溶血磷脂酸受体3和环氧合酶2及子宫内膜胞饮突与小鼠子宫内膜容受性的相关研究
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摘要
胚胎植入是妊娠成功的关键因素之一,子宫内膜容受性的建立是胚胎成功植入的决定因素。因此对子宫内膜胚胎容受性的研究显得尤为重要。子宫内膜容受性是指子宫内膜在卵巢甾体激素调节下,子宫内膜形态、组织结构和分泌蛋白等发生一序列变化,使子宫内膜处于一种允许囊胚定位、黏附、侵入并使内膜间质发生改变从而导致胚胎着床的状态。这个特定的时期称为“着床窗期”。此时子宫内膜和胚胎相互作用,在非常短的着床窗期共同完成着床过程。在此前后,子宫内膜对胚胎处于不容受状态。在这一过程中,众多因素包括类固醇激素、生长因子、细胞因子信号以及黏附分子等,他们在不同的时间和空间环境控制下表达并发挥作用,共同构成了支持胚胎成功植入的分子基础。任何一个或几个因素表达水平出现异常,都有可能导致内膜环境发生改变,影响子宫内膜容受性,从而导致不孕。目前,子宫内膜容受性建立的确切机制尚不甚清楚,这对提高助孕技术水平和调节生育方法的发展是极大的障碍,进一步了解参与调节子宫内膜容受性的信号途径,将有助于我们更好地理解胚胎种植失败的原因,从而提高临床妊娠率。
溶血磷脂酸(Lysophosphatidic acid LPA)是Mills等在卵巢癌腹水中发现的一种新的生长因子,为细胞膜脂类衍生物,是细胞间磷脂类信号分子。存在于机体的血清、眼房水和血浆等多种体液中,主要由活化的血小板、成纤维细胞和脂肪细胞以及癌细胞分泌,也可由某些炎症细胞、内皮细胞等产生。LPA主要通过与靶细胞上特异G蛋白偶联受体结合,发挥多种生物学功能:包括细胞的生存、增殖、分化、细胞骨架的重排、细胞间的相互作用以及肿瘤的形成和侵袭等。LPA受体主要有四种(Lysophosphatidic acid receptor LPAR)LPAR1-4,属内皮分化基因家族。LPAR1、LPAR2在机体内广泛存在,而LPAR3主要表达于卵巢、心脏、睾丸、前列腺等组织。最近研究发现,LPAR1、LPAR2主要参与小鼠神经系统的发育、颅面的形成,与神经系统疾病密切相关;LPAR3则主要与雌性生殖系统有关。敲除LPAR3基因的雌性小鼠,表现为胚胎种植延迟、分布空间异常、子宫内膜环氧合酶-2(Cyclooxygenase-2 COX-2)、前列腺素E2(prostaglandin E2 PGE2)、前列腺素I2(prostaglandin I2 PGI2)表达降低。COX-2是合成前列腺素的限速酶。对该基因缺失小鼠若给予外源性PGE2和PGI2类似物--前列环素(carbaprostacyclin cPGI),可有效改善LPAR3基因缺失所致的胚胎种植延迟,提示LPA可能通过LPAR3-COX2-PGS下游信号途径调节胚胎种植。目前对LPAR3研究较多的是其在肿瘤侵袭、转移中的作用。最新研究表明,卵巢癌高表达LPA及其受体LPAR2~3,可刺激肿瘤细胞的增殖、迁移、粘附、基质金属蛋白酶(matrix metalloproteinase,MMP)活化和血管生成因子的分泌,促进肿瘤细胞的侵袭转移。胚胎着床过程与肿瘤细胞的侵袭过程有一定的相似之处。目前对LPAR3在子宫内膜容受性的建立和胚胎着床方面的研究甚少。
胞饮突是扫描电镜下所见的子宫内膜上皮细胞膜顶端出现的大而平滑的膜状突起。在啮齿类动物,它的出现与子宫内膜着床窗完全一致。在人类,它出现在月经中期LH峰的第6~8d,正是囊胚开始与子宫内膜粘附的时期。所以,胞饮突被认为是代表子宫内膜容受性的特异性形态学标记物。发育完全的胞饮突一般只存在24小时,代表了暂时性的细胞状态。目前有关胞饮突调节生殖作用的研究较多,但与LPAR3间关系的研究,国内外尚未见报道。
控制性超促排卵(Controlled ovarian hyperstimulation COH)是决定体外受精-胚胎移植技术(In vitro fertilization-embryo transfer IVF–ET)成功与否的重要环节。在此过程中,为了获得多个同步发育的成熟卵子,常应用促性腺激素释放激素激动剂(Gonadotropin releasing hormone agonist GnRHa)和促排卵药物。目前临床上最常用GnRHa长方案超促排卵。大量研究显示,该方案能有效改善卵子质量,提高卵子回收率,受精率及优质胚胎率,但胚胎种植率和临床妊娠率仍较低。多数学者认为,这可能与GnRHa长方案超排卵后,干扰了内源性激素的平衡,影响了子宫内膜形态及分泌功能,使内膜发育与胚胎发育不同步,从而降低了子宫内膜容受性有关。但COH影响子宫内膜容受性的确切机制还不清楚。因此,探讨子宫内膜容受性降低的机制并寻找有效的拮抗方法,对提高IVF-ET的临床妊娠率将有着重要意义。那么,GnRHa长方案促排卵是否影响子宫内膜LPAR3及胞饮突的表达及发育?目前国内外未见报道。
因此,研究LPAR3、COX-2在小鼠围着床期子宫内膜中的表达、作用及其调节机制以及与胞饮突的关系,可能会为探讨子宫内膜容受性的建立,揭示COH影响子宫内膜容受性的分子机制,提供理论依据。
受人类临床取材的制约,本研究选用昆明小鼠作为研究对象,因小鼠和人类同属哺乳动物,着床过程类似。
第一部分溶血磷脂酸受体3和环氧合酶-2在小鼠围着床期子宫内膜的表达及胞饮突发育的研究
目的:探讨溶血磷脂酸受体3(Lysophosphatidic acid receptor 3 LPAR3) mRNA及其蛋白,环氧合酶(Cyclooxygenase-2 COX-2)在小鼠围着床期子宫内膜的表达以及胞饮突的发育变化。
方法:采用半定量RT-PCR和Western blotting法以及免疫组织化学SP法,检测真孕组和假孕组小鼠LPAR3 mRNA及其蛋白在围着床期子宫内膜组织的表达规律。应用免疫组织化学SP法检测COX-2蛋白在子宫内膜的表达。扫描电子显微镜观察小鼠围着床期子宫内膜胞饮突的发育。
结果:LPAR3 mRNA及其蛋白在动情期未孕、真孕、假孕组小鼠的子宫内膜均呈阳性表达。LPAR3蛋白主要分布于小鼠子宫内膜腔上皮、腺上皮和部分基质细胞的胞浆。在真孕组,LPAR3 mRNA及其蛋白性交后第3天(3 days post coitus 3d.p.c)表达开始明显上升,4 d.p.c达峰值,5 d.p.c、6 d.p.c骤然下降至基础水平。假孕组与相应同期真孕组的表达水平及变化规律一致( P > 0.05)。COX-2主要分布于小鼠子宫内膜腔上皮、腺上皮和基质细胞及血管内皮细胞的胞浆,在动情期未孕和真、假孕1~3 d.p.c不表达,4 d.p.c开始表达,并随妊娠天数增加,其表达逐渐向基质细胞延伸。基质细胞阳性染色增多、增强。假孕组和真孕组表达规律一致。胞饮突的发育模式:3 d.p.c为发育中的胞饮突,4 d.p.c出现完全发育的胞饮突,5 d.p.c为退化的胞饮突。假孕组和真孕组的发育模式一致。LPAR3 mRNA及其蛋白在子宫内膜上皮的表达峰值与完全发育的胞饮突的出现,在时间和部位上存在一致性。
结论: LPAR3、COX-2和胞饮突可能参与了胚胎的着床及子宫内膜容受性的建立过程。LPAR3和子宫内膜的超微结构-胞饮突,表达时序一致,可作为判断子宫内膜具有容受性的分子参考指标。LPAR3和胞饮突的变化与宫腔内是否有胚胎存在无显著相关性,说明主要受母体信号的调节。COX-2可能参与胚胎植入过程。
第二部分雌孕激素对小鼠子宫内膜及Ishikawa细胞LPAR3表达的影响
目的:探讨雌、孕激素和孕激素拮抗剂米非司酮(RU486)对去势雌性小鼠在体子宫内膜及体外培养的子宫内膜腺癌细胞株Ishikawa细胞LPAR3 mRNA及其蛋白表达的影响。
方法:建立去势雌性昆明小鼠动物模型,随机分为雌激素组,孕激素组,雌孕激素联合组以及孕激素+RU486组,应用半定量RT-PCR、Western blotting法,检测子宫内膜LPAR3 mRNA及其蛋白的表达。体外培养高分化子宫内膜腺癌细胞Ishikawa细胞,分别加入不同浓度17-β雌二醇(10-9M, 10-8M, 10-7M)、孕激素(10-7M, 10-6M, 10-5M),雌+孕激素(10-8M+10-6M)。采用免疫细胞化学方法检测给药刺激48 h后LPAR3蛋白的表达。
结果:去势雌性小鼠子宫内膜表达LPAR3 mRNA;孕激素单独作用,可显著提高小鼠子宫内膜LPAR3 mRNA的表达,呈时间依赖性,但无明显量效关系;雌激素单独作用,对LPAR3 mRNA表达无显著影响。雌、孕激素联合应用,雌激素降低孕激素对子宫内膜LPAR3 mRNA的表达上调作用。RU486减弱孕激素的表达上调作用,但无明显量效关系。同组LPAR3蛋白的表达与基因表达趋势一致。各浓度雌激素、孕激素及雌孕激素联合应用,对体外培养的Ishikawa细胞LPAR3蛋白的表达均无明显影响( P > 0.05)。
结论:在体动物实验:孕激素单独作用,显著提高小鼠子宫内膜LPAR3 mRNA及其蛋白的表达,呈时间依赖性,无明显量效关系;雌激素单独作用对小鼠子宫内膜LPAR3表达无明显影响;雌、孕激素联合作用,雌激素降低孕激素对LPAR3表达上调作用;RU486减弱孕激素的表达上调作用。雌、孕激素对Ishikawa细胞,LPAR3蛋白的表达无显著影响。
