.CrossRefGoogle Scholar
Chiesi, M & Schwaller, RInhibition of constitutive endothelial NO-synthase activity by tannin and quercetin. Biochem Pharmacol 1995 49, 495–501.CrossRefGoogle ScholarPubMed
Day, AJ, Mellon, F, Barron, D, Sarrazin, G, Morgan, MR & Williamson, GHuman metabolism of dietary flavonoids: identification of plasma metabolites of quercetin. Free Radic Res 2001 35, 941–952.CrossRefGoogle ScholarPubMed
de Pascual-Teresa, S, Johnston, KL, Dupont, MS, O'Leary, KA, Needs, PW, Morgan, LM, Clifford, MN, Bao, Y & Williamson, GQuercetin metabolites downregulate cyclooxygenase-2 transcription in human lymphocytes ex vivo but not in vivo. J Nutr 2004 134, 552–557.Google Scholar
Fan, PS, Gu, ZL, Sheng, R, Liang, ZQ, Wang, XX & Zhu, YInhibitory effect of quercetin on proliferation of human microvascular endothelial cells in vitro. Acta Pharmacol Sin 2003 24, 1231–1234.Google ScholarPubMed
Garcia-Closas, R, Agudo, A, Gonzalez, CA & Riboli, EIntake of specific carotenoids and flavonoids and the risk of lung cancer in women in Barcelona, Spain. Nutr Cancer 1998 32, 154–158.CrossRefGoogle ScholarPubMed
Garcia-Closas, R, Gonzalez, CA, Agudo, A & Riboli, EIntake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain. Cancer Causes Control 1999 10, 71–75.CrossRefGoogle ScholarPubMed
Gee, JM, Dupont, MS, Day, AJ, Plumb, GW, Williamson, G & Johnson, ITIntestinal transport of quercetin glycosides in rats involves both deglycosylation and interaction with the hexose transport pathway. J Nutr 2000 130, 2765–2771.CrossRefGoogle ScholarPubMed
Hasebe, Y, Egawa, K, Yamazaki, Y, Kunimoto, S, Hirai, Y & Ida, YNose, KSpecific inhibition of hypoxia-inducible factor (HIF)-1 alpha activation and of vascular endothelial growth factor (VEGF) production by flavonoids. Biol Pharm Bull 2003 26, 1379–1383.CrossRefGoogle ScholarPubMed
Hertog, MG, Feskens, EJ, Hollman, PC, Katan, MB & Kromhout, DDietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993 342, 1007–1011.CrossRefGoogle ScholarPubMed
Igura, K, Ohta, T, Kuroda, Y & Kaji, KResveratrol and quercetin inhibit angiogenesis in vitro. Cancer Lett 2001 171, 11–16.CrossRefGoogle ScholarPubMed
Janisch, KM, Williamson, G, Needs, P & Plumb, GWProperties of quercetin conjugates: modulation of LDL oxidation and binding to human serum albumin. Free Radic Res 2004 38, 877–884.CrossRefGoogle ScholarPubMed
Kaneider, NC, Mosheimer, B, Reinisch, N, Patsch, JR & Wiedermann, CJInhibition of thrombin-induced signaling by resveratrol and quercetin: effects on adenosine nucleotide metabolism in endothelial cells and platelet-neutrophil interactions. Thromb Res 2004 114, 185–194.CrossRefGoogle ScholarPubMed
Kimura, Y & Okuda, H, , \ Resveratrol isolated from Polygonum cuspidatum root prevents tumor growth and metastasis to lung and tumor-induced neovascularization in Lewis lung carcinomabearing mice. J Nutr 2001 131, 1844–1849.CrossRefGoogle ScholarPubMed
Knekt, P, Jarvinen, R, Reunanen, A & Maatela, JFlavonoid intake and coronary mortality in Finland: a cohort study. Br Med J 1996 312, 478–481.CrossRefGoogle ScholarPubMed
Knekt, P, Kumpulainen, J, Jarvinen, R, Rissanen, H, Heliovaara, M, Reunanen, A, Hakulinen, T & Aromaa, AFlavonoid intake and risk of chronic diseases. Am J Clin Nutr 2002 76, 560–568.CrossRefGoogle ScholarPubMed
Kobuchi, H, Roy, S, Sen, CK, Nguyen, HG & Packer, LQuercetin inhibits inducible ICAM-1 expression in human endothelial cells through the JNK pathway. Am J Physiol 1999 277, C403–C411.CrossRefGoogle ScholarPubMed
