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BOR - Papers in Press, published online ahead of print January 26, 2005.
Biol Reprod 2005, 10.1095/biolreprod.104.035840
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BIOLOGY OF REPRODUCTION 72, 1282–1288 (2005)
DOI: 10.1095/biolreprod.104.035840
© 2005 by the Society for the Study of Reproduction, Inc.

Induction of Epithelial Cell Apoptosis in the Uterus by a Mouse Uterine Ischemia-Reperfusion Model: Possible Involvement of Tumor Necrosis Factor-{alpha}

Mitsuo Okazaki 2,3, Toshifumi Matsuyama 1 3, Tomoko Kohno 3, Hisakazu Shindo 3, Takehiko Koji 4, Yoshiharu Morimoto 2, and Tadayuki Ishimaru 5

IVF Namba Clinic,2 Osaka 550-0015 Japan Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology,3 Department of Histology and Cell Biology,4 Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8523 Japan Department of Obstetrics and Gynecology,5 Nagasaki University School of Medicine, Nagasaki 852-8501, Japan


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Menstruation in primates is preceded by a period of intense vasoconstriction, with resultant ischemia-reperfusion. Although apoptosis is involved in endometrial breakdown, the relationship between ischemia-reperfusion and apoptosis in the female genital tract has not been determined. To investigate the relationship between ischemia-reperfusion and apoptosis in the uterus, we analyzed a uterine ischemia-reperfusion model using BDF1 and C57BL/6 mice. Ischemia was induced by clamping the uterine horn and uterine artery for 5 to 30 min, followed by 6, 12, 24, or 48 h of reperfusion (n = 4 for each group). The number of TUNEL-positive endometrial cells increased with the duration of ischemia and reached a maximum at 24 h of reperfusion, but then tended to decrease at 48 h. Transmission electron micrographs of endometrial cells revealed a typical nuclear condensation, confirming the occurrence of apoptosis. The mRNA expression level of the proinflammatory cytokine tumor necrosis factor-alpha (TNF{alpha}) in the uterus increased after reperfusion. Ischemia-reperfusion-induced endometrial apoptosis was markedly decreased in TNF-R p55-deficient mice, confirming the essential role of TNF{alpha} in the induction of apoptosis by ischemia-reperfusion (n = 4). Our results suggest that ischemia-reperfusion and subsequent TNF{alpha} expression may be critical factors in inducing endometrial cell apoptosis. Our mouse model could be suitable for investigating ischemia-related uterine injury in humans, particularly in menstruation.

apoptosis, cytokines, menstrual cycle, uterus


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Menstruation is characterized by bleeding at the end of the menstrual cycle in the primate uterus. Menstruation involves endometrial tissue degradation, resulting in blood loss from damaged vessels subsequent to a regeneration process [1]. Apoptosis in endometrial epithelial cells increases in the menstrual phase, and is involved in important mechanisms leading to endometrial breakdown during menstruation [2–4]. Several factors such as nitric oxide [5], tumor necrosis factor-alpha (TNF{alpha}) [6], Fas [7], and interleukin-1 [8] are known to induce apoptosis in the epithelial cells of the endometrium. In addition, ovarian hormone withdrawal may play a key role in the regulation of endometrial apoptosis [9, 10].

Markee described the important role of ischemia-reperfusion in the induction of menstruation in monkeys [11]. The endometrial bleeding depends on vasoconstrictors such as endothelin-1 [12], prostaglandins [13, 14], angiotensin II [15], and vasopressin [16]; and on vasodilators such as nitric oxide [5] and PTH-related protein [17]. Ischemia-reperfusion induces apoptosis in the testis, placenta, and other organs [18–21]. Although both ischemia and hormonal withdrawal must be considered as possible inductors of apoptosis in the human endometrium [3], the functional roles and mechanisms of ischemia-reperfusion in regulating menstruation are poorly understood. Furthermore, ischemia-reperfusion induces TNF{alpha}, followed by inflammation in affected organs such as the intestine [22], lung [23], heart [24], neuronal system [25], and kidney [26]. TNF{alpha} also induces tissue injury and apoptosis in the endometrium [6, 27]. We speculated that ischemia-reperfusion and the subsequently induced TNF{alpha} expression might play a key role in the induction of menstruation.