第三部分GnRHa长方案促排卵对围着床期小鼠子宫内膜LPAR3的表达及胞饮突发育的影响
目的:研究GnRHa/HMG/HCG控制性超促排卵(Controlled ovarian hyperstimulation COH)对小鼠子宫内膜LPAR3 mRNA及其蛋白表达的影响以及胞饮突发育的变化。探讨COH长方案促排卵影响子宫内膜容受性的可能分子机制,为临床改善促排卵方案提供理论依据。
方法:将雌性健康未孕昆明系小鼠随机分为COH组和自然受孕组(natural conception NC),用半定量RT-PCR、Western blotting方法,检测3 d.p.c～6d.p.c子宫内膜LPAR3 mRNA及其蛋白的表达,同时应用扫描电子显微镜观察子宫内膜胞饮突发育情况。全自动免疫测定仪检测小鼠血清雌、孕激素水平。
结果:COH组:3d.p.c LPAR3 mRNA及其蛋白的表达出现峰值,而NC组,孕4d.p.c达峰值。其余相应各时间点两组间LPAR3 mRNA及其蛋白的表达量无显著差异。COH组:3d.p.c胞饮突发育不同步,大小不一,有的为发育完全的胞饮突,有的为正在发育的胞饮突,表面不光滑,有微绒毛,多为发育不完全的胞饮突。胞饮突数量较对照组明显减少,呈局灶性分布。4d.p.c胞饮突发育不同步,大小不一,表面开始皱缩。5d.p.c子宫内膜大部分为被覆微绒毛的上皮细胞,可见少量退化的胞饮突。NC组:3d.p.c部分子宫内膜细胞表面开始突起,膜状突起表面覆盖微绒毛,绒毛短,稀疏,为发育中胞饮突;孕4d.p.c均匀分布着大量大小一致,发育同步,边界清楚的蘑菇状胞饮突,表面光滑。5d.p.c胞饮突表面皱缩,为退化的胞饮突。血清雌、孕激素水平:血清雌、孕激素在两组均随妊娠天数增加而升高;COH组各时间点雌孕激素浓度均高于相应同期NC组,两者比较有显著差异。( P < 0.05)
结论:COH影响小鼠内源性激素的平衡,使雌、孕激素异常升高。可能通过改变与子宫内膜容受性相关的分子和超微结构的时序变化影响子宫内膜容受性,从而影响着床。
Embryo implantation is one of the vital factors for successful pregnancy and the establishment of endometrial receptiblity is the determinative factor for a well embryo implantation. As a result, the reseach on endometrial embryo receptiblity is very important. The endometrial receptiblity is a special condition of endometrium, during this period a series of changes in morphosis and secreted protein within the endometrium occurre under the control of ovarial steriod homone. As a consequence the allowance is available of apposition, adhesion, invasion and embryo implantation by the alteration in endometrial mesenchymal. This special period aslo be called“the window of implantation”. The implantation procedure can accomplish in this short peroid by the reaction between endometrium and embryo. On the contrary, the implantation is impossible before or behind this peroid. It can be drawed from researchs on endometrial receptiblity that many factors play important roles in the implantation procedure, which include steroid hormone, growth factor, cell factor signal, adhesion molecule etc. those factors expression and action in different time and under the control of different space enviromental form the molecular basis of embryo implantation. The expression level of any factors is abnormal will contribute to change the enviroment of endometrium and the endometrial receptivity and lead to infertility. The knowledge about the mechanism of implantation has not completely understood. It becomes the great handicape to improve the assisted reproductive technology level. To explore the pathway about the signal that participate the moderation procedure of the endometrial receptiblity will benefit us to get information about the failure of embryo implantation and increase the pregnancy rate accordingly.
Lysophosphatidic acid (LPA)-a new growth factor, has been founded by Mills in abdominal fluids resulted from ovrian cancer, is a kind of derivation of cell membran lipid functioning as an intercell phospholipid signal. LPA, secreted by actived blood platelet, cancer cell, fibroblast and adipocyte or produced by some inflammatory cell and endothelial cell, exists in blood serum, ocular humor and blood plasma. LPA mainly exhibit multiple biological functions by connecting to the special G-protein couple receptor in the target cell that invovlved in many cellular processes including cellular survice, proliferation, differentiation, cytoskeletal reorganization, interaction with cell and tumour formation and cancer cell invasion and so on in many physiological and pathological process.There are at least four receptors for LPA, LPAR1-4. LPAR1 and LPAR2 are expressed in almost all tissues,but LPAR3 shows a limited expression pattern in the ovary, heart, testes and prostate. The lately research showed, LPAR1 and LPAR2 are participate in the development of neurology and the formation of