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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
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
) 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
in the induction of apoptosis by ischemia-reperfusion (n = 4). Our results suggest that ischemia-reperfusion and subsequent TNF
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
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