In the present study, we initially investigated endometrial apoptosis using a mouse uterine ischemia-reperfusion model. We next investigated the involvement of TNF{alpha} in ischemia-reperfusion-induced apoptosis. TNF{alpha} binds two receptors, TNF receptor I (TNF-R p55) and TNF receptor II (TNF-R p75). TNF-R p55 has been theorized to trigger an apoptotic signal [28]. However, the role of TNF{alpha} in ischemia-reperfusion injury has been controversial [25]. We evaluated TNF{alpha} mRNA expression and also examined the role of the TNF{alpha}-TNF-R p55 pathway in apoptosis with TNF-R p55-deficient mice. Our findings comprise the first report on uterine ischemia-reperfusion and apoptosis of endometrial cells in the uterus.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Animal Experiments

We used female BDF1 mice (6- to 10-wk-old, n = 68) (SCL, Shizuoka, Japan), TNF-R p55-deficient mice (n = 4) [29], and their related wild type, C57BL/6 (n = 15). Mice were quarantined in individual cages for more than 2 wk. They were then maintained in a 12L:12D environment and had free access to food and water. The mice were used for the following experiments at diestrus, as determined by a vaginal smear. They were anesthetized with sodium pentobarbital (40 mg/kg) between 1600 and 1900 h. A mid-abdominal incision was made under sterile conditions, followed by clamping of the lower uterine horn and uterine artery using smooth vascular clips (Vidrex, Fukuoka, Japan), modified as reported previously [30, 31]. The clips were maintained for a period of 5, 15, or 30 min, and then the uterus was reperfused by declamping for 6, 12, 24, or 48 h. The BDF1 mice were divided into 17 groups based on the duration of ischemia and reperfusion. The contralateral uterus was used as the control. TNF-R p55-deficient mice and their related wild types were investigated after 30 min of ischemia and 24 h of reperfusion. All experiments were approved by the Animal Ethics Committee of Nagasaki University.

Measurement of Uterine Blood Flow

Uterine blood flow and velocity were measured in mice for a period of 20 sec using a laser Doppler flow meter [32, 33] (ALF21N; Advance, Tokyo, Japan). A noncontact probe (outer diameter 1.0 mm) was kept 0.5 cm apart from the uterus. Control measurements of blood flow were performed in 17 mice before clamping. Measurements were also performed during 15 min of clamping, and after declamping. These assays were conducted at the middle of the uterus and the data were recorded on the built-in chart recorder (100 mm/min). Values were selected randomly at 1 sample/sec and the blood flow is expressed as a percentage of the control (before clamping).

Tissue Preparation and Terminal Deoxy-UTP Nick End Labeling

The uterus was fixed in neutral-buffered formalin (Ishizu, Osaka, Japan). After overnight fixation, the specimens were cut transversely, dehydrated, and embedded in paraffin. The tissue blocks were cut into 3-µm-thick sections, deparaffinized, and used in subsequent experiments. Some of the specimens were stained with hematoxylin-eosin for histochemical evaluation. After deparaffinization, the nuclei with fragmented DNA were detected using a TUNEL detection kit (Wako, Osaka, Japan). Briefly, tissue sections were digested with a protease for 5 min at 37°C. After washing with 0.01 M PBS for 15 min, the slides were incubated with the terminal deoxynucleotidyl transferase reaction mixture in a humidified chamber at 37°C for 1 h. The specimens were immersed in 3% H2O2 with 0.01 M PBS for 5 min at room temperature to reduce the endogenous peroxidase activity, and were washed again with 0.01 M PBS for 10 min. Then, the slides were treated with peroxidase-conjugated antibody for 10 min at 37°C. After washing with 0.01 M PBS for 15 min, the immunoreaction was visualized with diaminobenzidine and H2O2. Counterstaining was with methyl green dye. For quantification of apoptotic cells, more than 300 cells in a given endometrial epithelium per mouse were counted.

