VEGF及其在妊娠中的作用

VEGF具有促进血管通透性增加,血管内皮细胞分裂、增殖及诱导血管生成等作用。在人类胎盘滋养细胞及血管内皮细胞上有VEGR及其受体的表达。说明VEGF参与正常妊娠,胎盘血管生成的调节和滋养叶细胞生理性的侵入,妊高征患者外周血VEGF及妊高征胎盘中VEGFmRNA水平明显降低可造成滋养细胞侵入缺陷,而使母体子宫血管转变不足,造成胎盘灌注不足。     

VEGF及其在妊娠中的作用

VEGF具有促进血管通透性增加、血管内皮细胞分裂、增殖及诱导血管生成等作用.在人类胎盘滋养细胞及血管内皮细胞上有VEGR及其受体的表达,说明VEGF参与正常妊娠、胎盘血管生成的调节和滋养叶细胞生理性的侵入.妊高征患者外周血VEGF及妊高征胎盘中VEGF mRNA水平明显降低可造成滋养细胞侵入缺陷,而使母体子宫血管转变不足,造成胎盘灌注不足.     

不明原因绒毛炎致滋养细胞凋亡在胎儿生长受限发病中的作用

胎儿生长受限（fetal growth restriction,FGR）是产科常见并发症,临床上与多种围生儿不良结局有关。目前FGR发病机制不明,胎盘功能不全被认为是导致FGR发生的主要原因之一。不明原因绒毛炎（villitis of unknown etiology,VUE）是妊娠中、晚期常见的原因不明的非感染性胎盘炎症改变,以母体T细胞浸润绒毛间质和炎性细胞因子失调为特征。正常妊娠时滋养细胞有适度凋亡,VUE时增加的CD8⁺T淋巴细胞及霍夫鲍尔（Hofbauer）细胞活化后可分泌多种炎性细胞因子,促进滋养细胞凋亡,而滋养细胞凋亡可致胎盘发育不良、绒毛血管闭塞和胎盘血流灌注不足等,导致胎盘功能不全,与FGR的发病关系密切。目前VUE导致胎盘滋养细胞凋亡在FGR发生中的机制尚不明确。综述VUE时滋养细胞凋亡在FGR发病中的作用。     

人绒毛及绒毛外滋养细胞内皮一氧化氮合成酶的免疫组化定位及其在体外合体化过程中的表达

一氧化氮自由基(nitric oxide radical,NO)具有强烈的母体及胎儿胎盘血液动力学调节作用。合体滋养细胞(SC)由细胞滋养细胞(CC)合体化而形成。作者采用免疫组化法检测了早孕期绒毛内滋养细胞及足月妊娠羊膜胎盘基底板之绒毛外滋养细胞的内皮一氧化氮合成酶(e NOS)的表达,并作滋养细胞体外培养,观察CC合体化过程中的e NOS表达。 方法:收集孕8周自然宫内胚胎死亡清宫物的绒毛组织及足月妊娠分娩后的绒毛,羊膜、绒毛膜、蜕膜组织,于液氮-70℃保存备用。按Bax法提取足     

自噬在妊娠期糖尿病中的作用

自噬广泛存在于机体细胞中,能够保护细胞,维持正常的细胞功能和组织结构。过度自噬会引起细胞死亡,导致组织出现病理性损伤。胎盘通过自噬维持正常生理功能。在妊娠期糖尿病孕妇的胎盘中,高血糖能够诱导滋养细胞过度自噬,抑制胎盘血管生成,导致组织缺血、缺氧及细胞活性氧水平升高,出现胎盘功能障碍,增加早产、巨大儿等不良妊娠结局的发生风险。     

妊娠过程中凋亡级联的作用和调节

细胞凋亡是一种级联事件,在妊娠过程中发挥了重要的作用,主要体现在胎盘形成过程中滋养细胞层分化为合体细胞滋养层,滋养层入侵确保了胎盘锚固于母体血管系统以保证胎儿氧气及营养的供应。滋养层细胞的凋亡限制了子宫壁侵入,维持母体完整性,凋亡产生的多肽是胎儿特异性耐受建立的诱导物。整个级联过程受母体免疫系统的监控,妊娠妇女的免疫应答并没有显著降低,母体免疫系统能够识别胎儿移植物这个外源性抗原并作出应答。母胎界面特定的免疫耐受诱导机制使绒毛外滋养细胞（EVT）限制和容忍相互联系。细胞因子主要由自然杀伤细胞、T细胞分泌,白细胞通过细胞因子发挥其免疫调节作用。凋亡过程受到基因调控、激素及氧化应激等因素的影响。     

