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.
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.
van den Driesche
Sander
S
Obstetrics and Gynaecology, Department of Reproductive and Developmental Sciences, The Queen's Medical Research Institute, Centre for Reproductive Biology, University of Edinburgh, Edinburgh EH16 4TJ, UK. s.vandendriesche@hrsu.mrc.ac.uk
Myers
Michelle
M
Gay
Eva
E
Thong
K Joo
KJ
Duncan
W Colin
WC
D003994:Bucladesine / Q000494:pharmacology; D015687:Cell Hypoxia; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000494:pharmacology*; D003338:Corpus Luteum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006107:Granulosa Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
D006063:Chorionic Gonadotropin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D011374:Progesterone; D003994:Bucladesine