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Mol. Hum. Reprod. Advance Access originally published online on June 30, 2008
Molecular Human Reproduction 2008 14(8):455-464; doi:10.1093/molehr/gan040
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© The Author 2008. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

HCG up-regulates hypoxia inducible factor-1 alpha in luteinized granulosa cells: implications for the hormonal regulation of vascular endothelial growth factor A in the human corpus luteum

Sander van den Driesche1,2,4, Michelle Myers1,3, Eva Gay1, K. Joo Thong1 and W. Colin Duncan1

1Obstetrics and Gynaecology, Department of Reproductive and Developmental Sciences, The Queen's Medical Research Institute, Centre for Reproductive Biology, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK 2Present address: MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK 3Present address: Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, UK

4 Correspondence address. MRC Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. Tel: +44-131-242-9124; E-mail: s.vandendriesche{at}hrsu.mrc.ac.uk

Vascular endothelial growth factor (VEGF)-dependent angiogenesis is essential for normal luteal development. Although it is believed that hypoxia is the primary inducer of VEGF, in the corpus luteum it is up-regulated by human chorionic gonadotrophin (hCG). As hypoxia-inducible factor (HIF)1A has been shown to regulate VEGFA under ligand-stimulated conditions, we hypothesized that the effect of hCG on luteal VEGFA was mediated through HIF1A. We studied the effect of hCG on VEGFA and HIF1A expression in human luteinized granulosa cells in vitro and in human corpora lutea in vivo. HCG up-regulated VEGFA (P < 0.05) and HIF1A (P < 0.001) in vitro and VEGFA (P < 0.05) and HIF1A (P < 0.05) in vivo. There was a correlation between HIF1A and VEGFA in vivo (P < 0.005) and in vitro (P < 0.05). Nuclear HIF1A in granulosa-lutein cells was highest during luteal formation and absent from the fully functional corpus luteum (P < 0.05). Both VEGFA (P < 0.001) and HIF1A (P < 0.01) were up-regulated by dibutyryl-cAMP, through a PKA pathway. Hypoxia increased VEGFA (P < 0.001) and HIF1A (P < 0.05) expression and hCG further augmented VEGFA (P < 0.001) and HIF1A (P < 0.01) under hypoxic conditions. However, progesterone increased hCG-stimulated VEGFA but had no effect on HIF1A expression. The expression of HIF1A is therefore hormonally regulated in luteal cells in vitro and in vivo and may regulate VEGFA expression under normoxic and hypoxic conditions. However, the differential effects of progesterone suggest that not all regulation of VEGFA is associated with an up-regulation of HIF1A.

Key words: hCG/VEGFA/HIF1A/hypoxia/corpus luteum

Submitted on June 6, 2008; resubmitted on June 26, 2008; accepted on June 27, 2008.


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