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1.  Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium 
Reproduction (Cambridge, England)  2003;126(5):559-567.
Prostaglandins are bioactive lipids produced from arachidonic acid by cyclooxygenase (COX) enzymes and specific terminal prostanoid synthase enzymes. After biosynthesis, prostaglandins exert an autocrine–paracrine function by coupling to specific prostanoid G protein-coupled receptors to activate intracellular signalling and gene transcription. For many years, prostaglandins have been recognized as key molecules in reproductive biology by regulating ovulation, endometrial physiology and proliferation of endometrial glands and menstruation. More recently, a role for COX enzymes and prostaglandins has been ascertained in reproductive tract pathology, including carcinomas, menorrhagia, dysmenorrhoea and endometriosis. Although the mechanism by which prostaglandins modulate these pathologies is still unclear, a large body of evidence supports a role for COX enzymes, prostaglandins and prostaglandin receptor signalling pathways in angiogenesis, apoptosis and proliferation, tissue invasion and metastases and immunosuppression. Here, an overview is provided of some of the findings from these studies with specific emphasis on the role of COX enzymes, prostaglandin E2 and F2α in disorders of endometrial proliferation and menstruation in non-pregnant women.
PMCID: PMC2695735  PMID: 14611628
2.  Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice 
Many signaling pathways that contribute to tumorigenesis are also functional in pregnancy, although they are dysregulated in the former and tightly regulated in the latter. Transformation-related protein 53 (Trp53), which encodes p53, is a tumor suppressor gene whose mutation is strongly associated with cancer. However, its role in normal physiological processes, including female reproduction, is poorly understood. Mice that have a constitutive deletion of Trp53 exhibit widespread development of carcinogenesis at early reproductive ages, compromised spermatogenesis, and fetal exencephaly, rendering them less amenable to studying the role of p53 in reproduction. To overcome this obstacle, we generated mice that harbor a conditional deletion of uterine Trp53 and examined pregnancy outcome in females with this genotype. These mice had normal ovulation, fertilization, and implantation; however, postimplantation uterine decidual cells showed terminal differentiation and senescence-associated growth restriction with increased levels of phosphorylated Akt and p21, factors that are both known to participate in these processes in other systems. Strikingly, uterine deletion of Trp53 increased the incidence of preterm birth, a condition that was corrected by oral administration of the selective COX2 inhibitor celecoxib. We further generated evidence to suggest that deletion of uterine Trp53 induces preterm birth through a COX2/PGF synthase/PGF2α pathway. Taken together, our observations underscore what we believe to be a new critical role of uterine p53 in parturition.
doi:10.1172/JCI40051
PMCID: PMC2827950  PMID: 20124728
3.  Lysophosphatidic Acid (LPA) Signaling in Vertebrate Reproduction 
Lysophosphatidic acid (LPA) is a cell membrane phospholipid metabolite that can act as an extracellular signal. Its effects are mediated through at least five G protein-coupled receptors (GPCRs), LPA1-5, and likely others as well. Studies in multiple species including LPA receptor-deficient mice and humans have identified or implicated important roles for receptor-mediated LPA signaling in multiple aspects of vertebrate reproduction. These include ovarian function, spermatogenesis, fertilization, early embryo development, embryo implantation, embryo spacing, decidualization, pregnancy maintenance, and parturition. LPA signaling may also have pathological consequences, influencing aspects of endometriosis and ovarian cancer. Here we review recent progress in LPA signaling research relevant to female and male reproduction.
doi:10.1016/j.tem.2009.08.003
PMCID: PMC2818173  PMID: 19836970
4.  The role of steroids in follicular growth 
The steroidogenic pathway within the ovary gives rise to progestins, androgens and oestrogens, all of which act via specific nuclear receptors to regulate reproductive function and maintain fertility. The role of progestins in follicular growth and development is limited, its action confined largely to ovulation, although direct effects on granulosa cell function have been reported. Consistent with these findings, progesterone receptor knockout mice are infertile because they cannot ovulate. Androgens have been shown to promote early follicular growth, but also to impede follicular development by stimulating atresia and apoptosis. The inability of androgens to transduce a signal in mice lacking androgen receptors culminates in reduced fertility. Oestrogens are known to exert effects on granulosa cell growth and differentiation in association with gonadotrophins. Studies with oestrogen receptor knockouts and oestrogen depleted mice have shown us that oestrogen is essential for folliculogenesis beyond the antral stage and is necessary to maintain the female phenotype of ovarian somatic cells. In summary, the action of steroids within the ovary is based on the developmental status of the follicle. In the absence of any single sex steroid, ovarian function and subsequently fertility, are compromised.
doi:10.1186/1477-7827-4-16
PMCID: PMC1459164  PMID: 16603089
5.  ESR1 rs9340799 Is Associated with Endometriosis-Related Infertility and In Vitro Fertilization Failure 
Disease Markers  2013;35(6):907-913.
