Efecto sobre el endotelio linfático de la hipoxia tumoral e inhibición de la producción de vegf por flavonoides

Resum

Vascular endothelial growth factor (VEGF) is an important angiogenic and lymphangiogenic factor highly stimulated by hypoxia. We studied the effect of conditioned media obtained from H157 tumoral lung cancer cells incubated under normoxia (21% O2) or hypoxia (1% O2) on lymphatic endothelial cells (LECs). Gene expression was highly repressed in treated LECs and those related to cell adhesion and angiogenesis were highly perturbed. Functional assays concluded that hypoxic H157 conditioned medium induced LEC proliferation, and cellular adhesion to collagens I and IV, but not to laminin or fibronectin. However, conditioned media did not affect to the adhesion tumoral cells to LECs. On the other hand, we studied the effect of flavonoids on the production of VEGF stimulated by hypoxia. Fisetin, apigenin and luteolin were the most active compounds and hydroxyl substitutions at 3, 5, 7 and 4¿ were important for inhibition of VEGF production under hypoxic conditions. Moreover, our data showed that apoptotic flavonoids induced te phosphorylation of ERK 1/2. Finally, we demonstrated that the mechanism of action of these compounds involved a transcriptional regulation of VEGF gene that were independent of HIF- á expression.