胎盘生长因子、转化生长因子-β与妊娠期高血压疾病

胎盘生长因子促进妊娠早期时滋养细胞的增殖和分化,在正常妊娠胎盘形成和发育中起重要作用.转化生长因子-β可促进子宫内膜的蜕膜化过程,抑制滋养细胞的增生、迁移、浸润,参与胎盘结构的形成及功能调节,在胎盘和胚胎的生长发育中起重要作用.这两种因子表达异常可能与妊娠期高血压疾病滋养细胞功能低下、血管内皮损伤有关,可能参与妊娠期高血压疾病的发生和发展过程.     

胎盘生长因子、转化生长因子-β与妊娠期高血压疾病

胎盘生长因子促进妊娠早期时滋养细胞的增殖和分化,在正常妊娠胎盘形成和发育中起重要作用。转化生长因子-β可促进子宫内膜的蜕膜化过程,抑制滋养细胞的增生、迁移、浸润,参与胎盘结构的形成及功能调节,在胎盘和胚胎的生长发育中起重要作用。这两种因子表达异常可能与妊娠期高血压疾病滋养细胞功能低下、血管内皮损伤有关,可能参与妊娠期高血压疾病的发生和发展过程。     

胰岛素样生长因子系统在胎儿生长发育中的作用

胰岛素样生长因子(insulin-like growth factors,IGFs)作为一类多功能的促生长调节因子,在细胞的增殖、分裂以及个体的生长、发育中具有重要的促进作用。IGFs分为1型和2型,主要通过与IGF-1受体结合,参与调控妊娠过程中滋养细胞侵袭、物质转运、胎盘血管重塑以及胎儿生长发育等一系列重要生理过程。其中,IGF-1、IGF-2及其相关受体的表达和功能异常可导致胎盘功能不全及胎儿功能生长受限。深入了解IGFs与胎儿生长发育之间的关系对研究胎盘功能代谢、物质转运、胎儿生长发育等具有重要意义。     

胎盘生长因子在高危妊娠中的研究进展

妊娠是复杂的生理过程,胎盘通过营养、代谢、交换、内分泌等作用调节母儿循环,是母儿联系的桥梁,对胎儿的生长发育及母体生理机能改变起着重要的作用。胎盘的正常发育及良好的生理功能是维持妊娠及胎儿生长发育的先决条件。胎盘形成及功能异常与妊娠期高血压疾病(hypertensive disorders of pregnancy,HDP)、胎儿生长受限(fetal growth restriction,FGR)、流产和唐氏综合征(Down′s syndrome,DS)等的发生密切相关。胎盘生长因子(placenta growth factor,PlGF)是丰富表达于胎盘的一种重要的生长因子,与血管内皮生长因子(vascular endothelial growth factors,VEGF)具有高度同源性,主要由滋养细胞和绒毛间质内皮细胞分泌,对滋养细胞增殖、活化及胎儿胎盘血管网形成起重要作用,故对PlGF进行深入研究对胎盘形成异常相关疾病的病因学研究及临床监测均具有重要意义。     

胎盘生长因子在高危妊娠中的研究进展

妊娠是复杂的生理过程,胎盘通过营养、代谢、交换、内分泌等作用调节母儿循环,是母儿联系的桥梁,对胎儿的生长发育及母体生理机能改变起着重要的作用。胎盘的正常发育及良好的生理功能是维持妊娠及胎儿生长发育的先决条件。胎盘形成及功能异常与妊娠期高血压疾病(hypertensive disorders of pregnancy,HDP)、胎儿生长受限(fetal growth restriction,FGR)、流产和唐氏综合征(Down′s syndrome,DS)等的发生密切相关。胎盘生长因子(placenta growth factor,PlGF)是丰富表达于胎盘的一种重要的生长因子,与血管内皮生长因子(vascular endothelial growth factors,VEGF)具有高度同源性,主要由滋养细胞和绒毛间质内皮细胞分泌,对滋养细胞增殖、活化及胎儿胎盘血管网形成起重要作用,故对PlGF进行深入研究对胎盘形成异常相关疾病的病因学研究及临床监测均具有重要意义。     

缺氧诱导因子与妊娠期肝内胆汁淤积症

缺氧诱导因子（HIF）是广泛存在于人类细胞并调节细胞内氧代谢的关键因子,受缺氧信号调控,参与缺氧诱导多种基因的转录,目前研究较多的是HIF-1和-2。HIF类与正常妊娠胎盘胚胎的发育相关,其缺失或表达异常导致异常妊娠。妊娠期肝内胆汁淤积症（ICP）胎儿多有急慢性缺氧,近年对HIF类在ICP患者胎盘中作用开始有研究。其在胎盘中表达调节对维持胎盘功能起一定代偿作用,与该疾病发生发展有关。     

缺氧诱导因子与妊娠期肝内胆汁淤积症

缺氧诱导因子(HIF)是广泛存在于人类细胞并调节细胞内氧代谢的关键因子,受缺氧信号调控,参与缺氧诱导多种基因的转录,目前研究较多的是HIF-1和-2.HIF类与正常妊娠胎盘胚胎的发育相关,其缺失或表达异常导致异常妊娠.妊娠期肝内胆汁淤积症(ICP)胎儿多有急慢性缺氧,近年对HIF类在ICP患者胎盘中作用开始有研究,其在胎盘中表达调节对维持胎盘功能起一定代偿作用,与该疾病发生发展有关.     

