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Abstract
Vascular endothelial growth factor (VEGF) is a mitogen for endothelial cells and an inducer of angiogenesis. VEGF is also known as a vascular permeability factor because it can stimulate vascular permeability. In the rodent, increased uterine vascular permeability occurs at the sites of blastocysts with the onset of the attachment reaction. This is followed by stromal decidualization and angiogenesis. We examined the temporal and spatial expression of VEGF and its receptors, Flk-1 and Flt-1, in the mouse uterus during the peri-implantation period (days 1–8) using Northern and in situ hybridization to assess the involvement of VEGF in the process of implantation. Primarily, a major (≈4·2 kb) transcript for VEGF mRNA was detected in uterine poly(A) samples, except for the presence of two other minor (≈3·7 and 2·5 kb) transcripts in decidual samples. The steady-state levels of these transcripts did not vary much during the peri-implantation period, except for an increase in day-8 decidual samples. Results of in situ hybridization experiments demonstrated accumulation of VEGF mRNA in the luminal epithelium on days 1 and 2. In contrast, stromal cells exhibited a modest level of signals on day 3. On day 4, luminal epithelial cells and those in the subepithelial stromal bed accumulated VEGF mRNA. On days 5–7, a clear cell type-specific accumulation of this mRNA was noted. On day 5 after the initial attachment reaction, luminal epithelial and stromal cells immediately surrounding the blastocyst exhibited accumulation of VEGF mRNA. On days 6–8, the accumulation occurred in cells in the decidual bed at both the mesometrial and antimesometrial poles. The embryo, especially the trophoblast giant cells, also accumulated VEGF mRNA on day 8.
The expression of the VEGF receptors, Flk-1 and Flt-1, was also examined. A single transcript (≈6·5-7·0 kb) for Flk-1 mRNA and two transcripts (≈6·5 and 7·5 kb) for that of Flt-1 were detected in poly(A)+ uterine RNA samples. In situ hybridization studies showed accumulation of Flk-1 mRNA in a subset of cells in the stromal bed on day 4, but not in any uterine cell types on day 1. On days 5–8, cells in both the mesometrial and antimesometrial decidual beds exhibited accumulation of Flk-1 and Flt-1 mRNAs. Lectin binding (Dolichos biflorus agglutinin) was used to identify newly sprouting endothelial cells (angiogenesis), while an antibody to the von Willebrand factor (vWF) was employed to identify endothelial cells in general. The results suggest that vWF-positive stromal cells on day 4 and cells in the antimesometrial decidual bed on days 5–8 correlated with the expression of Flk-1 mRNA, as did the vWF- and lectin-positive cells in the mesometrial decidual bed. This implies that cells involved in angiogenesis at the mesometrial pole express the VEGF receptor mRNAs. In contrast, perhaps the endothelial cells of the existing blood vessels in the stromal bed on day 4 and those in the antimesometrial decidual bed on days 5–8 accumulated the receptor mRNAs, suggesting an involvement of VEGF in changes in vascular permeability. Flk-1 mRNA was also detected in embryonic tissues on day 8.
Collectively, the results suggest that VEGF participates in increased vascular permeability and/or angiogenesis occurring in the uterine vascular bed during implantation. Further, the data suggest that VEGF is involved in trophoblast differentiation and invasion, as well as in decidualization and placentation.
Journal of Endocrinology (1995) 147, 339–352
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ABSTRACT
The main objective of the present study was to analyse the hormonal dependence of the metrial gland formed in pseudopregnant animals following massive decidualization. On day 13 of pseudopregnancy (when the metrial gland reaches its maximal development) animals were ovariectomized and given s.c. implants of oestradiol and/or progesterone. A new implant technique for oestradiol delivery is described which provides circulating concentrations of oestradiol in the physiological range.
In addition, we extended our previous work concerning oestradiol receptor and progesterone receptor concentrations in the metrial gland of pseudopregnant rats. The low oestradiol receptor concentration which we previously reported up to day 17 was maintained until the end of pseudopregnancy (day 21–1·5 fmol/μg DNA), whereas the progesterone receptor concentration remained raised (≃3·5 fmol/μg DNA) from day 13 to day 19 and then decreased on day 21.
The correlation of metrial gland weight and kinetics of the tissue oestradiol and progesterone receptors contents with the circulating oestradiol and progesterone concentrations lead to the following conclusions. First, the maintenance of the metrial gland is strictly progesterone-dependent. It is unlike the deciduoma which regresses spontaneously, even in the presence of progesterone. Secondly, the production of oestradiol receptor, but not of progesterone receptor, appears to be repressed in the metrial gland under the influence of progesterone. Thus, the tissue retains its ability to respond to progesterone because of a high concentration of progesterone receptor. It is difficult to attribute this high tissue progesterone receptor concentration to oestradiol stimulation since, even at low levels, oestradiol induces tissue regression. We suggest that the high progesterone receptor concentration could be due to constitutive (basal) progesterone receptor production.
Journal of Endocrinology (1989) 120, 465–472
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stimulation, the endometrial stromal cells and endometrial ECM undergo decidualization. During decidualization, endometrial tissue remodulates, which includes secretory transformation of the uterine glands, influx of specialized uterine natural killer (NK
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decidualization during pregnancy to form specialized decidual cells that are required for embryo implantation ( Ramathal et al. 2010 ). The decidualization process occurs after ovulation during the mid-secretory phase of the menstrual cycle and the decidua is
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differentiated stromal cells form the maternal interface with the placenta and make up a tissue referred to as the decidua ( Bell 1983 ). The importance of decidualization for successful pregnancy is now irrefutable because mice lacking genes that are essential
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rat uterus ( Martel et al . 1989 , Papay & Kennedy 2000 , Shi et al . 2005 ). In the rat uterus, attachment and invasion of embryonic trophoblast is accompanied by decidualization of the adjacent endometrial stroma. Decidualization involves
Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Department of Obstetrics and Gynecology, Key Laboratory and Unit of Infertility in Chinese Medicine, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin, China
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Department of Traditional Chinese Medicine, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Department of Integrative Medicine and Neurobiology, State Key Lab of Medical Neurobiology, Shanghai Medical College and Institute of Acupuncture Research (WHO Collaborating Center for Traditional Medicine), Institute of Brain Science, Fudan University, Shanghai, China
Institute of Integrative Medicine of Fudan University, Shanghai, China
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Department of Gynecology Obstetrics and Gynecology, Hospital of Fudan University, Shanghai, China
Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai, China
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-regulated kinase (ERK) signaling pathway ( Gellersen & Brosens 2014 , Patel et al. 2015 ). While high levels of ERK1/2 expression and activation reflect the P4-PGR signaling-induced decidualization status in human and rodent uteri ( Thienel et al. 2002 , Lee
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described in the decidua of interleukin-11 receptor α null mice which are infertile due to aberrations in decidualization and trophoblast invasion ( Garcia et al . 2007 ). Studies in endometrial cancer-derived Ishikawa cells indicate that silencing of
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, polyploidization, and changes in gene expression including increased expression of decidual prolactin, IGF-binding protein 1 (IGFBP1) and fibroblast growth factor (FGF). Mice lacking genes that control decidualization cannot maintain pregnancy ( Laws et al. 2008
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stromal decidualization in this species ( Pawar et al. 2015 ). The pattern of expression of ERβ is distinct from that of ERα, with highest concentrations of mRNA encoding full-length ERβ1 in the secretory phase and immunoexpression in epithelial, stromal
