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Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, Edinburgh, United Kingdom EH3 9ET
Address all correspondence and requests for reprints to: Dr. H. N. Jabbour, Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, 37 Chalmers Street, Edinburgh, United Kingdom EH3 9ET. E-mail: h.jabbour{at}hrsu.mrc.ac.uk
Abstract
This study was designed to elucidate the sites of synthesis and action of PGE2 in the nonpregnant human uterus across the menstrual cycle. The sites of expression of PGE synthase and synthesis of PGE2 were investigated by immunohistochemistry using full thickness uterine biopsies. Expression of PGE synthase and synthesis of PGE2 were localized to glandular epithelial and endothelial cells in both basalis and functionalis regions of the human endometrium. By contrast, stromal staining was predominantly localized in the functionalis layer. Some cyclical variation in expression of PGE synthase and PGE2 synthesis was observed, with reduced expression/synthesis detected in the stromal compartment of the functionalis during the late secretory phase of the menstrual cycle. Subsequently, we assessed the site of action of PGE2 by investigating the expression of two PGE2 receptor isoforms, namely EP2 and EP4. Cyclical variation in endometrial EP2 and EP4 receptor mRNA expression was quantified by TaqMan quantitative RT-PCR using RNA isolated from endometrial tissue collected across the menstrual cycle. No differences in EP2 receptor mRNA expression were detected; however, EP4 receptor mRNA expression was significantly higher in late proliferative stage (P < 0.05) than in early, mid, and late secretory stage endometrium. Expression patterns of EP2 and EP4 receptors were localized by nonradioactive in situ hybridization using fluorescein isothiocyanate end- labeled oligonucleotide probes. Expression of both receptors was observed in endometrial glandular epithelial and vascular cells, with no notable spatial or temporal variation. Finally, signaling of EP2/EP4 receptors was assessed by investigating cAMP generation in vitro after stimulation with PGE2. Endometrial cAMP generation in response to PGE2 was significantly greater in proliferative tissue compared with early and midsecretory stage tissue (3.77 ± 0.85 vs. 1.96 ± 0.28 and 1.38 ± 0.23, respectively; P < 0.05). In conclusion, this study demonstrates glandular and vascular coexpression of PGE synthase, PGE2, EP2, and EP4 receptors and suggests an autocrine/paracrine role for PGE2 in epithelial/endothelial cell function in the human endometrium.
PGs ARE part of the eicosanoid family and
consist of five endogenous members, termed PGD2,
PGE2, PGF2
,
prostacyclin, and thromboxane A2
(1). Initially in the PG synthesis pathway, the enzyme
cyclooxygenase (COX) generates PGH2 from
arachidonic acid. To date, there are two identified isoforms of the COX
enzyme, COX-1 and COX-2. COX-1 is constitutively expressed in many
tissues and cell types and generates PG for normal physiological
function. By contrast, the expression of COX-2 is rapidly induced after
the stimulation of quiescent cells by growth factors and phorbol esters
(2). Once synthesized, PGH2 serves
as a substrate for specific PG synthase enzymes (3, 4, 5, 6, 7).
The PG synthase enzymes are named according to the PG they produce,
such that PGE2 is generated by PGE synthase and
PGF2 by PGF synthase. Once synthesized, PG
mediate their actions via seven-transmembrane G protein-coupled
receptors. These G protein-coupled receptors have been cloned in humans
and are denoted DP, EP, FP, IP, and TP according to their endogenous PG
ligand (1, 8). Only the EP receptor has been shown to
possess diverse receptor subtypes, of which there are now four members,
termed EP1, EP2, EP3, and EP4. EP1 receptors activate phospholipase C
and mobilization of the inositol trisphosphate pathway, EP2 and EP4
receptors activate adenylate cyclase and the cAMP/protein kinase A
pathway, whereas EP3 receptor activation can both inhibit adenylate
cyclase and activate phospholipase C (1).