craniofacial. They are closely correlated with neurologic disease. LPAR3 in particular is important in female reproductive system: The female mouse whose PLAR3 gene have been knocked out appeared a delayed embryo implantation, abnormal space distribution, decreased expression of COX-2 gene. COX-2 is a rate-limiting enzyme of prostaglandin synthesis. The fact that giving exogenous PGE2 and cPGI can compensate the delayed embryo implantation in LPAR3 gene absent showing the closed relationship between LPAR3, COX-2 and embryo implantation. Nowadays, the majority of researchs on LPA and its receptor were focus on the function in tumor invasion and migration. The latest study indicated that high level expression of PLA and its receptor LPAR2, LPAR3 can promote cancer cellular proliferation, migration, adhension and induce the activation of matrix metalloproteinase (MMP) and the secretion of angiogenesis factor in objects with ovarian cancer. The process of implantation was similar, in some sense, to the process of tumor cell invasion and migration. In the generation domain, there is lack of information about the function of LPAR3 on establishing endometrial receptiblity and embryo implantation until now.
Pinopodes is a smooth bigger size prominence formed by endometrial epithelium. The occurrence of completely developed pinopodes during implantation peroid is regarded as the morphological characteristic of endometrial receptiblity which existed only for 24 hours and match the endometrial receptivity period. In rodent, pinopodes accordance to the window of implantation. In huaman, mature pinopodes are seen only during a brief window following the midcycle luteinizing hormone (LH) surge between LH+6 and LH+8. It is the period that blastocyst begin to attach to endometrium. As an ultramicrostructure marker of implantation window openning, about pinopodes there have many correlated studies in its function on reproduction. But no literature can be found at home and abroad about the relationship with LPAR3.
Controlled ovarian hyperstimulation (COH) can get many ovum by using ovulation stimulants, is an important element in determination of whether the IVF-ET can success or not. Long protocol controlled ovarian hyperstimulation is the most commonly used protocol by Gonadotrophin releasing hormone agonist. Researchs demonstrated that this plan can improve the quality of ovum and got many ovum but compared with the high retrieval rate, the clinical pregnancy rate still in a low level.This may be because that the GnRHa long time superovulation program put a negative effect in the balance of internal hormone which affected the morphous and the secrete function of endometrium and resulted in asynchronization between the developtment of the endometrium and embryo. Decrease the endometrial receptiblity. Now the mechanism about the relationship between COH and decreasing in endometrial receptiblity is still unclear. So to evaluate the mechanism of decreasing in endometrial receptiblity and find an effective method to solve the problem plays a significent role in increasing the pregnancy rate by IVF-ET. Now it is absent in the document about the temporal and spatial interrelation with GnRHa long protocol controlled ovarian hyperstimulation on the expression of LPAR3 and pinopodes in mouse uterine endometrium during periimplantation periode.
In view of that, to study the expression of LPAR3 and COX-2 in uterine endometrium and the development of pinopodes during the periimplantation of mouse and the relationship of coexpression will provide clue of theory for the building endometrial receptivity and reveal the maybe molecule mechanism of endometrial receptivity.
The specimens of humen are limited, kunming mice and human are all mammals, the procedure of embryo implantation is similar, so we select kunming mouse as our study objectives.
