Study On The Mechanism Of Prostaglandins And Their Receptors On The Disintegration And Shedding Of The Endometrium During Menstruation

Mestruation is a unique physiology character in primates such as human being,in which,endometrium periodically breakdown and shed.The mechanism of endometrial breakdown and shedding is the key to understand mechanism and find the treatment strategy of endometrial abnormal bleeding.The period of menstrual cycle is long in the child-bearing period in female,which is very important to female health.The typical menstruation hypothesis is that progesterone withdrawal cause prostaglandins product and release in the late secretion in the menstrual cycle,then lead to uterine spiral contraction,finally endometrial breakdown and shedding.But other hypothesis is that prostaglandins does not have the effect of initial menstruation occurs.The hypothesis emphasize that PGs play the key role in endometrial breakdown and shedding.Early in 1957,Pickles firstly found PGs in menstrual blood.However,whether PGs play a key role in endometrial breakdown and shedding was in dispute.In the past published paper,it showed that PGs play the active role in this process,including the followings:1)PGE2 and PGF2? were founded in the menstrual blood;2)PGE2 and PGF2?were increased in the late secretion and menstrual period.3)injecting PGF2? lead to unterial contraction;4)The speed limiting synthetase cyclooxygenase(COX)inhibitor could reduce the metromenorrhagia blood.In our study,the mouse menstrual-like model and immortalized human endometrial stroma cell were used to explore the functional role of PGs and PGs receptor in menstruation.At first,mouse menstrual-like model was built,the expression and role of PGs and their receptors were explored.We found that PGE2 and PGF2? were increased,and PGF2? receptor mRNA and protein were also increased from 0h-24h after P4 withdrawal.It indicated that PTGFR plays a role in endometrial breakdown and shedding.Further,we found that it regulates vascular permeability via angiostatin to lead to endometrial breakdown and shedding:HIF1?,as the key gene in endometrial breakdown and shedding,its expression was consistent with PTGFR in time and space.According to the past study and our study here in our science group,that HIF1? and PTGFR play the key role in endometrial breakdown and shedding,so we concluded that HIF1? regulates PTGFR to lead to endometrial breakdown and shedding.Its regulation was verified also in the immortalized human endometrial stroma cell.Moreover,T-HESC firstly used to build immortalized human endometrial stroma cell model related with menstruation.Further,in order to prove the direct regulation ship between HIF1? and PTGFR,CHIP was applied and verified possibility in HIF1? directly regulating PTGFR in mouse menstrual-like model.The results were as follows:1.In mouse menstrual-like model,PGE2 in the uterus was increased in the period of endometrial breakdown and shedding,especially at 12-16 h after P4,it indicated that PGE2 was key to endometrial breakdown and shedding.PGF2? was increased at 8 h after P4,and reach the maximal at 16 h.Moreover,PTGFR mRNA and protein were also increased at 12-16 h after P4.They were just in the key period of endometrial breakdown and shedding,it indicated that PTGFR was very important to endometrium breakdown and shedding in mouse menstrual-like model.Moreover,Ptgfr mRNA was obviously increased and reached at 16 h after P4 withdrawal in immortalized human endometrial stroma cell model related with menstruation,it indicated that PTGFR was very important to endometrium breakdown and shedding at the cell level.2.In mouse menstrual-like model,PTGFR and PTGER2 receptor inhibitors were obviously inhibit endometrial breakdown,and inhibiting degree was bigger than PTGER2 inhibitor during endometrial breakdown and shedding.So it concluded that PTGFR play very important role in endometrial breakdown and shedding.3.In mouse menstrual-like model,PTGFR inhibitor promoted the expression of angiostatin and inhibited vascular permeability,so PTGFR regulated vascular permeality to endometrial breakdown and shedding by angiostatin.However,vascular endothelial growth factor VEGF and NF-?B P65 were not involved in the process.4.In mouse menstrual-like model,the expression pattern of HIF1? was consistent to PTGFR in time and space.Moreover,HIF1? inhibitor 2ME inhibited the PTGFR expression.According to the past study and our study here in our scientific group,that HIF1? and PTGFR play the key role in endometrial breakdown and shedding,so we concluded that HIF1? regulated PTGFR to lead to endometrial breakdown and shedding.Moreover,we firstly build T-HESC to build immortalized human endometrial stroma cell model related with menstruation and verify the regulationship between HIF1? and PTGF at cell level.Conclusion1.In mouse menstrual-like model,PGE2 and PGF2? in the uterus was increased in the period of endometrial breakdown and shedding.It indicated that PGF2?/PTGFR was very important to endometrium breakdown and shedding at the cell level.2.In mouse menstrual-like model,compared with control,PTGFR receptor inhibitors were obviously inhibit endometrial breakdown,and inhibiting degree was bigger than PTGER2 inhibitor during endometrial breakdown and shedding.3.In mouse menstrual-like model,PTGFR inhi'bitor inhibited vascular permeability by angiostatin to endometrial breakdown and shedding.4.HIF1? and PTGFR play the key role in endometrial breakdown and shedding.Moreover,HIF1? inhibitor 2ME inhibited the PTGFR expression.so we concluded that HIF1? regulated PTGFR to lead to endometrial breakdown and shedding.In mouse menstrual-like model,HIF1? entered the nucleus and may bind Ptgfr promoter to regulate Ptgfr expression.