Notch信号通路在胎盘血管中的作用及与子痫前期的关系

胎盘血管的发育和重建是胎盘功能、胎儿功能发育的关键,其异常将直接导致妊娠期并发症如子痫前期,并最终影响妊娠结局。对人类及其他哺乳动物胎盘的研究表明,Notch信号通路与胎盘血管形成、滋养细胞侵袭等多个过程相关。     

自噬对人类胎盘发育及相关疾病的作用

自噬在人类胎盘的生成及发育中发挥重要作用,但其在人类胎盘中的生物学意义仍不十分明确,可能的作用之一是防止因低氧或营养不足导致的滋养层细胞凋亡。人类胎盘是血窦绒毛型,即母体血液直接接触绒毛。因此,绒毛滋养细胞很容易暴露于因母体血液变化而导致的应激状态下。妊娠并发症(如子痫前期和胎儿生长受限)自噬通路被激活以维持细胞内稳态,从而允许滋养细胞在氧气和葡萄糖不足的情况下继续生存。因而,自噬参与人类胎盘及相关疾病的发展,细胞滋养细胞氧气和葡萄糖水平变化参与调节自噬的改变。     

胎儿死亡的胎盘病理

人类胎盘是一个妊娠期的临时器官,对胎儿发育和正常妊娠的维持起重要作用。妊娠期间,胎盘在母体和胎儿间建立沟通的桥梁,为胎儿提供营养物质,进行气体交换和废物清除,并建立免疫耐受环境,保障半异体胎儿不被母体排斥;胎盘还可作为妊娠期重要的内分泌器官,协调胎儿发育及母体多器官的妊娠适应性应答。胎盘发育不良往往导致胎儿生长异常及多种妊娠并发症,严重情况下可导致胎儿死亡。文章阐述了生理状况下人类胎盘的结构和功能,描述了因胎儿生长受限(FGR)、子痫前期(PE)、妊娠期糖尿病(GDM)等造成胎儿死亡的胎盘病理特征,进而展望通过靶向胎盘干预妊娠期疾病的可能前景。     

Expression and regulation of vascular endothelial growth factor in a first trimester trophoblast cell line

Embryo implantation and development are critically dependent upon the spatial and temporal regulation of angiogenesis and localized vascular permeability. A key mediator of these effects is the endothelial cell mitogen vascular endothelial growth factor (VEGF). VEGF has been shown to promote endometrial vascular permeability, fetal vasculogenesis and placental, fetal and maternal angiogenesis. However, the mechanism through which this regulation occurs in the placenta is poorly understood. This study was conducted to determine if the pro-angiogenic cytokines, TNF-alpha and TGF-beta1, affect VEGF expression in human first trimester trophoblasts. Culture of a first trimester trophoblast cell line (HTR-8/SVneo), in the presence of either TNF-alpha or TGF-beta1, resulted in the expression of significant levels of VEGF in culture. The trophoblast cell line also showed a time-dependent and a dose-dependent increase in VEGF mRNA levels when cultured in the presence of either TNF-alpha or TGF-beta1. These results suggest that both TNF-alpha and TGF-beta1 may regulate the production of VEGF in early gestational trophoblasts and may therefore serve to modulate placental vascular permeability and angiogenesis that are necessary for embryo implantation and placentation.     

Differential expression of placental villous angiopoietin-1 and -2 during early, mid and late baboon pregnancy