The partΙ: The expression of LPAR3 and COX-2 in uterine endometrium during the period of periimplantation of mouse embryos and the development of pinopodes
Object: To evaluate the dynamic change of lysophosphatidic acid receptor 3 mRNA, protein and distribution. The expression and location of COX-2 in mouse uterine endometrium during the period of periimplantation; To evaluate the pinopodes development in window of implantation.
Method: The expression of LPAR3 mRNA and protein in uterine endometrium tissues during periimplantation of pregnant and pseudopregnant mice were detected by using semiquantitative of PT-PCR, Western blotting and immunohistochemistry methods. The COX-2 expression and location was detected by immunohistochemistry SP methods. Using scanning electronmicroscope to observe the development of pinopodes during periimplantation peroid.
Result: LPAR3 mRNA and protein were positive in endometrium of unpregnancy, pregnancy and pseudopregnancy mouse. LPAR3 protein mainly distributed in luminal and glandular epithelium and part of stromal cells of mouse uterus. Around the embryo implantation procedure in mouse, the level of LPAR3 mRNA and protein began to increase on 3 days post coitus (3d.p.c), peak around 4d.p.c and returned suddenly to basal level on 5d.p.c and 6d.p.c. The temporal profile of LPAR3 mRNA in the uterus of pseudopregnancy mouse was similar to those observed in normal pregnant mouse. There was no significant different between the two groups ( P > 0.05). The tendency of LPAR3 protein in pregnant and pseudopregnancy was regularity to LPAR3 mRNA. The COX-2 mainly existed in luminal, glandular epithelium vascular endothelial cell and part of stromal cell, didn't express in normal and before 3d.p.c, but began to express on 4d.p.c and extend to stromal cell along with the progression of pregnancy. The expression of COX-2 increased and deepened positive staining in stromal cells. The mode expression of COX-2 in pregnancy mouse was similar to that of pseudopregnancy. The mode of pinopodes: developing pinopodes appeared on 3d.p.c; mature pinopodes on 4d.p.c and degenerated pinopodes on 5d.p.c.which was coincidence with the expression peak of LPAR3 in uterine endometrial. The pattern was similar in pregnancy and pseudopregnancy.
Conclusion: LPAR3, COX-2 and pinopodes may participate in the building of endometrial receptiblity. The concordance of LPAR3 and pinopodes was in the temporal and spatial and could be as a marker in judgement of endometrial receptibity. There was no relationship between the expression of LPAR3, the development of pinopodes and whether or not the presentation of embryo in uterus.That showed they were mainly regulated by matermal signal. COX-2 possiblely participated in the procedure of embryo implantation.
The partΠ: The regulatory effect of estradiol progesterone on the expression of LPAR3 in uterine endometrium tissue and Ishikawa cell lines
Object: To investigate the regulatory effect of estradiol, progesteronge and progensterone antagonist RU486 on the expression of LPAR3 gene and protein in uterine endometrium and Ishikawa cell lines.
Method: Ovariectomized kunming mice were randomly divided into four groups: estradiol group, progesterone group, combined with estradiol and progesterone group, progesterone and RU486 group.The expression of LPAR3 mRNA and protein in uterine endometrium were detected by using semiquantitative of PT-PCR, Western blotting methods. The highly differentiated endometril adenocarcinoma cells(Ishikawa cell line) were cultured in vitro with 17-beta estradiol (E2)(10-9M, 10-8M, 10-7M), progesterone (10-7M, 10-6M, 10-5M), E2 combined with progesterone (10-8M+10-6M), for 48 hours respectively and the expression of LPAR3 protein was detected by immunocytochemistrical methods.
Result: There was a positive LPAR3 mRNA expression in ovariectomized Kunming mouse endometrium tissue; Progesterone alone could improve the expression of LPAR3 mRNA in mouse endometrium markedly and showed a time dependent; Estradiol alone could not put significantly effect on LPAR3 mRNA expression; Estradiol combined with progesterone could counteracted the up-regulation effect of progesterone; RU486 could decrease the up-regulation effect of progesterone. The tendency expression of LPAR3 protein has a positive correlation with the mRNA. There was no significant effect on the expression of LPAR3 protein in Ishikawa cell lines by variety concentration of estradiol, progesterone, estradiol combined with progesterone.
Conclusion: In vivo animal experiment, progesterone alone could increase the expression of LPAR3, but estradiol alone had no effect on it. Estradiol combined with progesterone could counteracted the up-regulation effect of progesterone; RU486 could decrease the up-regulation effect of progesterone. There was no significant effect on the expression of LPAR3 protein in Ishikawa cell lines by estradiol and progesterone.
The partШ: The effect of long protocol controlled ovarian hyperstimulation by GnRHa on the expression of LPAR3 and the development of pinopodes in mouse uterine endometrium during periimplantation period
Object: To investigate the influence of controlled ovarian hyperstimulation by GnRHa/HMG/HCG long protocol treatment to the expression of LPAR3 mRNA and protein and the development of pinopodes; To evaluate the maybe molecular mechanism of adverse effect on endometrial receptivity by COH which may provide theory for selecting an ideal programe of ovarian hyperstimulation in clinical.
Method: Healthy femal unpregnant Kunming mice were randomly divided into COH group and natural conception group(NC).The expession of LPAR3 mRNA and protein in uterine endometrium tissue was detected by PT-PCR and Western blotting during the periimplantation period. The development of pinopodes on 3d.p.c~6d.p.c by using scanning electron microscope. The estrogen and progesterone level in mouse blood serum was detected by Abbott Laboratories A4sym automatic immune radiomete.
Result: The peak expression of LPAR3 mRNA and protein on 3d.p.c in COH group, which was similar to natural conception group on 4d.p.c. There was no significant difference in other days. In the COH group, on 3d.p.c, the development of pinopodes was out-of-step, which characteristic of variation in size and in alignment. Some were mature pinopodes, most were developing ones, which had an uneven surface and microvilli. The number of pinopodes in COH group was less than in natural conception group and the style of expression was focal. On 4d.p.c, the development of pinopodes were derangement and the size was vary and were out of sync. On 5d.p.c, there were few degenerated pinopodes and most endometrium was covered with microvilli cells. In natural conception group: on 4d.p.c, there were a lots of coincidence pinopodes, the development was synchron, homogeneous distribution, equal size, smooth surface and looked like mushroom which progectured the surface of cells. On 5d.p.c , the surface of pinopodes were introcession and were degenerated pinopodes. The concentration of estrogen and progesterone in blood serum ascensus obviously in both groups with the progress of pregnancy, but it was higher in COH group than in natural conception group at each time. There was significantly different between two groups.