Estrogen receptor alpha has a central role in human fertility by regulating estrogen action in all human reproductive tissues. Leukemia inhibitory factor (LIF) expression, a cytokine critical for blastocyst implantation, is mediated by estrogen signaling, so we hypothesized that ESR1 gene polymorphisms might be candidate risk markers for endometriosis-related infertility and in vitro fertilization (IVF) failure. We included 98 infertile women with endometriosis, 115 infertile women with at least one IVF failure and also 134 fertile women as controls. TaqMan SNP assays were used for genotyping LIF (rs929271), MDM2 (rs2279744), MDM4 (rs1563828), USP7 (rs1529916), and ESR1 (rs9340799 and rs2234693) polymorphisms. The SNP ESR1 rs9340799 was associated with endometriosis-related infertility (P < 0.001) and also with IVF failure (P = 0.018). After controlling for age, infertile women with ESR1 rs9340799 GG genotype presented 4-fold increased risk of endometriosis (OR 4.67, 95% CI 1.84–11.83, P = 0.001) and 3-fold increased risk of IVF failure (OR 3.33, 95% CI 1.38–8.03, P = 0.007). Our results demonstrate an association between ESR1 rs9340799 polymorphism and infertile women with endometriosis and also with women who were submitted to IVF procedures and had no blastocyst implantation.
doi:10.1155/2013/796290
PMCID: PMC3880708  PMID: 24427778
6.  Mammalian oocytes are targets for prostaglandin E2 (PGE2) action 
Background
The ovulatory gonadotropin surge increases synthesis of prostaglandin E2 (PGE2) by the periovulatory follicle. PGE2 actions on granulosa cells are essential for successful ovulation. The aim of the present study is to determine if PGE2 also acts directly at the oocyte to regulate periovulatory events.
Methods
Oocytes were obtained from monkeys and mice after ovarian follicular stimulation and assessed for PGE2 receptor mRNA and proteins. Oocytes were cultured with vehicle or PGE2 and assessed for cAMP generation, resumption of meiosis, and in vitro fertilization.
Results
Germinal vesicle intact (GV) oocytes from both monkeys and mice expressed mRNA for the PGE2 receptors EP2, EP3, and EP4. EP2 and EP4 proteins were detected by confocal microscopy in oocytes of both species. Monkey and mouse oocytes responded to PGE2 as well as agonists selective for EP2 and EP4 receptors with elevated cAMP, consistent with previous identification of EP2 and EP4 as Gαs/adenylyl cyclase coupled receptors. Incubation of mouse GV stage oocytes with PGE2 delayed oocyte nuclear maturation in vitro, but PGE2 treatment did not alter the percentage of mouse oocytes that fertilized successfully. PGE2 treatment also decreased the percentage of monkey oocytes that resumed meiosis in vitro. In contrast with mouse oocytes, the percentage of monkey oocytes which fertilized in vitro was lower after treatment with PGE2. Monkey oocytes with intact cumulus showed delayed nuclear maturation, but fertilization rate was not affected by PGE2 treatment.
Conclusions
Monkey and mouse oocytes express functional PGE2 receptors. PGE2 acts directly at mammalian oocytes to delay nuclear maturation. Surrounding cumulus cells modulate the effect of PGE2 to alter subsequent fertilization.
doi:10.1186/1477-7827-8-131
PMCID: PMC2988801  PMID: 21040553
7.  LPA3-mediated lysophosphatidic acid signalling in implantation and embryo spacing 
Nature  2005;435(7038):104-108.
