Multiple Female Reproductive Failures in Cyclooxygenase 2–Deficient Mice

Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City 66160, USA.
Cell (Impact Factor: 32.24). 10/1997; 91(2):197-208. DOI: 10.1016/S0092-8674(00)80402-X


Cyclooxygenase (COX) is the rate-limiting enzyme in the synthesis of prostaglandins (PGs) and exists in two isoforms, COX-1 and COX-2. In spite of long-standing speculation, definitive roles of PGs in various events of early pregnancy remain elusive. We demonstrate herein that the targeted disruption of COX-2, but not COX-1, in mice produces multiple failures in female reproductive processes that include ovulation, fertilization, implantation, and decidualization. Using multiple approaches, we conclude that these defects are the direct result of target organ–specific COX-2 deficiency but are not the result of deficiency of pituitary gonadotropins or ovarian steroid hormones, or reduced responsiveness of the target organs to their respective hormones.

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Available from: Sudhansu K Dey, Sep 14, 2015
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    • "These compounds have been reported to induce UFs in mature rats by single dose (Gaytán et al., 2003). Relevance of COX2 and PR to female fertility has been also demonstrated by Cox2-or Pr-deficient mice (Lim et al., 1997; Lydon et al., 1995). COX2 induction and PR activation occur via independent signaling pathways, as Pr is expressed in Cox2- deficient mice and vice versa, Cox2 is expressed in Pr-deficient mice (Richards et al., 1998). "
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    ABSTRACT: It is well-known that indomethacin (the cyclooxygenase 1 & 2 inhibitor) and RU486 (or mifepristone, the progesterone receptor antagonist) block follicular rupture in rats. To characterize genetic alterations in unruptured follicles, gene expression profiles in ovarian follicle were analyzed in indomethacin- and RU486-treated female Sprague-Dawley rats. Ovaries are collected at 22:00 on the proestrus day and 10:00 on the following estrus day after a single dose of indomethacin and RU486. Histopathologically, changes depicting responses to LH surge were observed in ovaries, uteri and vagina. Total RNA was extracted from pre-ovulatory follicles or unruptured follicles collected by laser microdissection and analyzed by Genechip(®). Among genes showing statistically significant changes compared to control groups, following changes were considered relevant to induction of unruptured follicles. In indomethacin-treated rats, Wnt4 was down-regulated, suggesting effect on tissue integrity and steroid genesis. In RU486-treated rats, Adamts1, Adamts9, Edn2, Ednra, Lyve1, Plat, and Pparg were down-regulated. These changes suggest effects on proteolysis for extra cellular matrix or surrounding tissue (Adamts1 & 9, and Plat), constriction of smooth muscle surrounding follicles (Edn2, Ednra, and Pparg), follicular fluid (Lyve1), and angiogenesis (Pparg). Down-regulation of angiogenesis related genes (Angpt2, Hmox1, and Vegfa) was observed in both treatment groups. Here, we clarify genetic alterations induced by the inhibition of cyclooxygenase or progesterone receptor.
    The Journal of Toxicological Sciences 05/2015; 40(3):413-25. DOI:10.2131/jts.40.413 · 1.29 Impact Factor
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    • "Several studies have shown that deficient decidualization results in early embryonic lethality and infertility. For example, mice deficient in COX-2 revealed abnormal implantation and decidualization (Lim et al., 1997). Furthermore, the use of COX inhibitors results in deficient decidual growth, whereas the supplementation of prostaglandin E2 (PGE2) or prostaglandin F2α (PGF2 α) restores it (Kennedy et al., 1983; Martel et al., 1985). "
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    ABSTRACT: The major endocannabinoid, anandamide (AEA), is widely distributed in the body, especially in the reproductive tissues, where it is implicated in early pregnancy events, particularly during implantation period. Although AEA is synthesized in decidual cells and showed to induce apoptosis through CB1 receptor, its roles in decidualization remain to be elucidated. This study examined the effect of AEA in the progression of decidualization both in vitro and in vivo and explored the involvement of COX-2 in its action. To determine the function of AEA during this differentiation process, we employed a primary culture system in which undifferentiated stromal cells isolated from pregnant rat uterus undergo decidualization. AEA treatment markedly interfered with the differentiation program, as revealed by α2-macroglobulin (α2-MG) expression and alkaline phosphatase activity. Additionally, it was evaluated the effects of AEA in decidual establishment in the pseudopregnant rat model. The abundance of AEA in the uterine lumen disrupted the decidualization process accompanied by a decreased expression of COX-2 and VEGF. It was also observed that uterine lumen, which failed the progression of decidualization in response to AEA, also presented lower expression of NAPE-PLD and FAAH. Thus, the mechanisms by which AEA inhibits decidualization can be either via direct actions on stromal cell differentiation within the reproductive tract system or by the inhibition of COX-2 derived products and, consequently, the vascular remodelling required to proper decidualization. In addition, the previous observations showing that higher AEA levels in pre-implantation sites are hostile to blastocyst survival may result from problems in decidual cell reaction more than with implantation failure. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 05/2015; 411. DOI:10.1016/j.mce.2015.04.024 · 4.41 Impact Factor
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    • "Blastocysts are positioned in the implantation chamber (crypt) in the afternoon of day 4 (Cha et al., 2014). Prior to and upon initiation of blastocyst attachment, changes in gene expression are observed in both LE and stromal cells encircling the blastocyst, suggesting blastocyst-uterine interactions (Das et al., 1994; Lim et al., 1997). We found that LE cells were tightly held together surrounding the blastocyst in the implantation chamber on the morning of day 5 of pregnancy. "
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    ABSTRACT: During implantation, uterine luminal epithelial (LE) cells first interact with the blastocyst trophectoderm. Within 30 hr after the initiation of attachment, LE cells surrounding the blastocyst in the implantation chamber (crypt) disappear, allowing trophoblast cells to make direct physical contact with the underneath stroma for successful implantation. The mechanism for the extraction of LE cells was thought to be mediated by apoptosis. Here, we show that LE cells in direct contact with the blastocyst are endocytosed by trophoblast cells by adopting the nonapoptotic cell-in-cell invasion process (entosis) in the absence of caspase 3 activation. Our in vivo observations were reinforced by the results of co-culture experiments with primary uterine epithelial cells with trophoblast stem cells or blastocysts showing internalization of epithelial cells by trophoblasts. We have identified entosis as a mechanism to remove LE cells by trophoblast cells in implantation, conferring a role for entosis in an important physiological process. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 04/2015; 11(3). DOI:10.1016/j.celrep.2015.03.035 · 8.36 Impact Factor
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