Signaling by hypoxia-inducible factors is critical for ovulation in mice.

Abstract

The steroid hormone progesterone, acting via its nuclear receptor, is a major regulator of the process of ovulation. Female mice lacking progesterone receptor (PGR) exhibit an anovulatory phenotype due to failure in follicular rupture. To identify the PGR-regulated pathways that control ovulation, we analyzed global changes in gene expression in the ovaries of wild-type and Pgr-null mice subjected to gonadotropin-induced superovulation. Our analysis uncovered several genes whose expression was reduced in the Pgr-null ovaries compared with the wild-type ovaries immediately preceding ovulation. Interestingly, these genes included three hypoxia-inducible factors (HIFs): HIF-1 alpha, HIF-2 alpha, and HIF-1 beta. These transcription factors form alphabeta-heterodimers, which regulate the transcription of specific cellular genes, thereby mediating adaptive response of the tissue to low-oxygen levels. We observed that the expression of mRNAs and proteins corresponding to HIF-1 alpha, HIF-2 alpha, and HIF-1 beta was induced in a PGR-dependent manner, specifically in the granulosa cells of the preovulatory follicles. Inhibition of the HIF transcriptional activity by echinomycin, a small-molecule inhibitor that suppresses the binding of HIF alphabeta-heterodimers to target genes, blocked ovulation by preventing the rupture of the preovulatory follicles. Echinomycin specifically inhibited the expression of genes that are known regulators of ovulation, such as a disintegrin and metalloproteinase with thrombospondin-like motifs-1 and endothelin-2. Furthermore, echinomycin reduced the expression of vascular endothelial growth factor A, a key factor controlling vascularization/angiogenesis during ovulation. Collectively, these findings unveiled a novel ovarian role for the HIF transcription factors during the ovulatory period in mice.

• Authors: Jaeyeon Kim, Indrani C Bagchi, Milan K Bagchi
• Journal: Endocrinology (Endocrinology) Vol. 150 Issue 7 Pg. 3392-400 (Jul 2009) ISSN: 1945-7170 [Electronic] United States
• PMID: 19325003 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Basic Helix-Loop-Helix Transcription Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Receptors, Progesterone
• Vascular Endothelial Growth Factor A
• Aryl Hydrocarbon Receptor Nuclear Translocator
• endothelial PAS domain-containing protein 1
• Echinomycin

Topics

• Animals
• Aryl Hydrocarbon Receptor Nuclear Translocator (physiology)
• Basic Helix-Loop-Helix Transcription Factors (physiology)
• Cell Hypoxia (physiology)
• Echinomycin (pharmacology)
• Female
• Gene Expression Profiling
• Granulosa Cells (drug effects, metabolism)
• Hypoxia-Inducible Factor 1, alpha Subunit (physiology)
• Mice
• Ovary (metabolism)
• Ovulation (physiology)
• Receptors, Progesterone (deficiency, physiology)
• Vascular Endothelial Growth Factor A (biosynthesis)