Every successful pregnancy requires proper embryo implantation. Low implantation rate is a major problem during infertility treatments using assisted reproductive technologies (ART) 1. Here we report a new molecular influence on implantation through the lysophosphatidic acid (LPA) receptor LPA3 2–4. Targeted deletion of LPA3 in mice resulted in significantly reduced litter size, which could be attributed to delayed implantation and altered embryo spacing. These two events led to delayed embryonic development, hypertrophic placentas shared by multiple embryos, and embryonic death. An enzyme demonstrated to influence implantation, cyclooxygenase-2 (COX-2) 5, was down-regulated in LPA3-deficient uteri during preimplantation. Down regulation of COX-2 led to reduced levels of prostaglandins that are critical for implantation 1. Exogenous administration of the prostaglandins PGE2 and cPGI into LPA3-deficient females rescued delayed implantation but did not rescue defects in embryo spacing. These data identify LPA3 receptor-mediated signalling as a new influence on implantation and further indicate linkage between LPA signalling and prostaglandin biosynthesis.
doi:10.1038/nature03505
PMCID: PMC1369590  PMID: 15875025
8.  Preliminary molecular genetic analysis of the Receptor Interacting Protein 140 (RIP140) in women affected by endometriosis 
Background
Endometriosis is a complex disease affecting 10–15% of women at reproductive age. Very few genes are known to be altered in this pathology. RIP140 protein is an important cofactor of oestrogen receptor and many other nuclear receptors. Targeting disruption experiments of nrip1 gene in mice have demonstrated that nuclear receptor interacting protein 1 gene (nrip1), the gene encoding for rip140 protein, is essential for female fertility. Specifically, mice null for nrip1 gene are viable, but females are infertile because of complete failure of mature follicles to release oocytes at ovulation stage. The ovarian phenotype observed in mice devoid of rip140 closely resembles the luteinized unruptured follicle (LUF) syndrome that is observed in a high proportion of women affected of endometriosis or idiopathic infertility. Here we present a preliminary work that analyses the role of NRIP1 gene in humans.
Methods
We have sequenced the complete coding region of NRIP1 gene in 20 unrelated patients affected by endometriosis. We have performed genetic association studies by using the DNA variants identified during the sequencing process.
Results
We identified six DNA variants within the coding sequence of NRIP1 gene, and five of them generated amino acid changes in the protein. We observed that three of twenty sequenced patients have specific combinations of amino-acid variants within the RIP140 protein that are poorly represented in the control population (p = 0.006). Moreover, we found that Arg448Gly, a common polymorphism located within NRIP1 gene, is associated with endometriosis in a case-control study (59 cases and 141 controls, pallele positivity test = 0.027).
Conclusion
Our results suggest that NRIP1 gene variants, separately or in combinations, might act as predisposing factors for human endometriosis.
doi:10.1186/1743-1050-2-11
PMCID: PMC1242355  PMID: 16131398
9.  Circadian Control of Neuroendocrine Circuits Regulating Female Reproductive Function 
Female reproduction requires the precise temporal organization of interacting, estradiol-sensitive neural circuits that converge to optimally drive hypothalamo-pituitary–gonadal (HPG) axis functioning. In mammals, the master circadian pacemaker in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus coordinates reproductively relevant neuroendocrine events necessary to maximize reproductive success. Likewise, in species where periods of fertility are brief, circadian oversight of reproductive function ensures that estradiol-dependent increases in sexual motivation coincide with ovulation. Across species, including humans, disruptions to circadian timing (e.g., through rotating shift work, night shift work, poor sleep hygiene) lead to pronounced deficits in ovulation and fecundity. Despite the well-established roles for the circadian system in female reproductive functioning, the specific neural circuits and neurochemical mediators underlying these interactions are not fully understood. Most work to date has focused on the direct and indirect communication from the SCN to the gonadotropin-releasing hormone (GnRH) system in control of the preovulatory luteinizing hormone (LH) surge. However, the same clock genes underlying circadian rhythms at the cellular level in SCN cells are also common to target cell populations of the SCN, including the GnRH neuronal network. Exploring the means by which the master clock synergizes with subordinate clocks in GnRH cells and its upstream modulatory systems represents an exciting opportunity to further understand the role of endogenous timing systems in female reproduction. Herein we provide an overview of the state of knowledge regarding interactions between the circadian timing system and estradiol-sensitive neural circuits driving GnRH secretion and the preovulatory LH surge.