Transmission Electron Microscopy

Tissue specimens were cut into approximately 1 mm3 pieces and fixed for 1 h in 2.5% glutaraldehyde in 0.1 M PBS. After rinsing four times for 10 min each with PBS, the tissues were fixed in 1% osmium tetroxide dissolved in PBS (pH 7.4) for 1 h at room temperature. The fixed specimens were rapidly dehydrated in a graded series of ethanol and propylene oxide, and then were embedded in Epon. Approximate sections were cut by an ultramicrotome at 85 µm using diamond knives, and were mounted on copper grids. The specimens were further stained with uranyl acetate and lead citrate, and then were examined with a JEOL 1200 electron microscope.

Total RNA Isolation and Reverse Transcription-Polymerase Chain Reaction

To elucidate the participation of TNF{alpha} in the induction of apoptosis, we examined the TNF{alpha} mRNA expression and investigated its role in our model using TNF-R p55-deficient mice. After mice had been killed, the total RNA was immediately isolated from the mouse uterus using the acid guanidium isothiocyanate-phenol-chloroform extraction method, as described by the supplier (Isogen; Wako). First-strand synthesis was performed on 1 µg of total RNA using random primers and reverse transcriptase. Complementary DNA was amplified using the GeneAmp system of DNA amplification (Perkin-Elmer). Samples were incubated in a thermocycler for 35 cycles after the addition of primers and Taq polymerase. Denaturation was carried out at 94°C for 1 min, followed by primer annealing at 58°C for 1 min and primer extension at 72°C for 2 min. The PCR products were then electrophoretically separated by size in a 1% agarose gel and stained with ethidium bromide. Primers were synthesized by Sawady Corporation (Tokyo). The sequences for the TNF{alpha} primers were 5'-ggcaggtctactttggagtcattgc-3' and 5'-ggcttaagtgacctcggagcttaca-3' (307 base pairs), and those for the ß-actin primers were 5'-tggaatcctgtggcatccatgaaac-3' and 5'-gcctgacaatgactcgacgcaaaat-3' (348 base pairs) [34]. For the real-time polymerase chain reaction (PCR), we used LightCycler-primer/probe sets for mouse TNF{alpha} and ß-actin, and performed the experiments according to the protocol provided by the manufacturer (Roche). The total RNAs were extracted 24 h after reperfusion, and the relative levels of TNF{alpha} mRNA were normalized to the respective amount of ß-actin.

Statistical Analysis

Tissue blood flow and velocity are expressed as means ± SEM. The TUNEL-positive cells are expressed as the number present per 300 total endometrial epithelial cells (means ± SEM). All data for different groups were compared for statistical difference using the Student t-test. A P value < 0.05 denotes the presence of a statistically significant difference.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Measurement of Tissue Blood Flow

The mean uterine blood flow decreased significantly after clamping compared with that of the control condition (before, 22.7 ± 1.9; clamp, 13.2 ± 1.1 ml LD min 100 g tissue; P < 0.01). Similar differences were noted for blood velocity (before, 2.1 ± 0.2; clamp, 1.1 ± 0.1 mm/sec; P < 0.05). After 15 min of ischemia, declamping was associated with significant increases in blood flow, to 21.7 ± 2.7 ml LD min 100 g tissue (P < 0.01), and velocity (1.7 ± 0.2 mm/sec; P < 0.05) within a few minutes, when returned to the control level (Fig. 1). The uterus appeared pale during clamping and pink-reddish after declamping.



