Sci Rep. 2020 May 12;10(1):7849. doi: 10.1038/s41598-020-63900-0.

Ashton Faulkner  1   2 , Eleanor Lynam  1 , Robert Purcell  1 , Coleen Jones  1 , Colleen Lopez  3 , Mary Board  3 , Kay-Dietrich Wagner  4 , Nicole Wagner  4 , Carolyn Carr  3 , Caroline Wheeler-Jones  5


1 Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.
Experimental Cardiovascular Medicine, Bristol Medical School, University of Bristol, Bristol, UK.
Department of Physiology Anatomy & Genetics, University of Oxford, Oxford, UK.
Université Côte d’Azur, Institute of Biology Valrose, Nice (iBV), CNRS UMR7277, INSERM U1091, Nice, France.
Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK.


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.

PMID: 32398728
DOI: 10.1038/s41598-020-63900-0