子宫螺旋动脉重铸与病理妊娠

子宫螺旋动脉重铸是妊娠正常进行的关键环节,绒毛外滋养细胞的增殖和侵袭是血管重铸过程的必要条件。滋养细胞生物学功能的完整和调控机制的协调起着至关重要的作用。滋养细胞浸润不足,栓塞螺旋动脉不彻底,母-胎循环的发生提前,使绒毛受到直接的机械损伤,氧化应激作用间接地造成细胞机能障碍和损伤,出现胎盘退化变性;人肿瘤蛋白p53(TP53)介导细胞通路对细胞周期蛋白依赖性激酶抑制剂1A(CDKN1A)和Bax基因的异常表达,微小RNA-520(miR-520)过度调控滋养细胞的凋亡导致母体出现复发性流产。由滋养细胞分泌产生的基质金属蛋白酶9(MMP-9)的异常表达和大量炎性因子的释放造成了胎盘缺血缺氧,表现出子痫前期的相关症状。胎盘绒毛的血管密度、绒毛间隙体积的降低、滋养细胞分化程度下降、微环境缺氧以及突触缺陷因子1(SYDE1)呈低水平表达,可能是造成胎儿生长受限的重要原因。因此研究螺旋动脉重铸过程对病理妊娠的早期诊治有着重要意义。     

滋养细胞凋亡的二阶段与子痫前期二阶段发病机制关系的探讨

子痫前期是产科的严重并发症,不仅影响孕产妇健康,而且影响后代远期预后,发病原因至今不清。该病是胎盘源性疾病,其发生发展可分为两个阶段：第1阶段为病理生理变化形成过程,以滋养细胞浸润异常,螺旋动脉重铸不良,胎盘血流灌注减少为特点;第2阶段为器官受损阶段,导致各种临床征象发生。滋养细胞凋亡在子痫前期发病中起重要作用,细胞凋亡失衡可导致其侵袭能力异常。在子痫前期发病的不同阶段,滋养细胞凋亡的机制也不同。总结相关文献发现,第1阶段为蜕膜自然杀伤细胞及诱导绒毛外滋养细胞凋亡引起螺旋动脉重铸不足的阶段,第2阶段为螺旋动脉重铸不足引起胎盘缺血缺氧导致合体滋养细胞凋亡的阶段。其相关的机制有待进一步研究。     

滋养细胞凋亡与妊娠

滋养细胞凋亡可见于正常妊娠的各个时期和各种病理妊娠的胎盘组织.正常妊娠时滋养细胞凋亡发生率随孕龄增加,可能与胎盘老化和分娩发动过程中的生物学变化关联.病理妊娠中因炎症细胞因子释放、血液灌注不足、营养缺乏、激素水平低下等使滋养细胞凋亡大量发生,反映了疾病程度并可改变妊娠结局.滋养细胞可能通过自身凋亡和诱导母体免疫活性细胞凋亡而维护妊娠.     

滋养细胞凋亡与妊娠

滋养细胞凋亡可见于正常妊娠的各个时期和各种病理妊娠的胎盘。正常 妊娠时滋养细胞凋亡发生率随孕龄增加，可能与胎盘老化和分娩发动过程中的生物学变化关联。病理妊娠中因炎症细胞因子释放、血液糖注不足、营养缺乏、激素水平低下等使滋养细胞凋亡大量发生，反映了疾病程度并可改变妊娠结局。滋养细胞可能通过自身凋亡和诱导母体免疫活性细胞凋亡而维护妊娠。     

Review: Fetal-maternal communication via extracellular vesicles – Implications for complications of pregnancies

