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Author Notes:

Corresponding author N. Sidell: Department of Gynecology and Obstetrics, Emory University School of Medicine, 1639 Pierce Drive, Atlanta, GA 30322, USA. Email: nsidell@emory.edu


Research Funding:

This work was supported by The Eunice Kennedy Schriver NICHD/NIH through Grants HD55379 and HD55787, as part of the Specialized Cooperative Center Program.

Retinoic acid stimulation of VEGF secretion from human endometrial stromal cells is mediated by production of reactive oxygen species


Journal Title:

Journal of Physiology


Volume 589, Number Pt 4


, Pages 863-875

Type of Work:

Article | Post-print: After Peer Review


It is widely accepted that vascular endothelial growth factor (VEGF) is involved in angiogenic functions that are necessary for successful embryonic implantation. We have shown that retinoic acid (RA), which is known to play a necessary role in early events in pregnancy, can combine with transcriptional activators of VEGF (e.g. TPA, TGF-β, IL-1β) to rapidly induce VEGF secretion from human endometrial stromal cells through a translational mechanism of action. We have now determined that this stimulation of VEGF by RA is mediated through an increased production of cellular reactive oxygen species (ROS). Results indicated that RA, but not TPA or TGF-β, directly increases ROS production in endometrial stromal cells and that the co-stimulating activity of RA on VEGF secretion can be mimicked by direct addition of H2O2. Importantly, co-treatment of RA with TPA or TGF-β further stimulated ROS production in a fashion that positively correlated with levels of VEGF secretion. The antioxidants N-acetylcysteine and glutathione monoethyl ester inhibited both RA + TPA and RA + TGF-β-stimulated secretion of VEGF, as well as RA-induced ROS production. Treatment of cells with RA resulted in a shift in the glutathione (GSH) redox potential to a more oxidative state, suggesting that the transduction pathway leading to increased VEGF secretion is at least partially mediated through the antioxidant capacity of GSH couples. The specificity of this action on GSH-sensitive signalling pathways is suggested by the determination that RA had no effect on the redox potential of thioredoxin. Together, these findings predict a redox-mediated mechanism for retinoid regulation of localized VEGF secretion in the human endometrium that may be necessary for the successful establishment of pregnancy.

Copyright information:

Journal compilation © 2011 The Physiological Society

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