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Signaling by Hypoxia-Inducible Factors Is Critical for Ovulation In Mice

Departments of Molecular and Integrative Physiology (J.K., M.K.B.) and Veterinary Biosciences (I.C.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801

Address all correspondence and requests for reprints to: Dr. Milan K. Bagchi, Center for Research in Reproduction and Infertility, Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, 534 Burrill Hall, 407 South Goodwin Avenue, Urbana, Illinois 61801. E-mail: mbagchi{at}life.uiuc.edu.

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, HIF-2, and HIF-1β. These transcription factors form β-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, HIF-2, and HIF-1β 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 β-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.

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				J. Kim, I. C. Bagchi, and M. K. Bagchi Control of ovulation in mice by progesterone receptor-regulated gene networks Mol. Hum. Reprod., December 1, 2009; 15(12): 821 - 828. [Abstract] [Full Text] [PDF]