Chromatin Immunoprecipitation Analysis of Gene Expression in the Rat Uterus<i>in Vivo</i>: Estrogen-Induced Recruitment of Both Estrogen Receptor α and Hypoxia-Inducible Factor 1 to the Vascular Endothelial Growth Factor Promoter

Kazi, Armina A.; Jones, Jenny M.; Koos, Robert D.

doi:10.1210/me.2004-0388

Cited by 109 publications

(117 citation statements)

References 76 publications

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“…Ang-2 is upregulated by chorionic gonadotropin in the rat testis (Haggstrom-Rudolfsson et al, 2003), while ACTH stimulated Ang-1 in the murine adult adrenal gland (Feraud et al, 2003) and Ang-2 in the human fetal adrenal in culture (Ishimoto et al, 2003). Moreover, hypoxia seems to have an important role in modulating Ang-2 formation in human placental villous explants (Zhang et al, 2001) and the action of estrogen on VEGF expression in the rodent uterus (Kazi et al, 2005). We suggest that the baboon provides an excellent nonhuman primate model to unravel in vivo the regulatory role that estrogen has on placental angiogenesis.…”

Section: Discussionmentioning

confidence: 90%

Regulation of placental villous angiopoietin‐1 and ‐2 expression by estrogen during baboon pregnancy

Albrecht

Babischkin

Pepe

2007

Molecular Reproduction Devel

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We recently showed an increase in vascular endothelial growth factor (VEGF), decrease in angiopoietin-1 (Ang-1) and unaltered Ang-2 expression by the villous placenta with advancing baboon pregnancy. Moreover, placental VEGF expression was increased by estrogen in early pregnancy. In the present study, we determined whether placental Ang-1 and Ang-2 are regulated by estrogen. Ang-1 and Ang-2 mRNA and protein were determined by RT-PCR and immunocytochemistry in the placenta of baboons on day 60 of gestation (term is 184 days) after administration of estrogen precursor androstenedione on days 25-59 or on day 54 after acute estradiol administration. Chronic androstenedione treatment increased serum estradiol levels 3-fold (P<0.001) and decreased (P<0.05) villous cytotrophoblast Ang-1 mRNA to a level (0.36 ± 0.08 relative to 18S rRNA) that was one-third of that in untreated animals (0.98 ± 0.26). Within 2 h of estradiol administration, cytotrophoblast Ang-1 mRNA was decreased to a level (0.24 ± 0.05) one-fifth (P<0.05) of that in untreated animals (1.14 ± 0.23). However, Ang-2 mRNA levels were unaltered. Ang-1, Ang-2 and estrogen receptors α and β protein were localized within villous cytotrophoblasts providing a mechanism for estrogen action at this site. In summary, estrogen increased VEGF, decreased Ang-1, and had no effect on Ang-2 expression within placental cytotrophoblasts during early baboon pregnancy. We propose that the estrogen-dependent differential regulation of these angioregulatory factors underpins the unique pattern of neovascularization established within the villous placenta during primate pregnancy.

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Section: Discussionmentioning

confidence: 90%

Regulation of placental villous angiopoietin‐1 and ‐2 expression by estrogen during baboon pregnancy

Albrecht

Babischkin

Pepe

2007

Molecular Reproduction Devel

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“…cis hypoxia-response element in their promoter or enhancer regions (10,44,45). Therefore, the present study treated pregnant rats with a HIF-1α specific small-molecule inhibitor, Ech, and then examined the levels of gene expression and progesterone secretion.…”

