着床后雌激素对兔妊娠及胎盘建立的作用和束缚应激对小鼠子宫内膜崩解的作用
发布时间：2018-11-15 16:41
【摘要】：胎盘形成过程中,伴随着母体子宫内膜螺旋动脉的重塑。螺旋动脉重塑不完整会导致子宫动脉管径较小、胎盘植入不足等。临床研究显示,低水平雌二醇容易造成着床不够深,而高雌激素水平生产低体重儿的风险增加,可见雌激素对胎盘植入深度存在精细调控。子宫内膜的状态是成功受孕的前提之一。月经是女性子宫内膜发生周期性脱落的生理现象,研究报道精神因素、工作压力等会导致女性月经不调,月经不调会影响生育。本研究以兔为模型,探讨妊娠早期雌激素对胎盘胎儿发育及血管重塑等方面的影响；以蜕膜化假孕小鼠为模型探讨束缚应激对子宫内膜的影响。主要结果如下：1.血管重塑过程中CD31在血管内皮细胞逐渐呈强阳性表达,α-SMA呈弱表达或不表达。CD31和α-SMA的表达动态揭示它们可能参与了妊娠过程中螺旋动脉的重塑。Real-time PCR结果显示妊娠9d组IL-8和MCP-1mRNA水平均高于未妊娠组(P0.01),妊娠13d组IL-8和MCP-1mRNA水平均高于妊娠9d组(P0.01),此结果说明IL-8和MCP-1可能也参与了妊娠过程中螺旋动脉的重塑。2.通过雌激素干预发现,来曲唑处理组妊娠后期胎儿胎盘湿重增加,雌激素处理组胎儿胎盘湿重减少。相对正常对照组,来曲唑处理组妊娠9d时子宫内膜血管周空泡化的蜕膜化细胞较少,说明来曲唑处理后子宫内膜的蜕膜化启动被延迟；雌激素处理组妊娠16d时胎盘结构出现异常,连接区形成受阻。3.CK7+17免疫组织化学结果显示,妊娠16d时,来曲唑处理组只在子宫肌层的部分血管内检测到CK7+17阳性信号,雌激素处理组在子宫肌层未检测到阳性信号。此结果说明雌激素干预抑制了滋养层细胞的侵袭。4.妊娠9d和妊娠13d时,来曲唑处理组CD31和α-SMA的信号均比正常对照组强；妊娠16d时,雌激素处理组CD31和α-SMA的信号均比正常对照组强。TUNEL的结果显示来曲唑处理组妊娠13d时只检测到零星的血管内皮细胞凋亡；妊娠16d时来曲唑处理组与正常对照组无明显差异,雌激素处理组多数血管内皮细胞处于凋亡状态。以上结果说明雌激素干预后螺旋动脉的重塑被延迟。妊娠9d时,Real-time PCR结果显示来曲唑处理组MCP-1 mRNA水平比正常对照组低,而13d时却比正常对照组高。5.束缚应激组血清中孕酮含量下降,皮质酮含量增加,提示孕酮撤退是束缚应激能够导致蜕膜化的假孕小鼠子宫内膜崩解出血的关键因素,且其与皮质酮的升高有关。6.束缚应激组卵巢中孕酮合成相关酶Cypllal和Star mRNA水平下调表达,提示束缚应激导致的孕酮撤退与Cypllal和Star mRNA水平的下调表达有关。综上所述,妊娠早期雌激素干预延缓子宫内膜螺旋动脉重塑,抑制滋养层细胞侵袭,胎盘结构出现异常。束缚应激通过影响HPA轴和HPO轴导致假孕小鼠子宫内膜崩解。
[Abstract]:The process of placental formation is accompanied by remodeling of the mother's endometrial spiral artery. Incomplete remodeling of spiral artery may result in small diameter of uterine artery and insufficient placenta accreta. Clinical studies show that low level estradiol is easy to cause implantation depth, and high level of estrogen production of low birth weight infant risk increased, we can see that estrogen on the depth of placenta accreta has a fine regulation. The state of the endometrium is one of the prerequisites for successful conception. Menstruation is a physiological phenomenon in which female endometrium periodically falls off. It is reported that mental factors, work pressure and so on will lead to irregular menstruation and irregular menstruation will affect fertility. In this study, the effects of estrogen on placental fetal development and vascular remodeling in early pregnancy were studied in rabbits, and the effects of restraint stress on endometrium in decidualized pseudopregnant mice were studied. The main results are as follows: 1. During vascular remodeling, CD31 was strongly expressed in vascular endothelial cells. The dynamic expression of CD31 and 伪-SMA suggests that 伪-SMA may be involved in the remodeling of spiral artery during pregnancy. Real-time PCR results showed that the levels of IL-8 and MCP-1mRNA in 9 day group were higher than those in non-pregnancy group Pregnancy group (P0.01), The levels of IL-8 and MCP-1mRNA in the 13th day group were higher than those in the 9th day group (P0.01), which suggested that IL-8 and MCP-1 might also be involved in the remodeling of the spiral artery during pregnancy. 2. It was found that the fetal placenta wet weight increased in letrozole group and decreased in estrogen treatment group. Compared with the normal control group, there were fewer decidualized cells in letrozole treated group on the 9th day of pregnancy, indicating that the decidualization of endometrium was delayed after letrozole treatment. On the 16th day of gestation, the placental structure was abnormal and the junction area was blocked in estrogen treatment group. The immunohistochemical results of 3.CK7 17 showed that the positive signal of CK7 17 was detected only in some vessels of uterine myometrium in letrozole treatment group at 16 days of gestation. No positive signals were detected in the myometrium of the estrogen treated group. The results suggested that estrogen inhibited the invasion of trophoblast cells. 4. 4. At day 9 and day 13, the signal of CD31 and 伪-SMA in letrozole treated group was stronger than that in normal control group. On the 16th day of gestation, the signals of CD31 and 伪-SMA in estrogen treated group were stronger than those in normal control group. The results of TUNEL showed that only sporadic apoptosis of vascular endothelial cells was detected in letrozole treated group on the 13th day of gestation. On the 16th day of gestation, there was no significant difference between letrozole group and normal control group, and most vascular endothelial cells in estrogen treated group were apoptotic. These results suggest that the remodeling of spiral artery is delayed after estrogen intervention. On the 9th day of gestation, Real-time PCR results showed that the level of MCP-1 mRNA in letrozole treated group was lower than that in normal control group, but at 13 days it was higher than that in normal control group. Serum progesterone content decreased and corticosterone content increased in restraint stress group, which suggested that progesterone withdrawal was the key factor of endometrium collapse and hemorrhage in decidualized pseudopregnant mice, and it was related to the increase of corticosterone. The expression of progesterone synthase related enzymes Cypllal and Star mRNA was down-regulated in the ovary of restraint stress group, suggesting that the withdrawal of progesterone induced by restraint stress was related to the down-regulation of Cypllal and Star mRNA levels. In conclusion, estrogen intervention in early pregnancy delayed endometrial spiral artery remodeling, inhibited trophoblast invasion and abnormal placental structure. Restraint stress induces endometrial disintegration in pseudopregnant mice by affecting the HPA axis and HPO axis.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R714.2