Conclusion: COH impacted the balance of endogenous hormone in mouse which resulting in an abnormal higher level of estrogen and progesteron. COH altered the endometrial receptibility through changing the relative factors for implantation and the change of ultrastructural in the temporal and spatial.
溶血磷脂酸(Lysophosphatidic acid LPA)是Mills等在卵巢癌腹水中发现的一种新的生长因子,为细胞膜脂类衍生物,是细胞间磷脂类信号分子。存在于机体的血清、眼房水和血浆等多种体液中,主要由活化的血小板、成纤维细胞和脂肪细胞以及癌细胞分泌,也可由某些炎症细胞、内皮细胞等产生。LPA主要通过与靶细胞上特异G蛋白偶联受体结合,发挥多种生物学功能:包括细胞的生存、增殖、分化、细胞骨架的重排、细胞间的相互作用以及肿瘤的形成和侵袭等。LPA受体主要有四种(Lysophosphatidic acid receptor LPAR)LPAR1-4,属内皮分化基因家族。LPAR1、LPAR2在机体内广泛存在,而LPAR3主要表达于卵巢、心脏、睾丸、前列腺等组织。最近研究发现,LPAR1、LPAR2主要参与小鼠神经系统的发育、颅面的形成,与神经系统疾病密切相关;LPAR3则主要与雌性生殖系统有关。敲除LPAR3基因的雌性小鼠,表现为胚胎种植延迟、分布空间异常、子宫内膜环氧合酶-2(Cyclooxygenase-2 COX-2)、前列腺素E2(prostaglandin E2 PGE2)、前列腺素I2(prostaglandin I2 PGI2)表达降低。COX-2是合成前列腺素的限速酶。对该基因缺失小鼠若给予外源性PGE2和PGI2类似物--前列环素(carbaprostacyclin cPGI),可有效改善LPAR3基因缺失所致的胚胎种植延迟,提示LPA可能通过LPAR3-COX2-PGS下游信号途径调节胚胎种植。目前对LPAR3研究较多的是其在肿瘤侵袭、转移中的作用。最新研究表明,卵巢癌高表达LPA及其受体LPAR2~3,可刺激肿瘤细胞的增殖、迁移、粘附、基质金属蛋白酶(matrix metalloproteinase,MMP)活化和血管生成因子的分泌,促进肿瘤细胞的侵袭转移。胚胎着床过程与肿瘤细胞的侵袭过程有一定的相似之处。目前对LPAR3在子宫内膜容受性的建立和胚胎着床方面的研究甚少。
胞饮突是扫描电镜下所见的子宫内膜上皮细胞膜顶端出现的大而平滑的膜状突起。在啮齿类动物,它的出现与子宫内膜着床窗完全一致。在人类,它出现在月经中期LH峰的第6~8d,正是囊胚开始与子宫内膜粘附的时期。所以,胞饮突被认为是代表子宫内膜容受性的特异性形态学标记物。发育完全的胞饮突一般只存在24小时,代表了暂时性的细胞状态。目前有关胞饮突调节生殖作用的研究较多,但与LPAR3间关系的研究,国内外尚未见报道。
控制性超促排卵(Controlled ovarian hyperstimulation COH)是决定体外受精-胚胎移植技术(In vitro fertilization-embryo transfer IVF–ET)成功与否的重要环节。在此过程中,为了获得多个同步发育的成熟卵子,常应用促性腺激素释放激素激动剂(Gonadotropin releasing hormone agonist GnRHa)和促排卵药物。目前临床上最常用GnRHa长方案超促排卵。大量研究显示,该方案能有效改善卵子质量,提高卵子回收率,受精率及优质胚胎率,但胚胎种植率和临床妊娠率仍较低。多数学者认为,这可能与GnRHa长方案超排卵后,干扰了内源性激素的平衡,影响了子宫内膜形态及分泌功能,使内膜发育与胚胎发育不同步,从而降低了子宫内膜容受性有关。但COH影响子宫内膜容受性的确切机制还不清楚。因此,探讨子宫内膜容受性降低的机制并寻找有效的拮抗方法,对提高IVF-ET的临床妊娠率将有着重要意义。那么,GnRHa长方案促排卵是否影响子宫内膜LPAR3及胞饮突的表达及发育?目前国内外未见报道。
因此,研究LPAR3、COX-2在小鼠围着床期子宫内膜中的表达、作用及其调节机制以及与胞饮突的关系,可能会为探讨子宫内膜容受性的建立,揭示COH影响子宫内膜容受性的分子机制,提供理论依据。
受人类临床取材的制约,本研究选用昆明小鼠作为研究对象,因小鼠和人类同属哺乳动物,着床过程类似。
第一部分溶血磷脂酸受体3和环氧合酶-2在小鼠围着床期子宫内膜的表达及胞饮突发育的研究
目的:探讨溶血磷脂酸受体3(Lysophosphatidic acid receptor 3 LPAR3) mRNA及其蛋白,环氧合酶(Cyclooxygenase-2 COX-2)在小鼠围着床期子宫内膜的表达以及胞饮突的发育变化。
方法:采用半定量RT-PCR和Western blotting法以及免疫组织化学SP法,检测真孕组和假孕组小鼠LPAR3 mRNA及其蛋白在围着床期子宫内膜组织的表达规律。应用免疫组织化学SP法检测COX-2蛋白在子宫内膜的表达。扫描电子显微镜观察小鼠围着床期子宫内膜胞饮突的发育。
结果:LPAR3 mRNA及其蛋白在动情期未孕、真孕、假孕组小鼠的子宫内膜均呈阳性表达。LPAR3蛋白主要分布于小鼠子宫内膜腔上皮、腺上皮和部分基质细胞的胞浆。在真孕组,LPAR3 mRNA及其蛋白性交后第3天(3 days post coitus 3d.p.c)表达开始明显上升,4 d.p.c达峰值,5 d.p.c、6 d.p.c骤然下降至基础水平。假孕组与相应同期真孕组的表达水平及变化规律一致( P > 0.05)。COX-2主要分布于小鼠子宫内膜腔上皮、腺上皮和基质细胞及血管内皮细胞的胞浆,在动情期未孕和真、假孕1~3 d.p.c不表达,4 d.p.c开始表达,并随妊娠天数增加,其表达逐渐向基质细胞延伸。基质细胞阳性染色增多、增强。假孕组和真孕组表达规律一致。胞饮突的发育模式:3 d.p.c为发育中的胞饮突,4 d.p.c出现完全发育的胞饮突,5 d.p.c为退化的胞饮突。假孕组和真孕组的发育模式一致。LPAR3 mRNA及其蛋白在子宫内膜上皮的表达峰值与完全发育的胞饮突的出现,在时间和部位上存在一致性。
结论: LPAR3、COX-2和胞饮突可能参与了胚胎的着床及子宫内膜容受性的建立过程。LPAR3和子宫内膜的超微结构-胞饮突,表达时序一致,可作为判断子宫内膜具有容受性的分子参考指标。LPAR3和胞饮突的变化与宫腔内是否有胚胎存在无显著相关性,说明主要受母体信号的调节。COX-2可能参与胚胎植入过程。
第二部分雌孕激素对小鼠子宫内膜及Ishikawa细胞LPAR3表达的影响
目的:探讨雌、孕激素和孕激素拮抗剂米非司酮(RU486)对去势雌性小鼠在体子宫内膜及体外培养的子宫内膜腺癌细胞株Ishikawa细胞LPAR3 mRNA及其蛋白表达的影响。
方法:建立去势雌性昆明小鼠动物模型,随机分为雌激素组,孕激素组,雌孕激素联合组以及孕激素+RU486组,应用半定量RT-PCR、Western blotting法,检测子宫内膜LPAR3 mRNA及其蛋白的表达。体外培养高分化子宫内膜腺癌细胞Ishikawa细胞,分别加入不同浓度17-β雌二醇(10-9M, 10-8M, 10-7M)、孕激素(10-7M, 10-6M, 10-5M),雌+孕激素(10-8M+10-6M)。采用免疫细胞化学方法检测给药刺激48 h后LPAR3蛋白的表达。