doi:10.3389/fendo.2012.00060
PMCID: PMC3356853  PMID: 22661968
suprachiasmatic; ovulation; kisspeptin; GnIH; RFRP-3; AVP; VIP
10.  Haploinsufficiency of COUP-TFII in Female Reproduction 
The chicken ovalbumin upstream promoter transcription factor II, COUP-TFII, is a member of the Orphan nuclear receptor transcription factor family. Genetic ablation of COUP-TFII results in early embryonic lethality and demonstrates that this gene is required for cardiac and vascular development. Expression of COUP-TFII persists throughout postnatal life in various tissues including the female reproductive tract. However, the physiological function of COUP-TFII in female reproduction has not been extensively analyzed. Here, we provide phenotypic evidences that haploinsufficiency of COUP-TFII in mice demonstrates an important role of COUP-TFII for normal female reproduction. COUP-TFII +/− females show significantly reduced fecundity, irregular estrus cycles, delayed puberty and retarded postnatal growth. Analysis of the reduced fertility revealed that although ovarian function was normal with respect to ovulation, the ovaries have reduced ability to synthesize progesterone in response to exogenous gonadotropins. This reduction is due to the reduction of the expression of steroidogenic enzymes important for P4 synthesis and the reduction of vascularization in COUP-TFII heterozygotes. Analysis of uterine function demonstrated a reduced response to an experimentally induced decidual cell reaction indicating that the ability of the uterus to support embryo implantation was reduced. Taken together, our data shows global impact of gene dosage effects of COUP-TFII on female postnatal life and indicates requirement of COUP-TFII in normal female reproduction, in particular for uterine endometrial functions during the peri-implantation period.
doi:10.1210/me.2005-0019
PMCID: PMC1198323  PMID: 15890675
11.  Prostaglandin E2-EP3 Axis in Fine-Tuning Excessive Skin Inflammation by Restricting Dendritic Cell Functions 
PLoS ONE  2013;8(7):e69599.
Prostaglandin E2 (PGE2) is produced in the skin and is suggested to play a role in the regulation of cutaneous immune homeostasis and responses. However, the multifaceted functions of PGE2 continue to elude our understanding, especially because of the multiplicity of PGE2 receptors—EP1, EP2, EP3, and EP4. While cAMP-elevating EP4 is known to activate the functions of cutaneous dendritic cells (DCs), including Langerhans cells (LCs) and dermal DCs, the role of cAMP-suppressing EP3 in this process remains unknown. Here we demonstrated that an EP3 receptor selective agonist, ONO-AE-248, inhibited chemotaxis and co-stimulatory molecule expressions of DCs in vitro. A suboptimal dose of antigen was sufficient to induce contact hypersensitivity in EP3-deficient mice. Intriguingly, EP3 deficiency did not impair skin inflammation at all when the antigen dose was sufficiently high. EP3 limited the functions of cutaneous DCs only when the antigen dose was low. In contrast to EP4, the observed unappreciated function of EP3 may stabilize the cutaneous DCs to halt the impetuous response to a suboptimal dose of antigen. Taken together, PGE2-EP3 signaling is essential for fine-tuning excessive skin inflammation by restricting DC functions.
doi:10.1371/journal.pone.0069599
PMCID: PMC3726673  PMID: 23922752
12.  Cloning and expression of the rabbit prostaglandin EP2 receptor 
BMC Pharmacology  2002;2:14.
Background
Prostaglandin E2 (PGE2) has multiple physiologic roles mediated by G protein coupled receptors designated E-prostanoid, or "EP" receptors. Evidence supports an important role for the EP2 receptor in regulating fertility, vascular tone and renal function.
Results
The full-length rabbit EP2 receptor cDNA was cloned. The encoded polypeptide contains 361 amino acid residues with seven hydrophobic domains. COS-1 cells expressing the cloned rabbit EP2 exhibited specific [3H]PGE2 binding with a Kd of 19.1± 1.7 nM. [3H]PGE2 was displaced by unlabeled ligands in the following order: PGE2>>PGD2=PGF2α=iloprost. Binding of [3H]PGE2 was also displaced by EP receptor subtype selective agonists with a rank order of affinity consistent with the EP2 receptor (butaprost>AH13205>misoprostol>sulprostone). Butaprost free acid produced a concentration-dependent increase in cAMP accumulation in rabbit EP2 transfected COS-1 cells with a half-maximal effective concentration of 480 nM. RNase protection assay revealed high expression in the ileum, spleen, and liver with lower expression in the kidney, lung, heart, uterus, adrenal gland and skeletal muscle. In situ hybridization localized EP2 mRNA to the uterine endometrium, but showed no distinct localization in the kidney. EP2 mRNA expression along the nephron was determined by RT-PCR and its expression was present in glomeruli, MCD, tDL and CCD. In cultured cells EP2 receptor was not detected in collecting ducts but was detected in renal interstitial cells and vascular smooth muscle cells. EP2 mRNA was also detected in arteries, veins, and preglomerular vessels of the kidney.