Recent studies have demonstrated a role for COX enzymes and PG in the regulation of epithelial cell growth and angiogenesis. COX-2 expression and PGE2 synthesis are associated with increased cellular proliferation and resistance to apoptosis (9, 10). Moreover, expression of COX-2 and synthesis of PGE2 in epithelial cells enhance the expression of angiogenic factors that act in a paracrine manner to induce endothelial cell migration and microvascular tube formation (11). COX-2 expression and PGE2 synthesis have also been associated directly with endothelial cell function (12). Treatment of endothelial cells with selective COX-2 inhibitors has been shown to reduce microvascular tube formation, and this effect is partially reversed by cotreatment with PGE2 (11, 13).
In the human endometrium, COX-2 enzyme expression and PGE2 synthesis have been associated with vascular function. COX enzyme expression and PGE2 synthesis are maximal during the menstrual and proliferative phases and are localized to epithelial and perivascular cells (14, 15, 16, 17, 18). Further evidence for a role for PGE2 in vascular function of the endometrium can be deduced from observations in women suffering from excessive blood loss at menstruation (menorrhagia). In this group of women, a positive relationship between the volume of blood loss and PGE2 release in utero has been reported (19).
The aims of this study were to characterize the site of synthesis and action of PGE2 in human endometrium across the menstrual cycle. This was assessed by investigating the cyclical changes in expression, localization, and functional signaling of PGE synthase, PGE2, and two PGE receptors, namely EP2 and EP4. The data from this study demonstrate epithelial and endothelial expression/synthesis of PGE synthase, PGE2, and EP2 and EP4 receptors in the human endometrium. Furthermore, cAMP production in response to PGE2 is higher in proliferative phase than secretory phase endometrium. These data strongly suggest a role for PGE2 in uterine epithelial cell function and angiogenesis, possibly through autocrine/paracrine signaling between endometrial epithelial and endothelial cells.
Materials and Methods
Patients and tissue collection
Endometrial biopsies (n = 33) at different stages of the menstrual cycle were collected with an endometrial suction curette (Pipelle, Laboratoire CCD, Paris, France) from women with regular menstrual cycles (25–35 d). In addition, full thickness endometrial biopsies (n = 18) at all stages of the menstrual cycle (n = 3 from early, mid, and late proliferative and n = 3 from early, mid, and late secretory) were collected from women undergoing hysterectomy for benign gynecological indications. Shortly after pipelle suction or hysterectomy, tissue was either snap-frozen in dry ice and stored at -70 C (for RNA extraction), fixed in neutral buffered formalin, and wax embedded (for immunohistochemical analyses) or placed in RPMI 1640 (containing 2 mmol/liter L-glutamine, 100 U penicillin, and 100 µg/ml streptomycin) and transported to the laboratory for in vitro culture. All subjects reported regular menstrual cycles (cycle length, 25–35 d), and no woman had received a hormonal preparation in the 3 months preceding biopsy collection. Biopsies were dated according to stated last menstrual period and were confirmed by histological assessment according to criteria of Noyes and co-workers (20). Furthermore, circulating E2 and progesterone concentrations at the time of biopsy were consistent for both stated last menstrual period and histological assignment of menstrual cycle stage. Ethical approval was obtained from Lothian research ethics committee, and written informed consent was obtained from all subjects before tissue collection.
Immunohistochemistry
Endometrial sections (5 µm) from across the menstrual cycle (n = 18) were dewaxed in xylene and rehydrated using decreasing grades of ethanol. An antigen retrieval step of 5 min of pressure cooking in 0.01 M sodium citrate buffer, pH 6.0, was carried out for PGE synthase. After rinsing in PBS, endogenous peroxidase activity was quenched with 3% H2O2 in methanol. Nonimmune swine serum (10% serum in PBS) was applied for 20 min before overnight incubation at 4 C with primary antibody. An avidin-biotin peroxidase detection system was then applied (DAKO Corp., High Wycombe, UK) with 3,3'-diaminobenzidine as the chromagen. Sections were counterstained with Harris’s hematoxylin before mounting. Rabbit antihuman PGE synthase antibody (Cayman Chemicals, Ann Arbor, MI) was used at a 1:250 dilution, and rabbit anti-PGE2 antibody (supplied by Prof. R. W. Kelly, Medical Research Council Human Reproductive Sciences Unit, Edinburgh, UK) was used at a dilution of 1:100. Preabsorption with PGE synthase-blocking peptide (100 µg/ml: Cayman Chemicals) was the PGE synthase negative control, and preabsorption with excess PGE2 was the PGE2 negative control. Both preabsorbed antibody preparations produced negligible immunoreactivity. All treatments were carried out at room temperature unless otherwise specified. The immunohistochemistry was repeated for each antibody at least three times.