结果:去势雌性小鼠子宫内膜表达LPAR3 mRNA;孕激素单独作用,可显著提高小鼠子宫内膜LPAR3 mRNA的表达,呈时间依赖性,但无明显量效关系;雌激素单独作用,对LPAR3 mRNA表达无显著影响。雌、孕激素联合应用,雌激素降低孕激素对子宫内膜LPAR3 mRNA的表达上调作用。RU486减弱孕激素的表达上调作用,但无明显量效关系。同组LPAR3蛋白的表达与基因表达趋势一致。各浓度雌激素、孕激素及雌孕激素联合应用,对体外培养的Ishikawa细胞LPAR3蛋白的表达均无明显影响( P > 0.05)。
结论:在体动物实验:孕激素单独作用,显著提高小鼠子宫内膜LPAR3 mRNA及其蛋白的表达,呈时间依赖性,无明显量效关系;雌激素单独作用对小鼠子宫内膜LPAR3表达无明显影响;雌、孕激素联合作用,雌激素降低孕激素对LPAR3表达上调作用;RU486减弱孕激素的表达上调作用。雌、孕激素对Ishikawa细胞,LPAR3蛋白的表达无显著影响。
第三部分GnRHa长方案促排卵对围着床期小鼠子宫内膜LPAR3的表达及胞饮突发育的影响
目的:研究GnRHa/HMG/HCG控制性超促排卵(Controlled ovarian hyperstimulation COH)对小鼠子宫内膜LPAR3 mRNA及其蛋白表达的影响以及胞饮突发育的变化。探讨COH长方案促排卵影响子宫内膜容受性的可能分子机制,为临床改善促排卵方案提供理论依据。
方法:将雌性健康未孕昆明系小鼠随机分为COH组和自然受孕组(natural conception NC),用半定量RT-PCR、Western blotting方法,检测3 d.p.c～6d.p.c子宫内膜LPAR3 mRNA及其蛋白的表达,同时应用扫描电子显微镜观察子宫内膜胞饮突发育情况。全自动免疫测定仪检测小鼠血清雌、孕激素水平。
结果:COH组:3d.p.c LPAR3 mRNA及其蛋白的表达出现峰值,而NC组,孕4d.p.c达峰值。其余相应各时间点两组间LPAR3 mRNA及其蛋白的表达量无显著差异。COH组:3d.p.c胞饮突发育不同步,大小不一,有的为发育完全的胞饮突,有的为正在发育的胞饮突,表面不光滑,有微绒毛,多为发育不完全的胞饮突。胞饮突数量较对照组明显减少,呈局灶性分布。4d.p.c胞饮突发育不同步,大小不一,表面开始皱缩。5d.p.c子宫内膜大部分为被覆微绒毛的上皮细胞,可见少量退化的胞饮突。NC组:3d.p.c部分子宫内膜细胞表面开始突起,膜状突起表面覆盖微绒毛,绒毛短,稀疏,为发育中胞饮突;孕4d.p.c均匀分布着大量大小一致,发育同步,边界清楚的蘑菇状胞饮突,表面光滑。5d.p.c胞饮突表面皱缩,为退化的胞饮突。血清雌、孕激素水平:血清雌、孕激素在两组均随妊娠天数增加而升高;COH组各时间点雌孕激素浓度均高于相应同期NC组,两者比较有显著差异。( P < 0.05)
结论:COH影响小鼠内源性激素的平衡,使雌、孕激素异常升高。可能通过改变与子宫内膜容受性相关的分子和超微结构的时序变化影响子宫内膜容受性,从而影响着床。
Embryo implantation is one of the vital factors for successful pregnancy and the establishment of endometrial receptiblity is the determinative factor for a well embryo implantation. As a result, the reseach on endometrial embryo receptiblity is very important. The endometrial receptiblity is a special condition of endometrium, during this period a series of changes in morphosis and secreted protein within the endometrium occurre under the control of ovarial steriod homone. As a consequence the allowance is available of apposition, adhesion, invasion and embryo implantation by the alteration in endometrial mesenchymal. This special period aslo be called“the window of implantation”. The implantation procedure can accomplish in this short peroid by the reaction between endometrium and embryo. On the contrary, the implantation is impossible before or behind this peroid. It can be drawed from researchs on endometrial receptiblity that many factors play important roles in the implantation procedure, which include steroid hormone, growth factor, cell factor signal, adhesion molecule etc. those factors expression and action in different time and under the control of different space enviromental form the molecular basis of embryo implantation. The expression level of any factors is abnormal will contribute to change the enviroment of endometrium and the endometrial receptivity and lead to infertility. The knowledge about the mechanism of implantation has not completely understood. It becomes the great handicape to improve the assisted reproductive technology level. To explore the pathway about the signal that participate the moderation procedure of the endometrial receptiblity will benefit us to get information about the failure of embryo implantation and increase the pregnancy rate accordingly.