The maternal physiology experiences numerous changes during pregnancy which are essential in controlling and maintaining maternal metabolic adaptations and fetal development. The human placenta is an organ that serves as the primary interface between the maternal and fetal circulation, thereby supplying the fetus with nutrients, blood and oxygen through the umbilical cord. During gestation, the placenta continuously releases several molecules into maternal circulation, including hormones, proteins, RNA and DNA. Interestingly, the presence of extracellular vesicles (EVs) of placental origin has been identified in maternal circulation across gestation. EVs can be categorised according to their size and/or origin into microvesicles (∼150–1000 nm) and exosomes (∼40–120 nm). Microvesicles are released by budding from the plasmatic membrane, whereas exosome release is by fusion of multivesicular bodies with the plasmatic membrane. Exosomes released from placental cells have been found to be regulated by oxygen tension and glucose concentration. Furthermore, maternal exosomes have the ability to stimulate cytokine release from endothelial cells. In this review, we will discuss the role of EVs during fetal-maternal communication during gestation with a special emphasis on exosomes.     

Review: The role of autophagy in extravillous trophoblast function under hypoxia

Autophagy, a process for cellular cleaning through the removal of intracellular components in lysosomes, is a well conserved mechanism from yeast to mammalian cells, and also contributes to the maintenance of cellular homeostasis and of the energetic balance, in cellular and tissue remodeling, and cellular defense against extracellular insults and pathogens. The role of autophagy in placentation has been clarified. Autophagy is induced in trophoblasts under physiological hypoxia during early pregnancy and seems to have a role in placentation. Recent findings suggest that impaired autophagy might induce poor placentation in preeclamptic cases. In this review, we discuss the role of autophagy and summarize the role of autophagy-related genes in placentas.     

Review: Oxygen and trophoblast biology--a source of controversy

Oxygen is necessary for life yet too much or too little oxygen is toxic to cells. The oxygen tension in the maternal plasma bathing placental villi is <20 mm Hg until 10-12 weeks' gestation, rising to 40-80 mm Hg and remaining in this range throughout the second and third trimesters. Maldevelopment of the maternal spiral arteries in the first trimester predisposes to placental dysfunction and sub-optimal pregnancy outcomes in the second half of pregnancy. Although low oxygen at the site of early placental development is the norm, controversy is intense when investigators interpret how defective transformation of spiral arteries leads to placental dysfunction during the second and third trimesters. Moreover, debate rages as to what oxygen concentrations should be considered normal and abnormal for use in vitro to model villous responses in vivo. The placenta may be injured in the second half of pregnancy by hypoxia, but recent evidence shows that ischemia with reoxygenation and mechanical damage due to high flow contributes to the placental dysfunction of diverse pregnancy disorders. We overview normal and pathologic development of the placenta, consider variables that influence experiments in vitro, and discuss the hotly debated question of what in vitro oxygen percentage reflects the normal and abnormal oxygen concentrations that occur in vivo. We then describe our studies that show cultured villous trophoblasts undergo apoptosis and autophagy with phenotype-related differences in response to hypoxia.     

The effects of apoptotic, deported human placental trophoblast on macrophages: possible consequences for pregnancy

During pregnancy, trophoblasts are shed into maternal blood from the placenta as they die. Trophoblasts are fetal cells and are therefore immunologically foreign to the maternal immune system, but the effects of shed trophoblasts on the maternal immune system are poorly characterized. We have used an in vitro villous explant model to harvest shed trophoblasts. These shed trophoblasts consist of multinucleated syncytial knots as well as mononuclear cells, and approximately 90% are apoptotic as determined by immunostaining with antibodies recognizing activated caspase-3 and the M30 cytokeratin neoepitope. U937 cells phagocytosed the shed apoptotic trophoblasts and, subsequently, secretion of the anti-inflammatory cytokine IL-10 was increased. In contrast, secretion of the proinflammatory cytokine Il-1beta by U937 cells was decreased after phagocytosis of apoptotic trophoblasts and the changes in both IL-10 and IL-1beta secretion were blocked by co-incubation with the phagocytosis inhibitor cytochalasin B. Shed trophoblasts caused a significant increase also in expression of the, immunosuppressive, tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase. We speculate that the shedding of trophoblasts may not be simply a mechanism the fetus uses to dispose of aged trophoblasts but rather shed apoptotic trophoblasts may provide a chronic source of tolerizing paternally derived antigens to regulate maternal immune responses to the fetus.     

