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The Dietary Flavones Apigenin and Luteolin Impair Smooth Muscle Cell Migration and VEGF Expression through Inhibition of PDGFR-β Phosphorylation

Authors' Affiliations: ¹ Laboratoire de Médecine Moléculaire, Hôpital Ste-Justine-Université du Québec à Montréal; ² Department of Pathology, Centre de Cancérologie Charles-Bruneau, Hôpital Ste-Justine, Montréal, Québec, Canada; and ³ Université Clermont 1, Laboratoire de Pharmacognosie/Biotechnologies, INSERM, U484, Groupe de Recherche Clinique, UFR Pharmacie, Clermont-Fd, France

Requests for reprints: Richard Béliveau, Laboratoire de Médecine Moléculaire, Centre de Cancérologie Charles-Bruneau, Hôpital Ste-Justine, 3175 Côte Ste-Catherine, Montréal, Québec, Canada H3T 1C5. Phone: 514-345-2366; Fax: 514-345-2359; E-mail: molmed{at}recherche-ste-justine.qc.ca.

Platelet-derived growth factor (PDGF)–dependent recruitment of mural cells such as pericytes and smooth muscle cells plays a central role in the maturation and stabilization of newly formed vasculature during angiogenesis. In this work, we show that the dietary flavones apigenin and luteolin may interfere with this event through their inhibitory effect on PDGF-dependent phosphorylation of PDGF receptor β (PDGFR-β) in smooth muscle cells. Inhibition of PDGFR-β activity by apigenin and luteolin occurred at low concentrations of the molecules and resulted in the inhibition of extracellular signal–regulated kinase and Akt phosphorylation triggered by PDGF, as well as in a marked reduction of the migratory and invasive properties of these cells. Apigenin and luteolin also strongly inhibit the PDGF-dependent increase in vascular endothelial growth factor (VEGF) mRNA levels and the secretion of VEGF by smooth muscle cells as well as vessel formation in the mouse Matrigel plug assay, suggesting that the inhibitory effects of both molecules on smooth muscle cell function result in impaired angiogenesis. Overall, these results identify apigenin and luteolin as dietary-derived inhibitors of PDGFR-β activity and suggest that this inhibitory effect may contribute to the chemopreventive properties of these molecules.