Faulkner, A and Lynam, E and Purcell, R and Jones, C and Lopez, C and Board, M and Wagner, K-D and Wagner, N and Carr, C and 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). ISSN 2045-2322
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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.
| Item Type: | Article |
|---|---|
| RVC Publication Type: | Journal Article |
| DOI: | https://doi.org/10.1038/s41598-020-63900-0 |
| Departments: | Comparative Biomedical Sciences |
| Research Programmes: | Comparative Physiology & Medicine > Cardiovascular and Inflammation Biology and Metabolism |
| Depositing User: | Michael Murphy |
| Last Modified: | 19 Feb 2021 14:32 |
| URI: | https://researchonline.rvc.ac.uk/id/eprint/12679 |
| Date Deposited: | 12 May 2020 |
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