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  		FIG. 1. Tissue blood flow and velocity in the BDF1 mouse uterus. Blood flow (A) and velocity (B) in the uterus are shown as mean ± SEM error bars before ischemia, at 15 min of clamping (clamp), and immediately after declamping (after). Statistically significant differences, *P < 0.01; **P < 0.05

Histological Changes in the Uterus and Following Ischemia-Reperfusion

The histological examination demonstrated the features of epithelial cell destruction. Detached endometrial cells in the lumen were observed after 30 min of ischemia followed by 6 h of reperfusion, and the endometrial vessels showed congestion. The number of detached cells in the lumen increased in the endometrium after 30 min of ischemia followed by 24 h of reperfusion (Fig. 2B). The uterus was restored to its normal appearance by 48 h. The epithelium in the control uterus showed the normal appearance (Fig. 2A).



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  		FIG. 2. The histological changes in the uterus after ischemia-reperfusion in BDF1 mice. A normal control uterus (A) and a uterus after 30 min of ischemia and 24 h of reperfusion (B) are shown. Arrows indicate the detached cells. Hematoxylin-eosin staining; magnification x100 in (A); x200 in (B)

Apoptosis of Endometrial Cells after Ischemia-Reperfusion

As shown in Figure 3A, there were few TUNEL-positive cells in the control endometrium. However, TUNEL-positive cells were observed in the endometrial glandular epithelium after 30 min of ischemia and 24 h of reperfusion (Fig. 3B). The number of TUNEL-positive glandular epithelial cells correlated with the duration of ischemia from 5 to 30 min, reached a maximum after 24 h, and decreased thereafter by 48 h (Fig. 4). Transmission electron microscopy showed nuclear condensation in apoptotic cells scattered throughout the endometrium after 15 min of ischemia and 6 h of reperfusion. We observed the nuclear condensation of cells in the glandular lumen and in the epithelium (Fig. 5, A and B). We could not see nuclear condensation in the endometrium of control uterus with transmission electron microscopy.



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  		FIG. 3. TUNEL staining of the uterus after ischemia-reperfusion. A) Control uterus, (B and C) uterus after 30 min of ischemia and 24 h of reperfusion; (A and B) BDF1 mouse, and (C) TNF-R p55-deficient mouse. Arrows indicate the TUNEL-positive cells. Magnification, x100 in (B), x200 in (A and C)



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  		FIG. 4. Distribution of TUNEL-positive nuclei in ischemia-reperfusion uteri (BDF1 mice). Experiments were performed four times and mean counts ± SEM of TUNEL-positive cells/300 endometrial cells are shown. *Significant difference (P < 0.05) for 30 min of ischemia and 24 h of reperfusion compared with that of control



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  		FIG. 5. Transmission electron microscopy of the endometrium. An epithelial cell showing compaction and segregation of chromatin against the nuclear envelope (arrow) observed in the lumen of glandular endometrium (A), and in the endometrium (B). The tissues were taken after 15 min of ischemia and 6 h of reperfusion. Magnification x4000 in (A and B)

Effects of Ischemia-Reperfusion on the Expressionof TNF{alpha} mRNA and TUNEL Staining in TNF-R p55-Deficient Mice

We determined the expression of TNF{alpha} mRNA in uterine tissues by reverse transcription-PCR. TNF{alpha} mRNA was barely detectable in the untreated control uterus. However, the increased expression of TNF{alpha} mRNA was found at 6 h after reperfusion and persisted until 24 h (Fig. 6A). To confirm the expression level of TNF mRNA quantitatively, we performed real-time PCR experiments at 24 h after reperfusion. TNF mRNA was elevated in the ischemia-reperfusion treated uterus compared with that of the contralateral, untreated uterus (Fig. 6B). We found, interestingly, that TNF-R p55-deficient uterus produced a higher basal level of TNF{alpha} mRNA, suggesting the possible compensatory production of TNF{alpha} in the absence of TNF-R p55. In addition, TNF-R p55-deficient uterus seemed rather resistant to the ischemia-reperfusion treatment, because the TNF mRNA levels remained unchanged (Fig. 6B). To investigate whether TNF{alpha} plays an essential role in the induction of apoptosis after ischemia-reperfusion, we compared the occurrence of apoptotic cells between TNF-R p55-deficient mice and mice of the wild type (C57Bl/6). After 30 min of ischemia and 24 h of reperfusion, the wild-type group showed a significant number of TUNEL-positive cells in the endometrium compared with that of the TNF-R p55-deficient group (wild type, 46.1 ± 4.8; p55-deficient, 2.5 ± 0.6 cells/300cells; P < 0.01; Figs. 3C and 7).



