Divergent effects of quercetin conjugates on angiogenesis.
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 and Q3'S are the two major conjugates in plasma, but their ratio is dependent on several factors, so that inhibition or activation of angiogenesis could be subtly shifted as a result of metabolism in vivo.
Donnini
Sandra
S
Section of Pharmacology, Department of Molecular Medicine, University of Siena, Via A. Moro 2, 53100 Siena, Italy.
Finetti
Federica
F
Lusini
Lorenzo
L
Morbidelli
Lucia
L
Cheynier
Veronique
V
Barron
Denis
D
Williamson
Gary
G
Waltenberger
Johannes
J
Ziche
Marina
M
D000818:Animals; D002417:Cattle; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003315:Cornea / Q000098:blood supply; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011794:Quercetin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
D042461:Vascular Endothelial Growth Factor A; C443401:quercetin 3-O-glucuronide; D011794:Quercetin