Signaling by Hypoxia-Inducible Factors Is Critical for Ovulation In Mice
-
- Jaeyeon Kim
- Departments of Molecular and Integrative Physiology (J.K., M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801
-
- Indrani C. Bagchi
- Departments of Veterinary Biosciences (I.C.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801
-
- Milan K. Bagchi
- Departments of Molecular and Integrative Physiology (J.K., M.K.B.), University of Illinois at Urbana-Champaign, Urbana, Illinois 61801
Description
<jats:p>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-1α, HIF-2α, and HIF-1β. These transcription factors form αβ-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-1α, HIF-2α, 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 αβ-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.</jats:p>
Journal
-
- Endocrinology
-
Endocrinology 150 (7), 3392-3400, 2009-03-26
The Endocrine Society
- Tweet
Details 詳細情報について
-
- CRID
- 1362262944489553920
-
- ISSN
- 19457170
- 00137227
- http://id.crossref.org/issn/00137227
-
- Data Source
-
- Crossref