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  		FIG. 6. Reverse transcription-PCR analysis for TNF{alpha} expression in the mouse uterus. A) Kinetics of TNF{alpha} mRNA expression (307 base pairs) in the mouse uterine ischemia-reperfusion model are shown. ß-Actin (348 base pairs) mRNA expression was used as a loading control. At the indicated time point (hours) after reperfusion, the uteri were obtained and analyzed. B) Real-time PCR experiments were performed to detect the level of TNF{alpha} mRNA quantitatively. The total RNAs were extracted 24 h after reperfusion, and the relative levels of TNF{alpha} mRNA normalized to the respective amount of ß-actin ± SEM are shown



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  		FIG. 7. TNF/TNF-R p55 is involved in the uterine ischemia-reperfusion model. A quantitative analysis of TUNEL-positive nuclei in C57Bl/6 wild-type and TNF-R p55-deficient mice after 30 min of ischemia and 24 h of reperfusion is shown. Experiments were performed four times and values are expressed as means per 300 cells ± SEM. *Statistically significant difference (P < 0.01) between TNF-R p55-deficient mice and TNF-R p55 +/+ mice


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Since Markee first reported that vasoconstriction induces menstruation [11], many studies have confirmed the relation between vascular integrity and human endometrial regression [2, 13, 35]. In the menstrual phase, ischemia-reperfusion is considered to be a critical event in inducing endometrial regression and regeneration. Progesterone withdrawal is involved in uterine vasoconstriction; however, other pathological factors such as uterine contraction and bleeding may also cause temporary uterine ischemia. Under the conditions in which ischemia lasts longer than 1 day, 60% of the endometrial tissue is reduced during menstrual bleeding in endometrial transplants within the eye chamber in the Rhesus monkey [11]. Our model concurred with these results, and suggested that the duration of the ischemic time and the amount of tissue blood flow regulate endometrial apoptosis. A recent laser Doppler study, however, reported that there are no significant ischemia-reperfusion changes in the menstrual phase [32]. Although the reason for the discrepancy in these reports regarding menstrual blood flow is unknown, the local vascular integrity may be difficult to detect by laser Doppler, because in the normal menstrual phase, the blood flow per microvessel is maintained, and the ischemia may be focal and it may last longer than 10 min [32].

In our study, apoptotic cells were observed in the glandular lumen and in the endometrium, which is consistent with the observation that two mechanisms are involved in the spread of endometrial apoptosis, one via the lumen to the endometrial cavity and one via direct transport through the basal membrane to the stroma [3, 36, 37]. These results are in agreement with a human clinical study on menstruation [3, 4]. We speculated that the ischemia-reperfusion model reflected some features of endometrial cell death, particularly on menstruation.

TNF{alpha} is an important mediator of cell death and inflammation in the endometrium. The expression of TNF{alpha} mRNA in the human endometrium increases in the late secretory phase and during menstruation [38]. As for the expression of TNF{alpha} in the mouse estrus cycle, no or only slight expression of TNF{alpha} mRNA was observed in uterine tissues during proestrus, estrus, and diestrus I, but the expression increased in diestrus II [39]. In the ischemia-reperfusion model, we demonstrated for the first time that the expression of TNF{alpha} mRNA was positively increased in the uterine tissue along with the increase in apoptotic cells. In human endometrial epithelial cells, TNF{alpha} mRNA expression increased progressively after TNF{alpha} stimulation and estrogen withdrawal [38]. In our study, ischemia-reperfusion may have also stimulated these two pathways. However, the TNF{alpha}-induced endometrial cell death remains to be solved, because TNF{alpha} not only mediates oxidative stress causing cell damage, but also leads to cell survival through the induction of NF-{kappa}B in human endometrial stromal cells and other organs [25, 40].

