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Context-dependent regulation of endothelial cell metabolism: differential effects of the PPARβ/δ agonist GW0742 and VEGF-A

Abstract : Peroxisome proliferator activated receptor β/δ (PPARβ/δ) has pro-angiogenic functions, but whether PPARβ/δ modulates endothelial cell metabolism to support the dynamic phenotype remains to be established. This study characterised the metabolic response of HUVEC to the PPARβ/δ agonist, GW0742, and compared these effects with those induced by VEGF-A. In HUVEC monolayers, flux analysis revealed that VEGF-A promoted glycolysis at the expense of fatty acid oxidation (FAO), whereas GW0742 reduced both glycolysis and FAO. Only VEGF-A stimulated HUVEC migration and proliferation whereas both GW0742 and VEGF-A promoted tubulogenesis. Studies using inhibitors of PPARβ/δ or sirtuin-1 showed that the tubulogenic effect of GW0742, but not VEGF-A, was PPARβ/δ- and sirtuin-1-dependent. HUVEC were reliant on glycolysis and FAO, and inhibition of either pathway disrupted cell growth and proliferation. VEGF-A was a potent inducer of glycolysis in tubulogenic HUVEC, while FAO was maintained. In contrast, GW0742-induced tubulogenesis was associated with enhanced FAO and a modest increase in glycolysis. These novel data reveal a context-dependent regulation of endothelial metabolism by GW0742, where metabolic activity is reduced in monolayers but enhanced during tubulogenesis. These findings expand our understanding of PPARβ/δ in the endothelium and support the targeting of PPARβ/δ in regulating EC behaviour and boosting tissue maintenance and repair.
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Submitted on : Wednesday, June 10, 2020 - 10:52:52 AM
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Ashton Faulkner, Eleanor Lynam, Robert Purcell, Coleen Jones, Colleen Lopez, et al.. Context-dependent regulation of endothelial cell metabolism: differential effects of the PPARβ/δ agonist GW0742 and VEGF-A. Scientific Reports, Nature Publishing Group, 2020, 10 (1), pp.7849. ⟨10.1038/s41598-020-63900-0⟩. ⟨inserm-02863371⟩

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