Expression of Hypoxia-inducible Factors in the Peri-implantation Mouse Uterus Is Regulated in a Cell-specific and Ovarian Steroid Hormone-dependent Manner
Open Access
- 1 February 2003
- journal article
- Published by Elsevier BV in Journal of Biological Chemistry
- Vol. 278 (9), 7683-7691
- https://doi.org/10.1074/jbc.m211390200
Abstract
Increased uterine vascular permeability and angiogenesis are hallmarks of implantation and placentation. These events are profoundly influenced by vascular endothelial growth factor (VEGF). We previously showed that VEGF isoforms and VEGF receptors are expressed in the uterus, suggesting the role of VEGF in uterine vascular permeability and angiogenesis required for implantation and decidualization. We have recently shown that estrogen promotes uterine vascular permeability but inhibits angiogenesis, whereas progesterone stimulates angiogenesis with little effect on vascular permeability. However, the mechanism of differential steroid hormonal regulation of uterine angiogenesis remains unresolved. Oxygen homeostasis is essential for cell survival and is primarily mediated by hypoxia-inducible factors (HIFs). These factors are intimately associated with vascular events and induce VEGF expression by binding to the hypoxia response element in the VEGF promoter. HIFalpha isoforms function by forming heterodimers with the aryl hydrocarbon nuclear translocator (ARNT) (HIF-beta) family members. There is very limited information on the relationship among HIFs, ARNTs, and VEGF in the uterus during early pregnancy, although the role of HIFs in regulating VEGF and angiogenesis in cancers is well documented. Using molecular and physiological approaches, we here show that uterine expression of HIFs and ARNTs does not correlate with VEGF expression during the preimplantation period (days 1-4) in mice. In contrast, their expression follows the localization of uterine VEGF expression with increasing angiogenesis during the postimplantation period (days 5-8). This disparate pattern of uterine HIFs, ARNTs, and VEGF expression on days 1-4 of pregnancy suggests HIFs have multiple roles in addition to the regulation of angiogenesis during the peri-implantation period. Using pharmacological, molecular, and genetic approaches, we also observed that although progesterone primarily up-regulates uterine HIF-1alpha expression, estrogen transiently stimulates that of HIF-2alpha.Keywords
This publication has 58 references indexed in Scilit:
- Cyclooxygenase-2 Differentially Directs Uterine Angiogenesis during Implantation in MicePublished by Elsevier BV ,2002
- Cellular adaptation to hypoxia: O2‐sensing protein hydroxylases, hypoxia‐inducible transcription factors, and O2‐regulated gene expressionThe FASEB Journal, 2002
- The bHLH/PAS Factor MOP3 Does Not Participate in Hypoxia ResponsesBiochemical and Biophysical Research Communications, 2002
- Estrogen Targets Genes Involved in Protein Processing, Calcium Homeostasis, and Wnt Signaling in the Mouse Uterus Independent of Estrogen Receptor-α and -βPublished by Elsevier BV ,2000
- Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFβ3JCI Insight, 2000
- Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1αGenes & Development, 1998
- Vascular endothelial growth factorEuropean Journal Of Cancer, 1996
- Nucleotide Sequence, Chromosomal Assignment and mRNA Expression of Mouse Hypoxia-Inducible Factor-1αBiochemical and Biophysical Research Communications, 1996
- Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities.Genes & Development, 1995
- Purification and Characterization of Hypoxia-inducible Factor 1Journal of Biological Chemistry, 1995