The effects of apoptotic,deported human placental trophoblast on macrophages: Possible consequences for pregnancy

During pregnancy, trophoblasts are shed into maternal blood from the placenta as they die. Trophoblasts are fetal cells and are therefore immunologically foreign to the maternal immune system, but the effects of shed trophoblasts on the maternal immune system are poorly characterized. We have used an in vitro villous explant model to harvest shed trophoblasts. These shed trophoblasts consist of multinucleated syncytial knots as well as mononuclear cells, and approximately 90% are apoptotic as determined by immunostaining with antibodies recognizing activated caspase-3 and the M30 cytokeratin neoepitope. U937 cells phagocytosed the shed apoptotic trophoblasts and, subsequently, secretion of the anti-inflammatory cytokine IL-10 was increased. In contrast, secretion of the proinflammatory cytokine Il-1β by U937 cells was decreased after phagocytosis of apoptotic trophoblasts and the changes in both IL-10 and IL-1β secretion were blocked by co-incubation with the phagocytosis inhibitor cytochalasin B. Shed trophoblasts caused a significant increase also in expression of the, immunosuppressive, tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase. We speculate that the shedding of trophoblasts may not be simply a mechanism the fetus uses to dispose of aged trophoblasts but rather shed apoptotic trophoblasts may provide a chronic source of tolerizing paternally derived antigens to regulate maternal immune responses to the fetus.     

Spatial and temporal patterns of expression of messenger RNA for insulin-like growth factors and their binding proteins in the placenta of man and laboratory animals

To better understand the role of the insulin-like growth factors (IGF-I and -II) and their binding proteins (IGFBPs 1-6) in placental development and function, it is important to review similarities and differences between species in expression of the respective mRNAs. In human placenta, IGF-II mRNA is expressed in chorionic mesoderm and first trimester villous cytotrophoblast, but not in syncytiotrophoblast. In contrast, in rhesus monkey placenta, IGF-II mRNA is expressed in syncytiotrophoblast but not in chorionic mesoderm. IGFBP-3 mRNA is present in the chorionic mesoderm of placental villi from both these species and may modulate IGF-II action through a paracrine mechanism. In rodent placentae, IGF-II mRNA is expressed both in fetal mesoderm and in the trophoblast of the placental labyrinth. In guinea pig, where IGFBP-5 mRNA is expressed in the marginal and interlobular syncytium and IGF-II mRNA in the labyrinth, interaction between IGF-II and IGFBP-5 mRNA may be involved in vascularization of the placenta by fetal vessels. In sheep placenta, IGF-II mRNA is expressed, not in the trophoblast layer, but in the fetal mesoderm immediately adjacent to it. In the basal plate of human, rhesus monkey and baboon placentae, extravillous trophoblasts express IGF-II mRNA and uterine decidual cells IGFBP 1-6 mRNAs. The inference is that there is interaction between IGF-II and IGFBPs at the maternal-fetal interface of the primate placenta during trophoblast invasion and decidualization. IGFBP-1 expressed by the decidua may also interact with alpha(5)beta(1)integrin expressed by the extravillous trophoblast. The placentae of rodents are also of the invasive type. Glycogen cells of the mouse placenta are analogous with human extravillous trophoblast and express IGF-II mRNA. However, expression of IGFBP mRNAs in the mouse, as in the guinea pig, is confined to non-decidualized endometrium and myometrium. IGF-II mRNA is strongly expressed by trophoblasts invading uterine vessels in human and guinea pig placentae. Interactions probably occur between IGF-II expressed by these trophoblasts and IGFBPs expressed in the vessel walls. However, it is possible that IGFBPs expressed by maternal vessels are associated with processes that are independent of trophoblast invasion. Thus, IGFBP-3 mRNA is highly expressed in the maternal blood vessels of the non-deciduate sheep placenta. Findings to date highlight the diversity in the expression of the IGF system among placentae of man and different laboratory animals, and even between closely related species. Comparative studies will continue to be required to understand the functional role of IGFs and IGFBPs in each species.     

