Projects per year
Placenta growth factor (PlGF) is a pro-inflammatory angiogenic mediator that promotes many pathologies including diabetic complications and atherosclerosis. Widespread endothelial dysfunction precedes the onset of these conditions. As very little is known of the mechanism(s) controlling PlGF expression in pathology we investigated the role of hyperglycaemia in the regulation of PlGF production in endothelial cells. Hyperglycaemia stimulated PlGF secretion in cultured primary endothelial cells, which was suppressed by IGF-1-mediated PI3K/Akt activation. Inhibition of PI3K activity resulted in significant PlGF mRNA up-regulation and protein secretion. Similarly, loss or inhibition of Akt activity significantly increased basal PlGF expression and prevented any further PlGF secretion in hyperglycaemia. Conversely, constitutive Akt activation blocked PlGF secretion irrespective of upstream PI3K activity demonstrating that Akt is a central regulator of PlGF expression. Knock-down of the Forkhead box O-1 (FOXO1) transcription factor, which is negatively regulated by Akt, suppressed both basal and hyperglycaemia-induced PlGF secretion, whilst FOXO1 gain-of-function up-regulated PlGF in vitro and in vivo. FOXO1 association to a FOXO binding sequence identified in the PlGF promoter also increased in hyperglycaemia. This study identifies the PI3K/Akt/FOXO1 signalling axis as a key regulator of PlGF expression and unifying pathway by which PlGF may contribute to common disorders characterised by endothelial dysfunction, providing a target for therapy.
|Number of pages||13|
|Publication status||Published - 11 Aug 2021|
Bibliographical noteFunding Information:
This work was supported by grants from the Medical Research Council (G0601295 and G0700288) and Birmingham Women’s Hospital Trust, Birmingham UK. S.S. was supported by a Medical Research Council DTP studentship. The authors wish to thank Dr Margaret Eggo for her considerable help and advice during the study.
© 2021, The Author(s).
FingerprintDive into the research topics of 'Hyperglycaemia up-regulates placental growth factor (PlGF) expression and secretion in endothelial cells via suppression of PI3 kinase-Akt signalling and activation of FOXO1'. Together they form a unique fingerprint.
- 2 Finished
Angiogenic Biomarkers as Predictive Tests for Early Onset Preeclampsia: A Population-Based Study
Ahmed, A., Daniels, J. & Khan, K.
1/07/08 → 30/06/11
Project: Research Councils
The Role of Endogenous Vascular Protection Factors in Preeclampsia
Ahmed, A., Hewett, P., Ahmad, S. & Cudmore, M.
9/06/08 → 14/03/12
Project: Research Councils