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

Faulkner, A; Lynam, E; Purcell, R; Jones, C; Lopez, C; Board, M; Wagner, K-D; Wagner, N; Carr, C; Wheeler-Jones, C

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.

Citation

Faulkner, A., Lynam, E., Purcell, R., Jones, C., Lopez, C., Board, M., Wagner, K.-D., Wagner, N., Carr, C., & Wheeler-Jones, C. (2020). Context-dependent regulation of endothelial cell metabolism: differential effects of the PPARβ/δ agonist GW0742 and VEGF-A. Scientific Reports, 10(1), https://doi.org/10.1038/s41598-020-63900-0

• Journal Article Type: Article
• Acceptance Date: Apr 7, 2020
• Publication Date: May 12, 2020
• Deposit Date: May 12, 2020
• Publicly Available Date: May 12, 2020
• Journal: Scientific Reports
• Electronic ISSN: 2045-2322
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 10
• Issue: 1
• DOI: https://doi.org/10.1038/s41598-020-63900-0
• Public URL: https://rvc-repository.worktribe.com/output/1377346