TNF-R p55 is present in endometrial epithelial cells and stromal cells, as well as in myometrial smooth muscle and connective tissue cells in mice. The TNF-R p55 mRNA signal intensity was found to be the highest during diestrus II by an in situ hybridization method [41]. On the other hand, TNF-R p55 mRNA expression in the human endometrium is higher in the secretory phase than in the menstrual phases, and is inversely related to TNF{alpha} [42]. However, the expression of these proteins in the endometrial epithelium remains constant throughout the menstrual cycle [6], indicating that apoptosis in endometrial glands is unlikely to be regulated at the receptor level. Therefore, the induction of TNF{alpha} is the key regulator, and the increased level of TNF{alpha} mediates apoptosis through TNF-R p55 in the ischemia-reperfusion model.

Clinically, dysmenorrhea is related to vasoconstriction, uterine contraction, and ischemia. Because the excessive production of prostaglandins leads to vasoconstriction [14], our data suggest that the differences between normal menstruation and dysmenorrhea might be due to ischemia-reperfusion, which causes the induction of TNF{alpha}. Furthermore, menstrual inflammatory reactions are augmented by reperfusion, and the accumulating TNF{alpha} can contribute to endometrial apoptosis.

In conclusion, our findings indicate that endometrial apoptosis is initiated by uterine ischemia-reperfusion as well as by ovarian hormone withdrawal. While menstruation is a physiological event, ischemia-reperfusion and TNF{alpha} could injure the female genital tract, leading to pathological conditions such as dysmenorrhea. We propose that the inhibition of TNF{alpha} may provide a novel therapeutic intervention for endometrial protection from ischemia-reperfusion injury.


   ACKNOWLEDGMENTS
 
The authors thank Ms. Yokoyama, Ms. Yamashita, and Mr. T. Suematsu for their excellent technical assistance.


   FOOTNOTES
 
1 Correspondence: Toshifumi Matsuyama, Division of Cytokine Signaling, Department of Molecular Microbiology and Immunology, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan. FAX: 81 95 849 7083;tosim{at}net.nagasaki-u.ac.jp Back

Received: 2 September 2004.

First decision: 28 September 2004.

