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Context-dependent regulation of endothelial cell metabolism: differential effects of the PPAR?/? 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


A Faulkner

E Lynam

R Purcell

C Jones

C Lopez

M Board

K-D Wagner

N Wagner

C Carr

C Wheeler-Jones


Peroxisome proliferator activated receptor ?/? (PPAR?/?) has pro-angiogenic functions, but whether PPAR?/? modulates endothelial cell metabolism to support the dynamic phenotype remains to be established. This study characterised the metabolic response of HUVEC to the PPAR?/? 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?/? or sirtuin-1 showed that the tubulogenic effect of GW0742, but not VEGF-A, was PPAR?/?- 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?/? in the endothelium and support the targeting of PPAR?/? in regulating EC behaviour and boosting tissue maintenance and repair.


Faulkner, A., Lynam, E., Purcell, R., Jones, C., Lopez, C., Board, M., …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),

Journal Article Type Article
Acceptance Date Apr 7, 2020
Publication Date May 12, 2020
Deposit Date May 12, 2020
Publicly Available Date Nov 20, 2020
Journal Scientific Reports
Publisher Nature Research
Peer Reviewed Peer Reviewed
Volume 10
Issue 1
Public URL


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