Kroll, J & Waltenberger, J, , \ VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun 1998 252, 743–746.CrossRefGoogle ScholarPubMed
Lin, MT, Yen, ML, Lin, CY & Kuo, MLInhibition of vascular endothelial growth factor-induced angiogenesis by resveratrol through interruption of Src-dependent vascular endothelial cadherin tyrosine phosphorylation. Mol Pharmacol 2003 64, 1029–1036.CrossRefGoogle ScholarPubMed
McCann, SE, Ambrosone, CB, Moysich, KB, Brasure, J, Marshall, JR, Freudenheim, JL, Wilkinson, GS & Graham, SIntakes of selected nutrients, foods, and phytochemicals and prostate cancer risk in Western New York. Nutr Cancer 2005 53, 33–41.CrossRefGoogle ScholarPubMed
Morbidelli, L, Donnini, S, Chillemi, F, Giachetti, A & Ziche, MAngiosuppressive and angiostimulatory effects exerted by synthetic partial sequences of endostatin. Clin Cancer Res 2003 9, 5358–5369.Google ScholarPubMed
Morbidelli, L & Ziche, MThe rabbit corneal pocket assay for the study of angiogenesis. Cancer Treat Rev 2004 117, 147–151.CrossRefGoogle Scholar
Neuhouser, MLDietary flavonoids and cancer risk: evidence from human population studies. Nutr Cancer 2004 50, 1–7.CrossRefGoogle ScholarPubMed
O'Leary, KA, Day, AJ, Needs, PW, Sly, WS, O'Brien, NM & Williamson, GFlavonoid glucuronides are substrates for human liver beta-glucuronidase. FEBS Lett 2001 503, 103–106.CrossRefGoogle ScholarPubMed
Parenti, A, Morbidelli, L, Cui, XL, Douglas, JG, Hood, J, Granger, HJ, Ledda, F & Ziche, MNitric oxide is an upstream signal for vascular endothelial growth factor-induced extracellular signal-regulated kinases1/2 activation in postcapillary endothelium. J Biol Chem 1998 273, 4220–4226.CrossRefGoogle Scholar
Saito, A, Sugisawa, A, Umegaki, K & Sunagawa, HProtective effects of quercetin and its metabolites on H2O2-induced chromosomal damage to WIL2-NS cells. Biosci Biotechnol Biochem 2004 68, 271–276.CrossRefGoogle ScholarPubMed
Sengupta, S, Toh, SA, Sellers, LA, Skepper, JN, Koolwijk, P, Leung, HW, Yeung, HW, Wong, RN, Sasisekharan, R & Fan, TPModulating angiogenesis: the yin and the yang in ginseng. Circulation 2004 110, 1219–1225.CrossRefGoogle Scholar
Tan, WF, Lin, LP, Li, MH, Zhang, YX, Tong, YG, Xiao, D & Ding, JQuercetin, a dietary-derived flavonoid, possesses antiangiogenic potential. Eur J Pharmacol 2003 459, 255–262.CrossRefGoogle ScholarPubMed
Tseng, SH, Lin, SM, Chen, JC, Su, YH, Huang, HY, Chen, CK, Lin, PY & Chen, YResveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin Cancer Res 2004 10, 2190–2202.CrossRefGoogle ScholarPubMed
Waltenberger, J, Claesson-Welsh, L, Siegbahn, A, Shibuya, M & Heldin, CHDifferent signal transduction properties of KDR and Flt1, two receptors for vascular endothelial growth factor. J Biol Chem 1994 269, 26988–26995.CrossRefGoogle ScholarPubMed
Williamson, GThe use of flavonoid aglycones in in vitro systems to test biological activities: based on bioavailability data, is this a valid approach?. Phytochem Rev 2003 1, 215–222.CrossRefGoogle Scholar
Zachary, I,\ VEGF signalling: integration and multi-tasking in endothelial cell biology. Biochem Soc Trans 2003 31, 1171–1177.CrossRefGoogle ScholarPubMed
Ziche, M, Morbidelli, L, Choudhuri, R, Zhang, HT, Donnini, S, Granger, HJ & Bicknell, RNitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest 1997 99, 2625–2634.CrossRefGoogle Scholar