PPAR delta agonists suppress angiogenesis in a VEGFR2-dependent manner

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that have a pleiotropic impact on the regulation of differentiation, cell growth, and the metabolism of lipids and glucose. PPAR delta agonists display a variety of effects on pro-and anti-tumor processes, and seem to have pro-angiogenic activity at very low concentrations. We analyzed the influence of higher concentrations of PPAR delta agonists on angiogenesis and its underlying mechanisms. We found that treatment with PPAR delta agonists inhibited the formation of capillary-like structures and endothelial cell migration. Since signaling via the vascular endothelial growth factor receptor-2 (VEGFR2) pathway is critical for angiogenic responses during chronic inflammation and tumor development, we explored whether PPAR delta agonist inhibition acted by diminishing VEGFR2 expression. PPAR delta agonists inhibited endothelial VEGFR2 protein expression in a time-and concentration-dependent manner. In contrast, neither tie-2, neuropilin-1 nor VEGFR1 expression was significantly affected by PPAR delta agonist treatment. We also demonstrated that PPAR delta agonists significantly suppressed accumulation of VEGFR2 mRNA. Consistent with these results, promoter luciferase assays showed that the inhibitory effects of PPAR agonists occur through suppression of VEGFR2 promoter activity. Hence, VEGFR-2 expression may be a critical molecular target of PPAR delta agonists, which may be responsible for their anti-angiogenic effects. These results may help to define the optimal therapeutic doses of PPAR delta agonists in prospective therapeutic applications.