VEGF异常与胎儿生长受限

VEGF正常表达是妊娠正常进行的关键环节,其对胎盘血管形成、胎盘绒毛细胞和子宫螺旋动脉的发生发展起着至关重要的作用。VEGF异常导致子宫、胎盘血管发育障碍,胎儿缺血缺氧,最终导致胎儿生长受限。本文主要从VEGF对胎盘血管生成、胎盘绒毛膜炎、绒毛细胞凋亡、子宫螺旋动脉重塑异常及生殖微生物等方面的影响进行简要综述,为今后临床通过VEGF早期预测胎儿生长受限并评估其治疗及预后提供理论依据。     

铅致胎盘损伤机制的研究进展(英文)

铅是一种嗜神经和嗜胎盘的毒性重金属,本综述主要是关于铅的胎盘毒性。孕期铅暴露可以导致胎盘重量减轻,滋养层增生,血管堵塞,细胞间隙增宽,血管周围大量的纤维蛋白沉积,以及粗面内质网扩张,膜上核糖体数量减少。当孕期铅暴露在一定范围内时,一氧化氮(NO),一氧化氮合酶(NOS)水平升高,以保证胎盘组织器官的正常结构和功能;进一步加重时,NO及NOS反而降低,导致胎儿-胎盘循环阻力增高,胎盘灌注量下降;孕期铅暴露时,丙二醛(MDA)升高,说明存在胎盘氧化与抗氧化系统平衡失调;基质金属蛋白酶-9(MMP-9)表达降低,而基质蛋白酶组织抑制因子-1(TIMP-1)表达增强,胎盘MMP-9/TIMP-1的表达失衡,导致滋养细胞浸润能力减弱,胎盘着床过浅,血管重铸障碍,从而影响胎盘发育及胎儿生长;染铅胎盘NF-kB的表达及血栓调节蛋白(TM)的表达明显高于对照组。NF-kB的激活又可以反式激活表皮生长因子,血小板生长因子等的表达,促进血管平滑肌细胞的增殖,细小动脉胶原纤维增加,血管痉挛性收缩;TM表达异常,说明孕期铅暴露可致胎盘血管内皮细胞损伤。总之,孕期铅暴露可引起胎盘病理及一系列的分子化学改变,从而影响胎盘功能和胎儿发育,可引起子代早产、出生体重低、智力障碍等。     

源于Ⅳ型胶原的肿瘤血管生成抑制剂

新血管生成是各种生理和病理过程发生的基础。在胚胎形成和胎盘发育等正常生理过程中,新血管的生成是至关重要的;然而对于一些疾病的产生,特别是肿瘤的生长、进展和转移,同样离不开血管生成的作用。伴随着“抗肿瘤血管生成疗法”的提出,控制血管生成“开关”的血管生成刺激因子和抑制因子成为研究的热点。Arresten、Canstatin、Tumstatin和Hexastatin是近些年发现的内源性的血管生成抑制因子,它们同系Ⅳ型胶原α链的非胶原区NC1,具有相似的结构和分子量大小,现有研究表明,它们能与内皮细胞表面整合素受体相结合,有效地抑制内皮细胞的增殖和迁移,降低肿瘤组织的微血管密度,切断肿瘤的营养和氧气供给,从而抑制肿瘤的生长和转移。对其作用机制的研究,将有助于肿瘤血管生成抑制剂新药的研发。     

动物克隆中的胎盘异常

核移植后,克隆胎儿的发育需要通过胎盘与母体进行物质交换。供体核重编程的错误常导致克隆胎盘异常,如胎盘过大、滋养层异常和血管缺陷等,这些现象通常与蛋白质表达的异常有关。克隆胎盘的缺陷会影响克隆胎儿的发育,降低胎儿的出生率,这可能是造成动物克隆效率低下的一个重要原因。     

白介素-18与新生血管性眼病

新生血管形成引起的眼病是眼科常见病和疑难病,常导致视功能严重障碍,由于对其发病机制研究有限,长期以来临床处理非常棘手,预后颇差.随着基础医学科学的发展,对眼内新生血管的形成有了重大发现,特别对某些促新生血管因子的研究,随之对抑制新生血管形成的研究也有了一些发展.目前,认为抑制新生血管生长是治疗这类疾病的关键,并且已有多种疗法问世.研究发现,白介素-18对新生血管有较强的抑制作用.本文从白介素-18的结构、功能、抑制新生血管的机制及其与眼部新生血管性疾病的关系等方面做一综述.     