In situ hybridization
Custom synthesis oligonucleotide double fluorescein isothiocyanate (FITC)-labeled cDNA probes for EP2 and EP4 receptor were obtained from Biognostik (Gottingen, Germany). Sections (5 µm) were cut onto gelatin-coated SuperFrost slides (BDH Laboratory Supplies, Poole, UK) from full thickness human uterine biopsies collected across the menstrual cycle (n = 18). Tissue was dewaxed in xylene and rehydrated using increasing concentrations of ethanol before proteinase K treatment (100 µg/ml in 100 mM Tris-HCl pH 7.6, containing 50 mM EDTA) for 15 min at 37 C to enhance cDNA probe access. After washing in diethylpyrocarbonate-H2O, hybridization mixture (25 µl; supplied with probe) was added to each section, and slides were incubated for 4 h at 30 C before adding cDNA probe (6 U/ml hybridization mix) and incubating overnight at 30 C. Posthybridization washes of 1 x SSC (standard saline citrate) for 5 min (twice) and 0.1 x SSC at 39 C for 15 min (twice) were completed before detecting the FITC-labeled probe using standard immunohistochemical reagents (TSA Biotin System, NEN Life Science Products, Hounslow, UK). Endogenous peroxidase activity was first blocked with 3% H2O2 in methanol for 30 min before incubating sections with blocking buffer for 30 min. Conjugated anti-FITC-horseradish peroxidase (Roche Molecular Biochemicals, Mannheim, Germany) was added in blocking buffer, and the sections were incubated for 60 min. After washing, biotinyl tyramide amplification reagent was applied to each slide and incubated for 15 min. Streptavidin-horseradish peroxidase was applied after washing and incubated for 30 min, and probe localization was visualized with 3,3'-diaminobenzidine. Control oligonucleotide double FITC-labeled cDNA probes containing the same proportion of cysteine (C) and guanine (G) bases as the EP2 and EP4 receptor probes were included to assess background hybridization. All treatments were carried out at room temperature unless otherwise specified.
Taqman quantitative RT-PCR
Endometrial RNA samples were extracted from endometrial biopsies (n = 33) using Tri-Reagent (Sigma, Poole, UK) following the manufacturer’s guidelines. Once extracted and quantified, RNA samples were reverse transcribed using MgCl2 (5.5 mM), deoxy (d)-NTPs (0.5 mM each), random hexamers (2.5 µM), ribonuclease inhibitor (0.4 U/µl), and multiscribe reverse transcriptase (1.25 U/µl; all from Applied Biosystems, Warrington, UK). The mix was aliquoted into individual tubes (16 µl/tube), and template RNA was added (4 µl/tube of 100 ng/µl RNA). After mixing by brief centrifugation, samples were incubated for 90 min at 25 C, 45 min at 48 C, and 5 min at 95 C. Thereafter, cDNA samples were stored at -20 C. A tube with no reverse transcriptase was included to control for any DNA contamination.