Accepted: 20 January 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Kooy J, Taylor NH, Healy DL, Rogers PAW. Endothelial cell proliferation in the endometrium of women with menorrhagia and in women following endometrial ablation. Hum Reprod 1996 11:1067-1072[Abstract/Free Full Text]
  2. Tabibzadeh S. The signals and molecular pathways involved in human menstruation, a unique process of tissue destruction and remodeling. Mol Hum Reprod 1996 2:77-92[Abstract/Free Full Text]
  3. Dahmoun M, Boman K, Cajander S, Westin P, Bäckström T. Apoptosis, proliferation, and sex hormone receptors in superficial parts of human endometrium at the end of the secretory phase. J Clin Endocrinol Metab 1999 84:1737-1743[Abstract/Free Full Text]
  4. Kokawa K, Shikone T, Nakano R. Apoptosis in the human uterine endometrium during the menstrual cycle. J Clin Endocrinol Metab 1996 81:4144-4147[Abstract/Free Full Text]
  5. Tschugguel W, Schneeberger C, Unfried G, Bräutigam G, Stonek F, Wieser F, Binstorfer EV, Czerwenka K, Weninger W, Kaider A, Bursch W, Breitschopf H, Huber JC. Elevation of inducible nitric oxide synthase activity in human endometrium during menstruation. Biol Reprod 1999 60:297-304[Abstract/Free Full Text]
  6. Tabibzadeh S, Zupi E, Babaknia A, Liu R, Marconi D, Romanini C. Site and menstrual cycle-dependent expression of proteins of the tumour necrosis factor (TNF) receptor family, and BCL-2 oncoprotein and phase-specific production of TNF{alpha} in human endometrium. Hum Reprod 1995 10:277-286[Abstract/Free Full Text]
  7. Harada T, Kaponis A, Iwabe T, Taniguchi F, Makrydimas G, Sofikitis N, Paschopoulos M, Paraskevaidis E, Terakawa N. Apoptosis in human endometrium and endometriosis. Hum Reprod Update 2004 10:29-38[Abstract/Free Full Text]
  8. Tanaka T, Umesaki N, Mizuno K, Chang L, Ohtaki S, Ogita S. Enhancement of apoptotic susceptibility by interleukin-1ß in human endometrial endothelial cells. Gynecol Endocrinol 1998 12:315-319[Medline]
  9. Slayden OD, Hirst JJ, Brenner RM. Estrogen action in the reproductive tract of rhesus monkeys during antiprogestin treatment. Endocrinology 1993 132:1845-1856[Abstract/Free Full Text]
  10. Rotello RJ, Lieberman RC, Lepoff RB, Gerschenson LE. Characterization of uterine epithelium apoptotic cell death kinetics and regulation by progesterone and RU 486. Am J Pathol 1992 140:449-456[Abstract]
  11. Markee JE. Menstruation in intraocular endometrial transplants in the rhesus monkey. Contrib Embryol 1940 177:219-307
  12. Salamonsen LA, Marsh MM, Findlay JK. Endometrial endothelin: regulator of uterine bleeding and endometrial repair. Clin Exp Pharmacol Physiol 1999 26:154-157[CrossRef][Medline]
  13. Lockwood CJ, Schatz F. A biological model for the regulation of peri-implantation hemostasis and menstruation. J Soc Gynecol Invest 1996 3:159-165[Medline]
  14. Sales KJ, Jabbour HN. Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium. Reproduction 2003 126:559-567[Abstract]
  15. Li XF, Ahmed A. Compartmentalization and cyclic variation of immunoreactivity of renin and angiotensin converting enzyme in human endometrium throughout the menstrual cycle. Hum Reprod 1997 12:2804-2809[Abstract/Free Full Text]
  16. Hauksson A, Åkerlund M, Melin P. Uterine blood flow and myometrial activity at menstruation, and the action of vasopressin and a synthetic antagonist. Br J Obstet Gynaecol 1988 95:898-904[Medline]
  17. Casey ML, MacDonald PC. The endothelin-parathyroid hormone-related protein vasoactive peptide system in human endometrium: modulation by transforming growth factor-beta. Hum Reprod 1996; (Suppl 2):62–82
  18. Turner TT, Tung KSK, Tomomasa H, Wilson LW. Acute testicular ischemia results in germ cell-specific apoptosis in the rat. Biol Reprod 1997 57:1267-1274[Abstract]
  19. Koji T, Hishikawa Y, Ando H, Nakanishi Y, Kobayashi N. Expression of Fas and Fas ligand in normal and ischemia-reperfusion testes: involvement of the Fas system in the induction of germ cell apoptosis in the damaged mouse testis. Biol Reprod 2001 64:946-954[Abstract/Free Full Text]
  20. Hung TH, Skepper JN, Charnock-Jones DS, Burton GJ. Hypoxia-reoxygenation: a potent inducer of apoptotic changes in the human placenta and possible etiological factor in preeclampsia. Circ Res 2002 90:1274-1281[Abstract/Free Full Text]