[Abstract]:The process of placental formation is accompanied by remodeling of the mother's endometrial spiral artery. Incomplete remodeling of spiral artery may result in small diameter of uterine artery and insufficient placenta accreta. Clinical studies show that low level estradiol is easy to cause implantation depth, and high level of estrogen production of low birth weight infant risk increased, we can see that estrogen on the depth of placenta accreta has a fine regulation. The state of the endometrium is one of the prerequisites for successful conception. Menstruation is a physiological phenomenon in which female endometrium periodically falls off. It is reported that mental factors, work pressure and so on will lead to irregular menstruation and irregular menstruation will affect fertility. In this study, the effects of estrogen on placental fetal development and vascular remodeling in early pregnancy were studied in rabbits, and the effects of restraint stress on endometrium in decidualized pseudopregnant mice were studied. The main results are as follows: 1. During vascular remodeling, CD31 was strongly expressed in vascular endothelial cells. The dynamic expression of CD31 and 伪-SMA suggests that 伪-SMA may be involved in the remodeling of spiral artery during pregnancy. Real-time PCR results showed that the levels of IL-8 and MCP-1mRNA in 9 day group were higher than those in non-pregnancy group Pregnancy group (P0.01), The levels of IL-8 and MCP-1mRNA in the 13th day group were higher than those in the 9th day group (P0.01), which suggested that IL-8 and MCP-1 might also be involved in the remodeling of the spiral artery during pregnancy. 2. It was found that the fetal placenta wet weight increased in letrozole group and decreased in estrogen treatment group. Compared with the normal control group, there were fewer decidualized cells in letrozole treated group on the 9th day of pregnancy, indicating that the decidualization of endometrium was delayed after letrozole treatment. On the 16th day of gestation, the placental structure was abnormal and the junction area was blocked in estrogen treatment group. The immunohistochemical results of 3.CK7 17 showed that the positive signal of CK7 17 was detected only in some vessels of uterine myometrium in letrozole treatment group at 16 days of gestation. No positive signals were detected in the myometrium of the estrogen treated group. The results suggested that estrogen inhibited the invasion of trophoblast cells. 4. 4. At day 9 and day 13, the signal of CD31 and 伪-SMA in letrozole treated group was stronger than that in normal control group. On the 16th day of gestation, the signals of CD31 and 伪-SMA in estrogen treated group were stronger than those in normal control group. The results of TUNEL showed that only sporadic apoptosis of vascular endothelial cells was detected in letrozole treated group on the 13th day of gestation. On the 16th day of gestation, there was no significant difference between letrozole group and normal control group, and most vascular endothelial cells in estrogen treated group were apoptotic. These results suggest that the remodeling of spiral artery is delayed after estrogen intervention. On the 9th day of gestation, Real-time PCR results showed that the level of MCP-1 mRNA in letrozole treated group was lower than that in normal control group, but at 13 days it was higher than that in normal control group. Serum progesterone content decreased and corticosterone content increased in restraint stress group, which suggested that progesterone withdrawal was the key factor of endometrium collapse and hemorrhage in decidualized pseudopregnant mice, and it was related to the increase of corticosterone. The expression of progesterone synthase related enzymes Cypllal and Star mRNA was down-regulated in the ovary of restraint stress group, suggesting that the withdrawal of progesterone induced by restraint stress was related to the down-regulation of Cypllal and Star mRNA levels. In conclusion, estrogen intervention in early pregnancy delayed endometrial spiral artery remodeling, inhibited trophoblast invasion and abnormal placental structure. Restraint stress induces endometrial disintegration in pseudopregnant mice by affecting the HPA axis and HPO axis.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2015
【分类号】：R714.2
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