To measure cDNA expression, a reaction mix was prepared containing TaqMan buffer (5.5 mM MgCl2, 200 µM dATP, 200 µM dCTP, 200 µM dGTP, and 400 µM dUTP), ribosomal 18S forward and reverse primers and probe (all at 50 nM), forward and reverse primers for EP receptor (300 nM), EP receptor probe (100 nM), AmpErase UNG (0.01 U/µl), and AmpliTaq Gold DNA Polymerase (0.025 U/µl; all from Applied Biosystems). After mixing, 48 µl were aliquoted into separate tubes, and 2 µl/replicate (40 ng) cDNA were added and mixed before placing duplicate 24-µl samples into a PCR plate. A no template control (containing water) was included in triplicate. Wells were sealed with optical caps, and the PCR reaction was carried out using an ABI Prism 7700 (Applied Biosystems). EP receptor primers and probe for quantitative PCR were designed using the PRIMER express program (Applied Biosystems). The sequences of the EP2 receptor primers and probe were: forward, 5'-GAC CGC TTA CCT GCA GCT GTA C-3'; reverse, 5'-TGA AGT TGC AGG CGA GCA-3'; and probe (6-carboxy fluoroscein labeled), 5'-CCA CCC TGC TGC TGC TTC TCA TTG TCT-3'. The sequences of the EP4 receptor primers and probe were: forward, 5'-ACG CCG CCT ACT CCT ACA TG-3'; reverse, 5'-AGA GGA CGG TGG CGA GAA T-3'; and probe (6-carboxy fluoroscein labeled), 5'-ACG CGG GCT TCA GCT CCT TCC T-3'. The ribosomal 18S primers and probe sequences were: forward, 5'-CGG CTA CCA CAT CCA AGG AA-3'; reverse, 5'-GCT GGA ATT ACC GCG GCT-3'; and probe (VIC labeled), 5'-TGC TGG CAC CAG ACT TGC CCT C-3'. Data were analyzed and processed using Sequence Detector version 1.6.3 (Applied Biosystems) as instructed by the manufacturer. Briefly, the software calculates the reaction cycle number at which fluorescence reaches a determined level for both 18S control and EP2/EP4 receptor. This is the relative abundance for EP2/EP4 receptor, and by comparing this to an internal positive control, relative expression can be determined. Results are expressed as relative expression to an internal positive standard included in all reactions.
Whole tissue cAMP assay
Endometrial biopsies from all stages of the menstrual cycle (n = 18; n = 6 from proliferative, early, and midsecretory phases) were minced finely with scissors and incubated in 2 ml RPMI (Sigma) medium containing 10% FCS, 2 mmol/liter L-glutamine, 100 IU penicillin, 100 µg streptomycin, and 3 µg/ml indomethacin for 1.5 h at 37 C in a humidified 5% CO2 incubator. Tissue specimens were incubated in the same medium containing isobutylmethylxanthine (Sigma) to a final concentration of 1 mM for 30 min at 37 C before adding 300 nM PGE2. Control tissue was treated similarly, but received no PGE2. Tissue was harvested by centrifugation at 2000 x g, the supernatant was discarded, and the tissue was homogenized in 0.1 M HCl. The cAMP concentration was quantified by ELISA using cAMP kits (Biomol, Affiniti, Exeter, UK) and was normalized to protein concentration of the homogenate. Protein concentrations were determined using protein assay kits (Bio-Rad Laboratories, Inc., Hemel Hempsted, UK). Data are presented as the fold induction of cAMP after treatment with PGE2, where fold induction was calculated relative to the control samples.
Statistics
Where appropriate, data were subjected to statistical analysis with ANOVA and Fisher’s protected least significant difference tests (StatView 4.0, Abacus Concepts, Inc., Berkeley, CA), and statistical significance was accepted at P < 0.05.
Results
Spatial localization of PGE synthase in full thickness endometrial
biopsies demonstrated marked differences in PGE synthase expression
between distinct uterine regions (Fig. 1
, a–f). In the functionalis layer, PGE synthase immunoreactivity
was expressed in glandular epithelial, stromal, and endothelial cells
(Fig. 1, b–e). Temporally, within the functionalis layer PGE synthase
immunoreactivity only varied in the late secretory phase, where reduced
staining of stromal cells was observed (Fig. 1e). Compared with the
functionalis region, little stromal staining for PGE synthase was
detected in the basalis compartment throughout the menstrual cycle;
however, comparable immunoreactivity for PGE synthase was observed in
epithelial and endothelial cells of this region (Fig. 1a). In the
myometrial region, only endothelial cells were immunopositive for PGE
synthase (Fig. 1f, inset). When viewed as a cross-section,
PGE synthase was expressed in all epithelial and endothelial cells
throughout the uterus, but stromal cell immunoreactivity diminished
from strong staining in the functionalis layer to minimal
immunoreactivity in the myometrial fibroblasts (Fig. 1f).
|
, b and c). Perinuclear PGE synthase expression
was consistent with the literature, where the majority of PGE synthase
activity elutes in the nuclear membrane fraction (21).