  21. Ikeda H, Suzuki Y, Suzuki M, Koike M, Tamura J, Tong J, Nomura M, Itoh G. Apoptosis is a major mode of cell death caused by ischaemia and ischaemia/reperfusion injury to the rat intestinal epithelium. Gut 1998 42:530-537[Abstract/Free Full Text]
  22. Yamamoto S, Tanabe M, Wakabayashi G, Shimazu M, Matsumoto K, Kitajima M. The role of tumor necrosis factor-alpha and interleukin-1 beta in ischemia-reperfusion injury of the rat small intestine. J Surg Res 2001 99:134-141[CrossRef][Medline]
  23. Khimenko PL, Bagby GJ, Fuseler J, Taylor AE. Tumor necrosis factor-alpha in ischemia and reperfusion injury in rat lungs. J Appl Physiol 1998 85:2005-2011[Abstract/Free Full Text]
  24. Prabhu SD, Chandrasekar B, Murray DR, Freeman GL. Beta-adrenergic blockade in developing heart failure: effects on myocardial inflammatory cytokines, nitric oxide, and remodeling. Circulation 2000 101:2103-2109[Abstract/Free Full Text]
  25. Hallenbeck JM. The many faces of tumor necrosis factor in stroke. Nature Science 2002 8:1363-1368
  26. Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR. Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol 1999 277:R922-R929
  27. Shalaby MR, Laegreid WW, Ammann AJ, Liggitt HD. Tumor necrosis factor-{alpha} associated uterine endothelial injury in vivo. Influence of dietary fat. Lab Invest 1989 61:564-570[Medline]
  28. Kanaly ST, Nashleanas M, Hondowicz B, Scott P. TNF receptor p55 is required for elimination of inflammatory cells following control of intracellular pathogens. J Immunol 1999 163:3883-3889[Abstract/Free Full Text]
  29. Pfeffer K, Matsuyama T, Kündig TM, Wakeham A, Kishihara K, Shahinian A, Wiegmann K, Ohashi PS, Krönke M, Mak TW. Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 1993 73:457-467[CrossRef][Medline]
  30. Checiu M. The effect of early hypoxy upon the development of rats and mice. Morphol Embryol 1992 3: –4 91-97
  31. Franklin JB, Brent RL. The effect of uterine vascular clamping on the development of rat embryos three to fourteen days old. J Morphol 1964 115:273-290[CrossRef][Medline]
  32. Gannon BJ, Carati CJ, Verco CJ. Endometrial perfusion across the normal human menstrual cycle assessed by laser Doppler fluxmetry. Hum Reprod 1997 12:132-139
  33. Hotta H, Uchida S, Shimura M, Suzuki H. Uterine contractility and blood flow are reflexively regulated by cutaneous afferent stimulation in anesthetized rats. J Auton Nerv Syst 1999 75:23-31[CrossRef][Medline]
  34. Balkwill FR. Cytokines, 2nd ed. Oxford, U.K.: IRL Press; 1995:57– 68
  35. Prill HJ, Götz F. Blood flow in the myometrium and endometrium of the uterus. Am J Obstet Gynecol 1961 82:102-108[Medline]
  36. Hopwood D, Levison DA. Atrophy and apoptosis in the cyclical human endometrium. J Pathol 1976 119:159-166[CrossRef][Medline]
  37. Davie R, Hopwood D, Levison DA. Intercellular spaces and cell junctions in endometrial glands: their possible role in menstruation. Br J Obstet Gynecol 1977 84:467-476[Medline]
  38. Tabibzadeh S, Satyaswaroop PG, Wolff MV, Strowitzki T. Regulation of TNF-{alpha} mRNA expression in endometrial cells by TNF-{alpha} and by oestrogen withdrawal. Mol Hum Reprod 1999 5:1141-1149[Abstract/Free Full Text]
  39. Roby KF, Hunt JS. Mouse endometrial tumor necrosis factor-{alpha} messenger ribonucleic acid and protein: localization and regulation by estradiol and progesterone. Endocrinology 1994 135:2780-2789[Abstract]
  40. Sugino N, Harada AK, Sakata A, Takiguchi S, Kato H. Nuclear factor-{kappa}B is required for tumor necrosis factor-{alpha}-induced manganese superoxide dismutase expression in human endometrial stromal cells. J Clin Endocrinol Metab 2002 87:3845-3850[Abstract/Free Full Text]
  41. Roby KF, Laham N, Hunt JS. Cellular localization and steroid hormone regulation of mRNA encoding tumour necrosis factor receptor I in mouse uterus. J Reprod Fertil 1996 106:285-290
  42. Chegini N, Dou Q, Williams RS. An inverse relation between the expression of tumor necrosis factor alpha (TNF{alpha}) and TNF{alpha} receptor in human endometrium. Am J Reprod Immunol 1999 42:297-302



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