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PPARδ agonists suppress angiogenesis in a VEGFR2-dependent manner

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Abstract

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. PPARδ 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 PPARδ agonists on angiogenesis and its underlying mechanisms. We found that treatment with PPARδ 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 PPARδ agonist inhibition acted by diminishing VEGFR2 expression. PPARδ 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 PPARδ agonist treatment. We also demonstrated that PPARδ 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 δ agonists, which may be responsible for their anti-angiogenic effects. These results may help to define the optimal therapeutic doses of PPARδ agonists in prospective therapeutic applications.

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Acknowledgments

This study was supported by a grant from the Wilhelm Sander Stiftung (M.M.) and the Held and Hecker Stiftung (M.M.).

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Authors and Affiliations

  1. Department of Dermatology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany

    Markus Meissner, Igor Hrgovic, Monika Doll & Roland Kaufmann

  2. Department of Dermatology, Venerology and Allergology, University of Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Markus Meissner

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  1. Markus Meissner
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  2. Igor Hrgovic
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Correspondence to Markus Meissner.

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Meissner, M., Hrgovic, I., Doll, M. et al. PPARδ agonists suppress angiogenesis in a VEGFR2-dependent manner. Arch Dermatol Res 303, 41–47 (2011). https://doi.org/10.1007/s00403-010-1091-y

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  • DOI: https://doi.org/10.1007/s00403-010-1091-y

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