Eph and ephrin expression in normal placental development and preeclampsia

Eph receptors and their ephrin ligands play a fundamental role in embryogenesis. Their functions include cell targeting and angiogenesis. In placental development, trophoblasts migrate and invade maternal tissue and spiral arteries, where they play a role in both anchoring the placenta to the uterus and increasing blood flow to the developing fetus (interstitial and endovascular invasions). We investigated the cellular distribution and expression patterns of representative Eph and ephrin RNA and protein in an effort to identify the molecules involved in trophoblast migration during normal placental development and placental pathologies. We found ephrin-A1 expressed exclusively in the invasive extravillous trophoblast (EVT) cell lineage. We therefore proceeded to investigate ephrin-A1 in placental pathologies with defects in EVT invasion. In preeclampsia, where trophoblast invasion is shallow, we observed ephrin-A1 expression similar to normal placenta. Furthermore, in initial experiments on the deeply invading trophoblasts of placenta accreta, which lacks decidua, ephrin-A1 is found to be expressed highly in extravillous trophoblasts that have invaded the myometrium. In addition, we found the prototype ephrin-A1 receptor, EphA2, localized in several placental cell types. EphB4 and ephrin-B2 molecules, which have specific expression patterns during artery and vein development, respectively, were also expressed in the placenta. The cell specific distribution of ephrin-A1 suggests that it may play a role in targeting and migration of trophoblasts, and in the vascular remodeling induced by the invading extravillous trophoblasts. Failure of ephrin-A1 expression is unlikely to be the primary cause in defective migration of trophoblasts observed in preeclampsia. Specific roles for other Eph and ephrin proteins remain to be investigated.     

In vitro perfusion study of the human placenta at term: preliminary results.

Dual perfusion of the human placental lobule in vitro is a useful method for studying the transfer of molecules across the placenta, including the transfer of endogenous substances and xenobiotics. To establish the first model of in vitro placental dynamic study in our country, we used a dual recirculating perfusion system modified from that described by Miller et al. A placental lobule without tears or gross lesions was chosen. Both the fetal and maternal sides of the placenta were perfused with Medium 199 in addition to heparin, glucose, dextran and antibiotics. Perfusate samples were obtained periodically and analyzed for blood gas, glucose, lactate, human placental lactogen (hPL) and human chorionic gonadotropin (hCG). The stability of this human placental lobule preparation during 10 hours of perfusion was reflected by the stability of the arterial pressure and by the constant volume in the fetal compartment. A constant rate of oxygen was delivered by the maternal circulation system, and a steady rate of oxygen was gained by the fetal circulation system. Neither oxygen nor glucose consumption by the tissue was significantly reduced during the period of perfusion. The releasing rates of hCG and hPL did not change significantly during perfusion. The development of this dual perfusion system for the human placenta can provide for the study of placental hemodynamics and transplacental transport in perinatal medicine in our country.     

Autophagy in term normal human placentas

Autophagy is an inducible catabolic process that responds to environment and is essential for cell survival during stress, starvation and hypoxia. Its function in the human placenta it is not yet understood. We collected 14 placentas: 7 at vaginal delivery and 7 at elective caesarean section after uneventful term pregnancies. The presence of autophagy was assessed in different placental areas by immunoblotting, immunohistochemistry and electron microscopy. We found that autophagy is significantly higher in placentas obtained from cesarean section than in those from vaginal delivery. Moreover there is a significant inverse relationship between autophagy and umbilical arterial glucose concentration.     

Ultrastructure of the chorioallantoic placenta and chorionic vesicles of the lesser bush baby (Galago senegalensis)

The ultrastructure of the chorioallantoic placenta of the lesser bush baby (Galago senegalensis) has been studied. The placenta was shown to be of the diffuse, epitheliochorial and adeciduate type. The trophoblasts of the chorionic villi, other than those lining the chorionic vesicles, were characterized by the presence of many lipid droplets. In the later stage of gestation, the fetal capillaries indented the trophoblastic epithelium reducing the distance between fetal and maternal circulations. In addition chorionic vesicles were observed. The trophoblasts lining the chorionic vesicles have outward bulging apical surfaces. There are clefts between these cells and this region is occupied by microvilli of adjacent cells. Several layers of fusiform cells that did not extend up into the cores of the chorionic vesicle villi formed the outer component of the vesicular wall. Granulated cells were observed within the maternal connective tissue and their possible role is discussed.