Conclusion
EP2 expression pattern is consistent with the known functional roles for cAMP coupled PGE2 effects in reproductive and vascular tissues and renal interstitial cells. It remains uncertain whether it is also expressed in renal tubules.
doi:10.1186/1471-2210-2-14
PMCID: PMC117438  PMID: 12097143
13.  How Contemporary Human Reproductive Behaviors Influence the Role of Fertility-Related Genes: The Example of the P53 Gene 
PLoS ONE  2012;7(4):e35431.
Studies on human fertility genes have identified numerous risk/protective alleles involved in the occurrence of reproductive system diseases causing infertility or subfertility. Investigations we carried out in populations at natural fertility seem to suggest that the clinical relevance that some fertility genes are now acquiring depends on their interaction with contemporary reproductive behaviors (birth control, delayed childbearing, and spacing birth order, among others). In recent years, a new physiological role in human fertility regulation has emerged for the tumor- suppressor p53 gene (P53), and the P53 Arg72Pro polymorphism has been associated with recurrent implantation failure in humans. To lend support to our previous observations, we examined the impact of Arg72Pro polymorphism on fertility in two samples of Italian women not selected for impaired fertility but collected from populations with different (premodern and modern) reproductive behaviors. Among the women at near-natural fertility (n = 98), the P53 genotypes were not associated with different reproductive efficiency, whereas among those with modern reproductive behaviors (n = 68), the P53 genotypes were associated with different mean numbers of children [Pro/Pro = 0.75
doi:10.1371/journal.pone.0035431
PMCID: PMC3332113  PMID: 22532853
Breast Cancer Research : BCR  2000;2(5):345-352.
Natural, synthetic and environmental estrogens have numerous effects on the development and physiology of mammals. Estrogen is primarily known for its role in the development and functioning of the female reproductive system. However, roles for estrogen in male fertility, bone, the circulatory system and immune system have been established by clinical observations regarding sex differences in pathologies, as well as observations following menopause or castration. The primary mechanism of estrogen action is via binding and modulation of activity of the estrogen receptors (ERs), which are ligand-dependent nuclear transcription factors. ERs are found in highest levels in female tissues critical to reproduction, including the ovaries, uterus, cervix, mammary glands and pituitary gland. Since other affected tissues have extremely low levels of ER, indirect effects of estrogen, for example induction of pituitary hormones that affect the bone, have been proposed. The development of transgenic mouse models that lack either estrogen or ER have proven to be valuable tools in defining the mechanisms by which estrogen exerts its effects in various systems. The aim of this article is to review the mouse models with disrupted estrogen signaling and describe the associated phenotypes.
doi:10.1186/bcr79
PMCID: PMC138656  PMID: 11250727
estrogen receptor; estrogen receptor knockout; transgenic
In the last 30 years, remarkable progress has been made in our understanding of the biological role of endothelins in the regulation of reproductive function and fertility. A peptide hormone identified for its ability to regulate blood pressure has now been shown as a potent mediator of several reproductive pathways. Ligand- and receptor-specific roles have been identified and/or postulated during follicular development and ovulation as well as in the function and regression of the corpus luteum. In this review we have attempted to organize endothelin-mediated ovarian processes in a process-specific manner, rather than compile a review of ligand- or isoform-specific actions. Further, we have included a discussion on “post-ovarian” or oviductal function, as well as the future directions that we believe will increase our understanding of endothelin biology as a whole.