Spatial and temporal syntheses of PGE2 in the
uterus were assessed by immunohistochemistry. In the functionalis
layer, PGE2 synthesis was detected in epithelial,
stromal, and endothelial cells (Fig. 2, b–f), with less apparent stromal cell immunoreactivity in late
secretory tissue (Fig. 2e). As observed with PGE synthase expression,
PGE2 synthesis in the basalis region was minimal
in the stromal compartment, whereas epithelial and endothelial
immunoreactivities were unchanged. Full thickness endometrial biopsies
clearly demonstrated the gradient in PGE2
synthesis from strong immunoreactivity in cells of the functionalis
layer to weak staining in the myometrium, where no fibroblast
PGE2 synthesis was observed. In the myometrium,
similar to PGE synthase expression, PGE2
synthesis was detected only in endothelial cells (Fig. 2F, inset).
|
). EP4 receptor mRNA
expression, in contrast, was significantly higher (P <
0.05) in late proliferative biopsies (0.162 ± 0.034; n = 5)
than in early (0.075 ± 0.024; n = 7), mid (0.063 ±
0.014; n = 6), and late (0.07 ± 0.033; n = 6) secretory
phase samples (Fig. 3b). It is noteworthy that receptor expression in
these experiments was investigated in a heterogeneous population of
uterine cells, and it is conceivable that variation in receptor
expression across the menstrual cycle may be different in specific
target cells.
|
, a–h). Furthermore, epithelial and
vascular EP2 and EP4 receptor expression was present at all stages of
the menstrual cycle in both the basalis and functionalis regions of the
endometrium. Vascular EP2 and EP4 receptor mRNA expression was
localized in both endothelial (Fig. 4, a and c, for EP2; Fig. 4, b and
d, for EP4) and perivascular cells throughout the endometrium (Fig. 4g
for EP2; Fig. 4h for EP4).
|
).
|
The data presented in this manuscript demonstrate the expression and localization of PGE synthase and its product, PGE2, in stromal, epithelial, and endothelial cells of the human endometrium across the menstrual cycle. PGE synthase expression and PGE2 synthesis were detected at all stages of the menstrual cycle, with apparent reduced expression/synthesis during the late secretory phase. This is in agreement with previous studies, which have localized COX expression in epithelial and perivascular cells of the human endometrium (14, 16, 17, 18). Moreover, culture studies have demonstrated that both epithelial and stromal cells can synthesize PGE2in vitro (22) and that the PGE2 biosynthetic capacity of the endometrium is reduced in the late secretory phase (23). The sites of action of PGE2 were elucidated using in situ hybridization studies for two receptor subtypes, namely EP2 and EP4. EP2 and EP4 receptor expression was localized in epithelial and vascular cells of human endometrium. These data indicate that PGE2 acts in an autocrine/paracrine manner within multiple cellular compartments of the human endometrium.
In premenopausal women, the human endometrium undergoes phases of proliferation and apoptosis during successive menstrual cycles. These phases are observed predominantly in the functionalis layer of the endometrium, which is shed at menstruation before regenerating during the proliferative phase of the subsequent menstrual cycle. Interestingly, stromal expression of PGE synthase and synthesis of PGE2 are predominantly localized in the functionalis layer of the endometrium and are minimal in the basalis and myometrial regions. The exact role of PGE2 in the human endometrium is not fully elucidated, but previous studies suggest a crucial role for PGE2 in cellular mitogenesis and survival. In colon epithelial cells, overexpression of COX-2 and enhanced synthesis of PGE2 have been shown to promote the proliferation and survival of cells through inhibition of apoptosis (9, 10). The latter effect is mediated via up-regulated expression of antiapoptotic genes such as bcl-2 (10). It is plausible that in the human endometrium, PGE2 may be activating similar mechanisms that promote glandular epithelial cell proliferation and/or survival. This is supported by recent data confirming higher expression of bcl-2 in the proliferative compared with secretory phase endometrium and its localization to glandular epithelial cells (24, 25, 26). PGE2 function in glandular epithelial cells may also be associated with the regulation of uterine angiogenesis. Overexpression of COX-2 and increased production of PGE2 in epithelial cells have been associated with the expression of angiogenic factors, such as vascular endothelial growth factor, which, in turn, act in a paracrine manner to induce endothelial cell migration and microvascular tube formation (11). In the human endometrium, vascular endothelial growth factor expression is localized to the glandular epithelial cells throughout the menstrual cycle (27, 28), and PGE2 has been shown previously to up-regulate the expression of vascular endothelial growth factor in a number of different cell types via cAMP (29, 30, 31, 32).