Lysophosphatidic acid (LPA)-a new growth factor, has been founded by Mills in abdominal fluids resulted from ovrian cancer, is a kind of derivation of cell membran lipid functioning as an intercell phospholipid signal. LPA, secreted by actived blood platelet, cancer cell, fibroblast and adipocyte or produced by some inflammatory cell and endothelial cell, exists in blood serum, ocular humor and blood plasma. LPA mainly exhibit multiple biological functions by connecting to the special G-protein couple receptor in the target cell that invovlved in many cellular processes including cellular survice, proliferation, differentiation, cytoskeletal reorganization, interaction with cell and tumour formation and cancer cell invasion and so on in many physiological and pathological process.There are at least four receptors for LPA, LPAR1-4. LPAR1 and LPAR2 are expressed in almost all tissues,but LPAR3 shows a limited expression pattern in the ovary, heart, testes and prostate. The lately research showed, LPAR1 and LPAR2 are participate in the development of neurology and the formation of craniofacial. They are closely correlated with neurologic disease. LPAR3 in particular is important in female reproductive system: The female mouse whose PLAR3 gene have been knocked out appeared a delayed embryo implantation, abnormal space distribution, decreased expression of COX-2 gene. COX-2 is a rate-limiting enzyme of prostaglandin synthesis. The fact that giving exogenous PGE2 and cPGI can compensate the delayed embryo implantation in LPAR3 gene absent showing the closed relationship between LPAR3, COX-2 and embryo implantation. Nowadays, the majority of researchs on LPA and its receptor were focus on the function in tumor invasion and migration. The latest study indicated that high level expression of PLA and its receptor LPAR2, LPAR3 can promote cancer cellular proliferation, migration, adhension and induce the activation of matrix metalloproteinase (MMP) and the secretion of angiogenesis factor in objects with ovarian cancer. The process of implantation was similar, in some sense, to the process of tumor cell invasion and migration. In the generation domain, there is lack of information about the function of LPAR3 on establishing endometrial receptiblity and embryo implantation until now.
Pinopodes is a smooth bigger size prominence formed by endometrial epithelium. The occurrence of completely developed pinopodes during implantation peroid is regarded as the morphological characteristic of endometrial receptiblity which existed only for 24 hours and match the endometrial receptivity period. In rodent, pinopodes accordance to the window of implantation. In huaman, mature pinopodes are seen only during a brief window following the midcycle luteinizing hormone (LH) surge between LH+6 and LH+8. It is the period that blastocyst begin to attach to endometrium. As an ultramicrostructure marker of implantation window openning, about pinopodes there have many correlated studies in its function on reproduction. But no literature can be found at home and abroad about the relationship with LPAR3.
Controlled ovarian hyperstimulation (COH) can get many ovum by using ovulation stimulants, is an important element in determination of whether the IVF-ET can success or not. Long protocol controlled ovarian hyperstimulation is the most commonly used protocol by Gonadotrophin releasing hormone agonist. Researchs demonstrated that this plan can improve the quality of ovum and got many ovum but compared with the high retrieval rate, the clinical pregnancy rate still in a low level.This may be because that the GnRHa long time superovulation program put a negative effect in the balance of internal hormone which affected the morphous and the secrete function of endometrium and resulted in asynchronization between the developtment of the endometrium and embryo. Decrease the endometrial receptiblity. Now the mechanism about the relationship between COH and decreasing in endometrial receptiblity is still unclear. So to evaluate the mechanism of decreasing in endometrial receptiblity and find an effective method to solve the problem plays a significent role in increasing the pregnancy rate by IVF-ET. Now it is absent in the document about the temporal and spatial interrelation with GnRHa long protocol controlled ovarian hyperstimulation on the expression of LPAR3 and pinopodes in mouse uterine endometrium during periimplantation periode.
In view of that, to study the expression of LPAR3 and COX-2 in uterine endometrium and the development of pinopodes during the periimplantation of mouse and the relationship of coexpression will provide clue of theory for the building endometrial receptivity and reveal the maybe molecule mechanism of endometrial receptivity.
The specimens of humen are limited, kunming mice and human are all mammals, the procedure of embryo implantation is similar, so we select kunming mouse as our study objectives.
The partΙ: The expression of LPAR3 and COX-2 in uterine endometrium during the period of periimplantation of mouse embryos and the development of pinopodes
Object: To evaluate the dynamic change of lysophosphatidic acid receptor 3 mRNA, protein and distribution. The expression and location of COX-2 in mouse uterine endometrium during the period of periimplantation; To evaluate the pinopodes development in window of implantation.
Method: The expression of LPAR3 mRNA and protein in uterine endometrium tissues during periimplantation of pregnant and pseudopregnant mice were detected by using semiquantitative of PT-PCR, Western blotting and immunohistochemistry methods. The COX-2 expression and location was detected by immunohistochemistry SP methods. Using scanning electronmicroscope to observe the development of pinopodes during periimplantation peroid.