PMCID: PMC3030473  PMID: 21196365
Endothelin; ovary; oviduct; ovulation; follicle; corpus luteum
Persistent organic pollutants (POPs), such as polychlorinated dibenzo-p-dioxins (PCDDs) and dibenzofurans (PCDFs), polychlorinated biphenyls (PCBs), and polybrominated ethers (PBDEs), chloronaftalens (PCNs), and bisphenol A (BPA), are stable, lipophilic pollutants that affect fertility and cause serious reproductive problems, including ovotoxic action, lack of ovulation, premature ovarian failure (POF), or polycystic ovarian syndrome (PCOS). Most of the representatives of POPs influence the activation of transcription factors, not only activation of aromatic hydrocarbon receptor (AhR), but also the steroid hormone receptors. This minireview will focus on a variety of PAH activities in oocyte, ovary, placenta, and mammary gland. The complexity and diversity of factors belonging to POPs and disorders of the reproductive function of women indicate that the impact of environmental pollution as an important determinant factor in fertility should not be minimize.
doi:10.1155/2013/828532
PMCID: PMC3674739  PMID: 23762054
Hypertension is a well established risk factor for cardiovascular diseases such as stroke and is the leading cause of chronic kidney failure. Although a number of pharmacologic agents are available for the treatment of hypertension including agents that affect the renin-angiotensin-aldosterone system (RAAS), unmet needs in the treatment of hypertension suggest that identification of novel pharmacological targets would be an important healthcare goal. One potential target is prostaglandin E2 (PGE2), a potent lipid mediator with a diverse and sometimes opposing range of biological effects. PGE2 signals through four subtypes of G-protein coupled receptors designated EP1 through EP4. PGE2 functions primarily as a vasodepressor; under certain conditions PGE2 administration mediates vasopressor activity. This review focuses on the current understanding of the roles of PGE2 receptors in vascular reactivity, hypertension and end-organ damage.
doi:10.1016/j.prostaglandins.2011.07.001
PMCID: PMC3208062  PMID: 21801847
Prostaglandin E2; hypertension; GPCR; mouse; rat
Biochemical pharmacology  2008;77(4):547-559.
In recent years, many studies have emphasized how changes in aryl hydrocarbon receptor (AHR)-mediated gene expression result in biological effects, raising interest in this receptor as a regulator of normal biological function. This review focuses on what is known about the role of the AHR in the female reproductive system, which includes the ovaries, fallopian tubes or oviduct, uterus and vagina. This review also focuses on the role of the AHR in reproductive outcomes such as cyclicity, senescence, and fertility. Specifically, studies using potent AHR ligands, as well as transgenic mice lacking the AHR signaling pathway are discussed from a viewpoint of understanding the endogenous role of this ligand-activated transcription factor in the female reproductive lifespan. Based on findings highlighted in this paper, it is proposed that the AHR has a role in physiological functions including ovarian function, establishment of an optimum environment for fertilization, nourishing the embryo and maintaining pregnancy, as well as in regulating reproductive lifespan and fertility. The mechanisms by which the AHR regulates female reproduction are poorly understood, but it is anticipated that new models and the ability to generate specific gene deletions will provide powerful experimental tools for better understanding how alterations in AHR pathways result in functional changes in the female reproductive system.
doi:10.1016/j.bcp.2008.09.037
PMCID: PMC2657805  PMID: 18977336
aryl hydrocarbon receptor; ovary; uterus; vagina; oviduct; female reproduction
Prostaglandins are important regulators of female reproductive functions to which aldose reductases exhibiting hydroxysteroid dehydrogenase activity also contribute. Our work on the regulation of reproductive function by prostaglandins (PGs), lead us to the discovery that AKR1B5 and later AKR1B1were highly efficient and physiologically relevant PGF synthases. PGE2 and PGF2α are the main prostanoids produced in the human endometrium and proper balance in their relative production is important for normal menstruation and optimal fertility. Recent evidence suggests that PGE2/EP2 and PGF2α/FP may constitute a functional dyad with physiological relevance comparable to the prostacyclin-thromboxane dyad in the vascular system. We have recently reported that AKR1B1 was expressed and modulated in association with PGF2α production in response to IL-1β in the human endometrium. In the present study, we show that the human AKR1B1 (gene ID: 231) also known as ALDR1 or ALR2 is a functional PGF2α synthase in different models of living cells and tissues. Using human endometrial cells, prostate, and vascular smooth muscle cells, cardiomyocytes and endothelial cells we demonstrate that IL-1β is able to up regulate COX-2 and AKR1B1 proteins as well as PGF2α production under normal glucose concentrations. We show that the promoter activity of AKR1B1 gene is increased by IL-1β particularly around the multiple stress response region containing two putative antioxidant response elements adjacent to TonE and AP1. We also show that AKR1B1 is able to regulate PGE2 production through PGF2α acting on its FP receptor and that aldose reductase inhibitors like alrestatin, Statil (ponalrestat), and EBPC exhibit distinct and characteristic inhibition of PGF2α production in different cell models. The PGF synthase activity of AKR1B1 represents a new and important target to regulate ischemic and inflammatory responses associated with several human pathologies.