Section: Discussionmentioning

confidence: 99%

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Zhang

Pan

et al. 2015

Mol Med Report

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Abstract. Vascular endothelial growth factor (VEGF) is vital in normal and abnormal angiogenesis in the ovary, particularly during the early development of the corpus luteum in the ovary. However, the molecular regulation of the expression VEGF during luteal development in vivo remains to be fully elucidated. As the expression of VEGF is mediated by hypoxia-inducible factor (HIF)-1α in luteal cells cultured in vitro, determined in our previous study, the present study was performed to confirm the hypothesis that HIF-1α is induced and then regulates the expression of VEGF and VEGF-dependent luteal development/function in vivo. This was investigated using a pregnant rat model treated with a small-molecule inhibitor of HIF-1α, echinomycin (Ech). The development of the corpus luteum in the pregnant rat ovary was identified via performing assays of the serum progesterone, testosterone and estradiol concentrations by radioimmunoassay, accompanied with determination of the changes in the expression levels of HIF-1α and VEGF by reverse transcription-quantitative polymerase chain reaction at different days of the developmental process. On day 5, serum progesterone levels were markedly increased, whereas serum levels of testosterone and estradiol did not change significantly. On day 17, the highest level of serum progesterone was observed, however, this was not the case for testosterone and estradiol. Further analysis of the expression levels of HIF-1α and VEGF revealed that their changes were consistent with the changes in serum levels of progesterone, which occurred in the development of the corpus luteum in the ovaries of pregnant rats. Further investigation demonstrated that Ech inhibited luteal development through inhibiting the expression of VEGF, mediated by HIF-1α, and subsequent luteal function, which was determined by detecting changes in serum progesterone on days 8 and 14. Taken together, these results demonstrated that HIF-1α-mediated expression of VEGF may be one of the important mechanisms regulating ovarian luteal development in mammals in vivo, which may provide novel strategies in treatment for fertility control and for certain types of ovarian dysfunction, including polycystic ovarian syndrome, ovarian hyperstimulation syndrome and ovarian neoplasia.

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“…Another study revealed that a direct interaction between BRCA1 and ER regulates VEGF transcription and secretion (Kawai et al 2002). Notably, estrogen has also been associated with HIF1a regulation of VEGF, and induced recruitment of both ER and HIF1a to the VEGF promoter in the rat uterus (Kazi et al 2005). Thus, the co-binding of the activated ER with other transcription factors, to non-classical binding sites on gene promoters, appears to be a common mechanism underlying estrogen regulation of gene transcription.…”

Section: Discussionmentioning

confidence: 99%

Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor α and c-Myc

Dadiani¹,

Seger²,

Kreizman³

et al. 2009

Endocrine-Related Cancer

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The role of c-Myc in estrogen regulation of vascular endothelial growth factor (VEGF) and of the vasculature function has been investigated in breast cancer cells and tumors. The studies were performed on MCF7 wild-type cells and MCF7-35im clone, stably transfected with an inducible c-Myc gene. In vitro and ex vivo methods for investigating molecular events were integrated with in vivo magnetic resonance imaging of the vascular function. The results showed that the c-Myc upregulation by estrogen is necessary for the transient induction of VEGF transcription; however, overexpression of c-Myc alone is not sufficient for this induction. Furthermore, both c-Myc and the activated estrogen receptor a (ERa) were shown to co-bind the VEGF promoter in close proximity, indicating a novel mechanism for estrogen regulation of VEGF. Studies of long-term estrogen treatment and overexpression of c-Myc alone demonstrated regulation of stable VEGF expression levels in vitro and in vivo, maintaining steady vascular permeability in tumors. However, withdrawal of estrogen from the tumors resulted in increased VEGF and elevated vascular permeability, presumably due to hypoxic conditions that were found to dominate VEGF overexpression in cultured cells. This work revealed a cooperative role for ERa and c-Myc in estrogen regulation of VEGF and the ability of c-Myc to partially mimic estrogen regulation of angiogenesis. It also illuminated the differences in estrogen regulation of VEGF during transient and long-term sustained treatments and under different microenvironmental conditions, providing a complementary picture of the in vitro and in vivo results.

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Chromatin Immunoprecipitation Analysis of Gene Expression in the Rat Uterusin Vivo: Estrogen-Induced Recruitment of Both Estrogen Receptor α and Hypoxia-Inducible Factor 1 to the Vascular Endothelial Growth Factor Promoter

Cited by 109 publications

References 76 publications

Regulation of placental villous angiopoietin‐1 and ‐2 expression by estrogen during baboon pregnancy

Regulation of placental villous angiopoietin‐1 and ‐2 expression by estrogen during baboon pregnancy

Expression and contribution of the HIF‑1α/VEGF signaling pathway to luteal development and function in pregnant rats

Estrogen regulation of vascular endothelial growth factor in breast cancer in vitro and in vivo: the role of estrogen receptor α and c-Myc

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