Result: LPAR3 mRNA and protein were positive in endometrium of unpregnancy, pregnancy and pseudopregnancy mouse. LPAR3 protein mainly distributed in luminal and glandular epithelium and part of stromal cells of mouse uterus. Around the embryo implantation procedure in mouse, the level of LPAR3 mRNA and protein began to increase on 3 days post coitus (3d.p.c), peak around 4d.p.c and returned suddenly to basal level on 5d.p.c and 6d.p.c. The temporal profile of LPAR3 mRNA in the uterus of pseudopregnancy mouse was similar to those observed in normal pregnant mouse. There was no significant different between the two groups ( P > 0.05). The tendency of LPAR3 protein in pregnant and pseudopregnancy was regularity to LPAR3 mRNA. The COX-2 mainly existed in luminal, glandular epithelium vascular endothelial cell and part of stromal cell, didn't express in normal and before 3d.p.c, but began to express on 4d.p.c and extend to stromal cell along with the progression of pregnancy. The expression of COX-2 increased and deepened positive staining in stromal cells. The mode expression of COX-2 in pregnancy mouse was similar to that of pseudopregnancy. The mode of pinopodes: developing pinopodes appeared on 3d.p.c; mature pinopodes on 4d.p.c and degenerated pinopodes on 5d.p.c.which was coincidence with the expression peak of LPAR3 in uterine endometrial. The pattern was similar in pregnancy and pseudopregnancy.
Conclusion: LPAR3, COX-2 and pinopodes may participate in the building of endometrial receptiblity. The concordance of LPAR3 and pinopodes was in the temporal and spatial and could be as a marker in judgement of endometrial receptibity. There was no relationship between the expression of LPAR3, the development of pinopodes and whether or not the presentation of embryo in uterus.That showed they were mainly regulated by matermal signal. COX-2 possiblely participated in the procedure of embryo implantation.
The partΠ: The regulatory effect of estradiol progesterone on the expression of LPAR3 in uterine endometrium tissue and Ishikawa cell lines
Object: To investigate the regulatory effect of estradiol, progesteronge and progensterone antagonist RU486 on the expression of LPAR3 gene and protein in uterine endometrium and Ishikawa cell lines.
Method: Ovariectomized kunming mice were randomly divided into four groups: estradiol group, progesterone group, combined with estradiol and progesterone group, progesterone and RU486 group.The expression of LPAR3 mRNA and protein in uterine endometrium were detected by using semiquantitative of PT-PCR, Western blotting methods. The highly differentiated endometril adenocarcinoma cells(Ishikawa cell line) were cultured in vitro with 17-beta estradiol (E2)(10-9M, 10-8M, 10-7M), progesterone (10-7M, 10-6M, 10-5M), E2 combined with progesterone (10-8M+10-6M), for 48 hours respectively and the expression of LPAR3 protein was detected by immunocytochemistrical methods.
Result: There was a positive LPAR3 mRNA expression in ovariectomized Kunming mouse endometrium tissue; Progesterone alone could improve the expression of LPAR3 mRNA in mouse endometrium markedly and showed a time dependent; Estradiol alone could not put significantly effect on LPAR3 mRNA expression; Estradiol combined with progesterone could counteracted the up-regulation effect of progesterone; RU486 could decrease the up-regulation effect of progesterone. The tendency expression of LPAR3 protein has a positive correlation with the mRNA. There was no significant effect on the expression of LPAR3 protein in Ishikawa cell lines by variety concentration of estradiol, progesterone, estradiol combined with progesterone.
Conclusion: In vivo animal experiment, progesterone alone could increase the expression of LPAR3, but estradiol alone had no effect on it. Estradiol combined with progesterone could counteracted the up-regulation effect of progesterone; RU486 could decrease the up-regulation effect of progesterone. There was no significant effect on the expression of LPAR3 protein in Ishikawa cell lines by estradiol and progesterone.
The partШ: The effect of long protocol controlled ovarian hyperstimulation by GnRHa on the expression of LPAR3 and the development of pinopodes in mouse uterine endometrium during periimplantation period
Object: To investigate the influence of controlled ovarian hyperstimulation by GnRHa/HMG/HCG long protocol treatment to the expression of LPAR3 mRNA and protein and the development of pinopodes; To evaluate the maybe molecular mechanism of adverse effect on endometrial receptivity by COH which may provide theory for selecting an ideal programe of ovarian hyperstimulation in clinical.
Method: Healthy femal unpregnant Kunming mice were randomly divided into COH group and natural conception group(NC).The expession of LPAR3 mRNA and protein in uterine endometrium tissue was detected by PT-PCR and Western blotting during the periimplantation period. The development of pinopodes on 3d.p.c~6d.p.c by using scanning electron microscope. The estrogen and progesterone level in mouse blood serum was detected by Abbott Laboratories A4sym automatic immune radiomete.
Result: The peak expression of LPAR3 mRNA and protein on 3d.p.c in COH group, which was similar to natural conception group on 4d.p.c. There was no significant difference in other days. In the COH group, on 3d.p.c, the development of pinopodes was out-of-step, which characteristic of variation in size and in alignment. Some were mature pinopodes, most were developing ones, which had an uneven surface and microvilli. The number of pinopodes in COH group was less than in natural conception group and the style of expression was focal. On 4d.p.c, the development of pinopodes were derangement and the size was vary and were out of sync. On 5d.p.c, there were few degenerated pinopodes and most endometrium was covered with microvilli cells. In natural conception group: on 4d.p.c, there were a lots of coincidence pinopodes, the development was synchron, homogeneous distribution, equal size, smooth surface and looked like mushroom which progectured the surface of cells. On 5d.p.c , the surface of pinopodes were introcession and were degenerated pinopodes. The concentration of estrogen and progesterone in blood serum ascensus obviously in both groups with the progress of pregnancy, but it was higher in COH group than in natural conception group at each time. There was significantly different between two groups.
Conclusion: COH impacted the balance of endogenous hormone in mouse which resulting in an abnormal higher level of estrogen and progesteron. COH altered the endometrial receptibility through changing the relative factors for implantation and the change of ultrastructural in the temporal and spatial.
引文
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