doi:10.3389/fphar.2012.00098
PMCID: PMC3360414  PMID: 22654757
prostaglandins; biosynthesis; regulation; endometrium; menstrual cycle
Prostaglandins (PGs), a group of key lipid mediators, are involved in numerous physiological and pathological processes including inflammation and cardiovascular homeostasis. Each PG acts on its specific and distinct cell surface G protein-coupled receptors (GPCRs) or peroxisome proliferator-activated receptors (PPARs). Prostaglandin F2α receptor (FP) is required for female reproductive function such as luteolysis and parturition. It has recently been implicated in blood pressure regulation, atherosclerosis and other inflammation-related disorders. The emerging role of FP in cardiovascular diseases is highlighted and potential therapeutic translation is discussed in the current review.
doi:10.3389/fphar.2010.00116
PMCID: PMC3095374  PMID: 21607067
prostaglandin F2alpha; hypertension; atherosclerosis; FP receptor
Molecular and Cellular Biology  2007;27(12):4416-4430.
A number of studies have identified cytosolic prostaglandin E2 synthase (cPGES)/p23 as a cytoplasmic protein capable of metabolism of prostaglandin E2 (PGE2) from the cyclooxygenase metabolite prostaglandin endoperoxide (PGH2). However, this protein has also been implicated in a number of other pathways, including stabilization of the glucocorticoid receptor (GR) complex. To define the importance of the functions assigned to this protein, mice lacking detectible cPGES/p23 expression were generated. cPGES/p23−/− pups die during the perinatal period and display retarded lung development reminiscent of the phenotype of GR-deficient neonates. Furthermore, GR-sensitive gluconeogenic enzymes are not induced in the prenatal period. However, unlike GR-deficient embryos, cPGES/p23−/− embryos are small and a proliferation defect is observed in cPGES/p23−/− fibroblasts. Analysis of arachidonic acid metabolites in embryonic tissues and primary fibroblasts failed to support a function for this protein in PGE2 biosynthesis. Thus, while the growth retardation of the cPGES/p23−/− pups and decreased proliferation of primary fibroblasts identify functions for this protein in addition to GR stabilization, it is unlikely that these functions include metabolism of PGH2 to PGE2.
doi:10.1128/MCB.02314-06
PMCID: PMC1900037  PMID: 17438133
Prostanoids, bioactive lipids derived from arachidonic acid (AA), are important for vascular homeostasis. Among them, prostaglandin E2 (PGE2) enhances aggregation of platelets submaximally stimulated in vitro. This results from activation of EP3, one of the four PGE2 receptors, which decreases the threshold at which agonists activate platelets to aggregate. Although PGE2 altered venous thrombosis induced by administration of AA, its role in pathophysiopathological conditions has remained speculative. We report that arterial walls subjected to inflammatory stimuli produce PGE2. In several models, we show that PGE2 produced by the arterial wall facilitates arterial thrombosis. Next, we detected PGE2 in mouse atherosclerotic plaques. We demonstrate that this plaque-produced PGE2 is not altered and is still able to activate EP3. In addition, we present evidence that PGE2 can leave the plaque and activate EP3 on blood platelets. Consistent with these findings, we observed that atherothrombosis induced in vivo by mechanical rupture of the plaque was drastically decreased when platelets lacked EP3. In conclusion, PGE2 facilitates the initiation of arterial thrombosis and, hence, contributes to atherothrombosis. Inhibition of the platelet EP3 receptor should improve prevention of atherothrombosis.
doi:10.1084/jem.20061617
PMCID: PMC2118736  PMID: 17242161
Seminars in immunopathology  2012;35(2):123-137.