Expression of EP2/EP4 receptors in perivascular and endothelial cells suggests a possible role for PGE2 in vascular function and angiogenesis in the human endometrium. PGE2 induces vasodilatation via perivascular EP2/EP4 receptors (1), whereas activation of EP receptors on endothelial cells may regulate angiogenesis. Endometrial angiogenesis takes place throughout the menstrual cycle, as measured by endothelial cell proliferation, with a significantly elevated endothelial cell proliferative index in the functionalis compared with the basalis phase (33). Recently, COX-2 and PGE2 have been linked directly with endothelial cell function and angiogenesis (12). Treatment of endothelial cells with selective COX-2 inhibitors has been shown to reduce microvascular tube formation, and this effect is partially reversed by cotreatment with PGE2 (13). Hence, it is feasible that in vivo angiogenesis in the endometrium may be regulated by PGE2 via an epithelial-endothelial and an endothelial-endothelial cell interaction. This is supported by the data presented in this study, which localized the site of expression of PGE synthase, PGE2, and EP2/EP4 receptors to epithelial and endothelial cells of the endometrium.
Measuring cAMP generation in human endometrium after treatment with PGE2 assessed functional signaling of EP2/EP4 receptors. A significantly higher cAMP generation was observed in proliferative compared with secretory endometrium. This enhanced signaling is associated with greater expression of EP4 receptors in the proliferative phase. The increased cAMP generation observed during the proliferative phase may mediate the mitogenic effect of PGE2 on glandular epithelial and endothelial cells. PGE2 has been shown previously to induce epithelial cell proliferation via the cAMP/protein kinase A pathway (34).
Further evidence of a role for PGE2 in uterine vascular function can be derived from studies of menorrhagia. Nonsteroidal antiinflammatory drugs, which inhibit PG synthesis, are the treatment of choice to alleviate excessive blood loss in women reporting menorrhagia (35). Interestingly, increased binding of PGE2, suggesting increased receptor expression, has been observed in the uteri of patients reported to suffer from menorrhagia (36). Moreover, treatment with fenamates (nonsteroidal antiinflammatory drugs) to reduce menstrual blood loss also reduces PGE2-binding sites within the uterus (37). Together these data indicate an in vivo relationship between EP receptor expression and menstrual blood loss.
In conclusion, the data presented herein confirm the expression of PGE synthase, PGE2, and functional EP2 and EP4 receptors in epithelial and endothelial cells of human endometrium. In addition, we observed increased EP4 receptor and PGE2-induced cAMP production in proliferative phase tissue. We hypothesize that PGE2 is an integral modulator of cell proliferation and/or differentiation within the endometrium and acts as an autocrine/paracrine factor between epithelial and endothelial cells.
Acknowledgments
We thank Ms. J. Creiger for tissue collection, and Prof. Hilary O. D. Critchley for uterine wedge biopsies. We are also grateful to Drs. Sharon Battersby and Julie Brooks for their assistance with laboratory techniques.
Footnotes
Abbreviations: COX, Cyclooxygenase; dNTP, deoxy-NTP; FITC, fluorescein isothiocyanate; PG, prostaglandin.
Received January 30, 2001.
Accepted May 13, 2001.
