Context-Dependent Regulation Of Endothelial Cell Metabolism: Differential Effects Of The Ppar Beta/Delta Agonist Gw0742 And Vegf-A
SCIENTIFIC REPORTS(2020)
摘要
Peroxisome proliferator activated receptor beta/delta (PPAR beta/delta) has pro-angiogenic functions, but whether PPAR beta/delta modulates endothelial cell metabolism to support the dynamic phenotype remains to be established. This study characterised the metabolic response of HUVEC to the PPAR beta/delta 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 PPAR beta/delta or sirtuin-1 showed that the tubulogenic effect of GW0742, but not VEGF-A, was PPAR beta/delta- 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 PPAR beta/delta in the endothelium and support the targeting of PPAR beta/delta in regulating EC behaviour and boosting tissue maintenance and repair.
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