Prostaglandin E2 (PGE2) is a bioactive lipid that elicits a wide range of biological effects associated with inflammation and cancer. PGE2 exerts diverse effects on cell proliferation, apoptosis, angiogenesis, inflammation and immune surveillance. This review concentrates primarily on gastrointestinal cancers, where the actions of PGE2 are most prominent, most likely due to the constant exposure to dietary and environmental insults and the intrinsic role of PGE2 in tissue homeostasis. A discussion of recent efforts to elucidate the complex and interconnected pathways that link PGE2 signaling with inflammation and cancer is provided, supported by the abundant literature showing a protective effect of NSAIDs and the therapeutic efficacy of targeting mPGES-1 or EP receptors for cancer prevention. However, suppressing PGE2 formation as a means of providing chemoprotection against all cancers may not ultimately be tenable, undoubtedly the situation for patients with inflammatory bowel disease. Future studies to fully understand the complex role of PGE2 in both inflammation and cancer will be required to develop novel strategies for cancer prevention that are both effective and safe.
doi:10.1007/s00281-012-0342-8
PMCID: PMC3568185  PMID: 22996682
PGE2; inflammation; gastrointestinal cancer; NSAIDs; COX-2; mPGES-1
Journal of Clinical Investigation  1999;104(2):181-188.
The angiotensin subtype-1 (AT1) receptor mediates renal prostaglandin E2 (PGE2) production, and pharmacological blockade of the angiotensin subtype-2 (AT2) receptor potentiates the action of angiotensin II (Ang II) to increase PGE2 levels. We investigated the role of the AT2 receptor in prostaglandin metabolism in mice with targeted deletion of the AT2 receptor gene. Mice lacking the AT2 receptor (AT2-null) had normal blood pressure that was slightly elevated compared with that of wild-type (WT) control mice. AT2-null mice had higher renal interstitial fluid (RIF) 6-keto-PGF1α (a stable hydrolysis product of prostacyclin [PGI2]) and PGE2 levels than did WT mice, and had similar increases in PGE2 and 6-keto-PGF1α in response to dietary sodium restriction and Ang II infusion. In contrast, AT2-null mice had lower PGF2α levels compared with WT mice during basal conditions and in response to dietary sodium restriction or infusion of Ang II. RIF cAMP was markedly higher in AT2-null mice than in WT mice, both during basal conditions and during sodium restriction or Ang II infusion. AT1 receptor blockade with losartan decreased PGE2, PGI2, and cAMP to levels observed in WT mice. To determine whether increased vasodilator prostanoids prevented hypertension in AT2-null mice, we treated AT2-null and WT mice with indomethacin for 14 days. PGI2, PGE2, and cAMP were markedly decreased in both WT and AT2-null mice. Blood pressure increased to hypertensive levels in AT2-null mice but was unchanged in WT. These results demonstrate that in the absence of the AT2 receptor, increased vasodilator prostanoids protect against the development of hypertension.
PMCID: PMC408474  PMID: 10411547
Prostanoids, consisting of prostaglandins (PGs) and thromboxanes (TXs), are oxygenated products of C20 unsaturated fatty acids. They include PGD2, PGE2, PGF2α, PGI2, and TXA2. Given that aspirin-like nonsteroidal anti-inflammatory drugs exert their actions by suppressing prostanoid production, prostanoids have been implicated in processes inhibited by these drugs, including inflammation, fever, and pain. Prostanoids also contribute to vascular homeostasis, reproduction, and regulation of kidney and gastrointestinal functions. How prostanoids exert such a variety of actions had remained unclear, however. Prostanoids are released outside of cells immediately after their synthesis and exert their actions by binding to receptors on target cells. We have identified a family of eight types or subtypes of G protein–coupled receptors that mediate prostanoid actions. Another G protein–coupled receptor was also identified as an additional receptor for PGD2. Genes for these receptors have been individually disrupted in mice, and analyses of these knockout mice have not only elucidated the molecular and cellular mechanisms of known prostanoid actions but also revealed previously unknown actions. In this article, I review the physiological and pathophysiological roles of prostanoids and their receptors revealed by these studies.
doi:10.2183/pjab/83.296
PMCID: PMC3859365  PMID: 24367153
prostaglandin; thromboxane; cyclooxygenase; G protein–coupled receptor

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