References
and PGE2 from
separated cells of human endometrium and decidua. Prostaglandins
Leukotriene Essent Fatty Acids 33:91–96[CrossRef][Medline]
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S. Battersby, H. O. D. Critchley, K. Morgan, R. P. Millar, and H. N. Jabbour Expression and Regulation of the Prokineticins (Endocrine Gland-Derived Vascular Endothelial Growth Factor and Bv8) and Their Receptors in the Human Endometrium across the Menstrual Cycle J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2463 - 2469. [Abstract] [Full Text] [PDF]
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T. Sun, S.-J. Li, H.-L. Diao, C.-B. Teng, H.-B. Wang, and Z.-M. Yang Cyclooxygenases and prostaglandin E synthases in the endometrium of the rhesus monkey during the menstrual cycle Reproduction, April 1, 2004; 127(4): 465 - 473. [Abstract] [Full Text] [PDF]
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S Battersby, H O D Critchley, A J de Brum-Fernandes, and H N Jabbour Temporal expression and signalling of prostacyclin receptor in the human endometrium across the menstrual cycle Reproduction, January 1, 2004; 127(1): 79 - 86. [Abstract] [Full Text] [PDF]
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J. A. Arosh, S. K. Banu, P. Chapdelaine, and M. A. Fortier Temporal and Tissue-Specific Expression of Prostaglandin Receptors EP2, EP3, EP4, FP, and Cyclooxygenases 1 and 2 in Uterus and Fetal Membranes during Bovine Pregnancy Endocrinology, January 1, 2004; 145(1): 407 - 417. [Abstract] [Full Text] [PDF]
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G. B. Perchick and H. N. Jabbour Cyclooxygenase-2 Overexpression Inhibits Cathepsin D-Mediated Cleavage of Plasminogen to the Potent Antiangiogenic Factor Angiostatin Endocrinology, December 1, 2003; 144(12): 5322 - 5328. [Abstract] [Full Text] [PDF]
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H. N. Jabbour and S. C. Boddy Prostaglandin E2 Induces Proliferation of Glandular Epithelial Cells of the Human Endometrium via Extracellular Regulated Kinase 1/2-Mediated Pathway J. Clin. Endocrinol. Metab., September 1, 2003; 88(9): 4481 - 4487. [Abstract] [Full Text] [PDF]
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J. A. Arosh, S. K. Banu, P. Chapdelaine, V. Emond, J. J. Kim, L. A. MacLaren, and M. A. Fortier Molecular Cloning and Characterization of Bovine Prostaglandin E2 Receptors EP2 and EP4: Expression and Regulation in Endometrium and Myometrium during the Estrous Cycle and Early Pregnancy Endocrinology, July 1, 2003; 144(7): 3076 - 3091. [Abstract] [Full Text] [PDF]
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 T. Schmitz, M.J. Leroy, E. Dallot, M. Breuiller-Fouche, F. Ferre, and D. Cabrol Interleukin-1{beta} induces glycosaminoglycan synthesis via the prostaglandin E2 pathway in cultured human cervical fibroblasts Mol. Hum. Reprod., January 1, 2003; 9(1): 1 - 8. [Abstract] [Full Text] [PDF]
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D. K. Hapangama, H. O. D. Critchley, T. A. Henderson, and D. T. Baird Mifepristone-Induced Vaginal Bleeding Is Associated with Increased Immunostaining for Cyclooxygenase-2 and Decrease in Prostaglandin Dehydrogenase in Luteal Phase Endometrium J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 5229 - 5234. [Abstract] [Full Text] [PDF]
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S. Battersby, S. C. Boddy, H. O. D. Critchley, and H. N. Jabbour Expression and Localization of Endothelial Monocyte-Activating Polypeptide II in the Human Endometrium across the Menstrual Cycle: Regulation of Expression by Prostaglandin E2 J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3928 - 3935. [Abstract] [Full Text] [PDF]
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J. Parent, P. Chapdelaine, J. Sirois, and M. A. Fortier Expression of Microsomal Prostaglandin E Synthase in Bovine Endometrium: Coexpression with Cyclooxygenase Type 2 and Regulation by Interferon-{tau} Endocrinology, August 1, 2002; 143(8): 2936 - 2943. [Abstract] [Full Text] [PDF]
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 M. Tamura, S. Sebastian, S. Yang, B. Gurates, K. Ferrer, H. Sasano, K. Okamura, and S. E. Bulun Up-regulation of Cyclooxygenase-2 Expression and Prostaglandin Synthesis in Endometrial Stromal Cells by Malignant Endometrial Epithelial Cells. A PARACRINE EFFECT MEDIATED BY PROSTAGLANDIN E2 AND NUCLEAR FACTOR-kappa B J. Biol. Chem., July 12, 2002; 277(29): 26208 - 26216. [Abstract] [Full Text] [PDF]
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