Although vascular endothelial growth factor (VEGF), angiopoietin-1 (Ang-1) and Ang-2 have important roles in angiogenesis, very little is known about the regulation of these factors in the villous placenta during human pregnancy. In the present study, to investigate whether placental expression of Ang-1, Ang-2 and VEGF was altered in a cell-specific manner with advancing baboon gestation, the mRNA levels of these growth factors were determined by RT-PCR in cells isolated by Percoll gradient centrifugation from and protein localization assessed by immunocytochemistry in the villous placenta at early (day 60), mid (day 100) and late (day 170, term is 184 days) baboon gestation. Mean (+/-SE) Ang-1 mRNA levels, relative to 18S rRNA, in villous syncytiotrophoblast (3.92+/-0.68) and cytotrophoblast (1.31+/-0.31) cell fractions were highest on day 60 of gestation, then decreased by approximately 2.5-fold (P<0.05) to 1.39+/-0.29 and 0.49+/-0.07, respectively, on day 170. Moreover, Ang-1 mRNA levels in the villous stromal cells and Ang-2 mRNA levels in all placental villous cell fractions were similar on days 60, 100, and 170 of gestation. In contrast to Ang-1 and Ang-2, placental villous cytotrophoblast VEGF mRNA levels were increased 2.94-fold (P<0.05) between mid (0.67+/-0.15) and late (1.97+/-0.49) gestation. A corresponding decrease in Ang-1, absence of change in Ang-2, and increase in VEGF protein immunocytochemical expression were exhibited in placental trophoblast with advancing baboon pregnancy. Ang-1/Ang-2 and the angiopoietin Tie-2 receptor were expressed in vascular endothelial cells of the villous placenta, indicating that these blood vessel cells are a major site of ligand-receptor interaction for angiogenesis during primate pregnancy. We conclude that there is a cell-specific differential change in placental villous trophoblast expression of VEGF, Ang-1, and Ang-2 which we propose is important in regulating angiogenesis in the villous placenta during primate pregnancy.     

Epigenetic features of the mouse trophoblast

Trophoblast cells are required for the growth and survival of the fetus during pregnancy, and failure to maintain appropriate trophoblast regulation is associated with placental insufficiencies and intrauterine growth restriction. Development of the trophoblast lineage is mediated by interactions between genetic and epigenetic factors. This review will focus on new insights that have been gained from analysis of mouse models into the epigenetic mechanisms that are required for the early establishment of the trophoblast lineage and for the development of specialized cell types of the fetal placenta. In particular, the importance of DNA methylation, 5-hydroxymethylcytosine and histone modifications in orchestrating trophoblast gene expression and functional outcome will be discussed. These insights are beginning to be extended towards human studies and initial results suggest that the causes and consequences of a variety of placental pathologies are related to epigenetic processes. Furthermore, the epigenetic landscape that regulates trophoblast cells seems to be particularly vulnerable to perturbation during development. This has major implications for diet and other environmental factors during pregnancy.The placenta is required for the growth and survival of the fetus during pregnancy. Placental insufficiencies, including pre-eclampsia and intrauterine growth restriction, occur in ～10% of pregnancies and are associated with serious complications for mother and baby. Better understanding of how the placenta is formed is critical for the development of early diagnoses and therapies for treatment. Studies of animal models have revealed several critical pathways that are required for the proper development and function of the placenta. In particular, epigenetic processes, which determine how genes are switched on and off, are necessary for the early establishment of the placental lineage and also for the development of specialized cell types within the mature placenta. These crucial and recent insights form the basis for this review. Importantly, much of our understanding gleaned from animal models are now beginning to be extended towards human studies. Initial results suggest that the causes and consequences of a variety of placental pathologies are related to epigenetic pathways. As epigenetic processes can be susceptible to alterations by environmental factors, these studies have major implications for diet and other external influences during pregnancy.     

Angiogenesis and intrauterine growth restriction

Human placental development involves co-ordinated angiogenesis and trophoblast outgrowth that are compromised in intrauterine growth restriction. Adaptive angiogenesis in IUGR placental villi is a result of an imbalance in the orderly progression of the expression profile of vascular endothelial growth factor, placenta growth factor and angiopoietin during placental development. VEGF receptors and the angiopoietin receptor Tie-2 are expressed on trophoblast, and their activation leads to trophoblast proliferation, migration and production of nitric oxide. Thus, these vascular factors act as autocrine regulators of trophoblast behaviour in the development of the utero-/feto-placental circulation, an action independent of their well-established roles in vascular endothelium.     

Molecular regulation and role of angiogenesis in reproduction

Angiogenesis is an essential process for proper functioning of the female reproductive system and for successful pregnancy realization. The multitude of factors required for physiological angiogenesis and the complexity of regulation of their temporal–spatial activities contribute to aberrations in human fertilization and pregnancy outcomes. In this study, we reviewed the current knowledge of the temporal expression patterns, functions, and regulatory mechanisms of angiogenic factors during foliculogenesis, early implantation/placentation and embryo development, as well as recurrent spontaneous abortions. Angiogenic factors including vascular endothelial growth factors and angiopoietins have documented roles in the development of primordial follicles into mature antral follicles. They also participate in decidualization, which is accompanied by the creation of an extensive network of vessels in the stromal bed that support the growth of the embryo and the placenta, and maintain early pregnancy. During placentation angiogenic and angiomodulatory cytokines, T and B lymphocytes and macrophages affect angiogenesis in a context-dependent manner. Defects in angiogenesis at the maternal–fetal interface contribute to miscarriage in humans. The establishment of more polymorphisms in the genes involved in angiogenesis/vasculogenesis, and their pathological phenotype and expression could give opportunities for prediction, creating a therapeutic strategy, and treatment of diseases related to female reproductive health and problematic conception.