胎盘发育过程中的表观遗传学改变及其相关疾病

胎盘介于胎儿与母体之间,是维持胎儿宫内生长发育的重要器官。在胎盘的正常发育过程中,子宫正常蜕膜化、滋养层细胞粘附与侵袭、胎盘血管生成与形成、胎盘印记基因表达都受到表观遗传修饰(如DNA甲基化、组蛋白修饰、非编码RNA等)的调控。研究已经证实环境因素如重金属、化合物、现代辅助生殖技术、营养物质均可导致胎盘上多种基因的表观遗传修饰异常。此外,胎盘基因表达存在性别差异也可能与表观遗传修饰有关。目前,在临床上可运用产前DNA甲基化水平分析技术检测异常的表观遗传修饰,并在疾病早期发现并做出诊断,从而为疾病预防及治疗提供依据。本文对胎盘正常发育过程中表观遗传修饰的调控及环境因素所致的胎盘基因表观遗传改变进行了综述,以期对胎盘相关疾病的诊断与治疗提供借鉴和参考。     

VEGF 家族及其在肿瘤生长中作用的研究

血管内皮生长因子(Vascular Endothelial Growth Factor,VEGF)家族是一类多功能的细胞因子,在血管生成和淋巴管生成中具有直接和间接的调控作用,可促进内皮细胞增殖、促进血管生成以及增加血管的通透性。VEGF/VEGFR轴由多重配基和受体质量叠加交错组成,并且受体与配基结合具有专一性,在不同的细胞中具有不同的细胞类型表达和功能.启动VEGF信号通路,触发了一个网状的信号过程,从而促进血管内皮细胞生长、转移和存活。进来研究发现,VEGF的一个重要作用表现为可动员内皮祖细胞从骨髓向远处转移从而形成新生血管,因而有必要设计和发展针对这一途径的抑制因子。随着研究的深入,VEGF促进肿瘤血管生成的作用和与人类癌症的发病机制的关系是确定的,因此,抑制VEGF途径被确认为是一种重要的有效的抗癌模式     

胎盘发生中的表观遗传学

胚外组织尤其是胎盘的正常发生对于维持哺乳动物胎儿在子宫中的发育和生长是必须的。胎盘发生是一个复杂的基因表达调控的过程,近年来的研究表明表观遗传在该过程中也起着重要作用。表观遗传调控在胎盘发生过程的几个主要事件中发挥作用,包括表观遗传对滋养层细胞分化和发育的调控、印记基因对胎盘发生和营养转运的调控、胎盘中的X染色体失活,以及胎盘表观遗传调控异常所导致的妊娠相关疾病。     

血管紧张素AT1受体抗体阳性孕鼠后代高盐饮食后血管功能障碍

血管紧张素AT1受体抗体(AT1-Ab)可损伤胎盘发育,进而导致胎儿宫内生长受限(intrauterine growth restriction,IUGR).根据胎儿源性成人疾病学说,IUGR会明显增加成人后患心血管疾病的几率.本研究旨在观察AT1-Ab阳性孕鼠后代生长至成年后血管功能有无异常.24只雌性Wistar大...     

雌性生殖系统中血管生成的分子调控

血管生成是新血管在原有血管的基础上向无血管区扩展的过程。成年生理性血管生成仅限于雌性生殖道中卵巢、子宫、胎盘的周期性发育。因此,血管生成对这些组织的生长和功能起重要作用。血管生成异常会导致多种妇科疾病。近来的研究证实,多种因素包括血管内皮生长因子(VEGF)和血管生成素(Ang)及其受体参与了血管生成的调节。本文主要介绍近年来雌性生殖系统中有关血管生成调控的研究进展。     

Angiogenesis in the placenta

The mammalian placenta is the organ through which respiratory gases, nutrients, and wastes are exchanged between the maternal and fetal systems. Thus, transplacental exchange provides for all the metabolic demands of fetal growth and development. The rate of transplacental exchange depends primarily on the rates of uterine (maternal placental) and umbilical (fetal placental) blood flows. In fact, increased uterine vascular resistance and reduced uterine blood flow can be used as predictors of high risk pregnancies and are associated with fetal growth retardation. The rates of placental blood flow, in turn, are dependent on placental vascularization, and placental angiogenesis is therefore critical for the successful development of viable, healthy offspring. Recent studies, including gene knockouts in mice, indicate that the vascular endothelial growth factors represent a major class of placental angiogenic factors. Other angiogenic factors, such as the fibroblast growth factors or perhaps the angiopoietins, also may play important roles in placental vascularization. In addition, recent observations suggest that these angiogenic factors interact with the local vasodilator nitric oxide to coordinate placental angiogenesis and blood flow. In the future, regulators of angiogenesis that are currently being developed may provide novel and powerful methods to ensure positive outcomes for most pregnancies.     

Placental and fetal growth and development in late rat gestation is dependent on adrenomedullin

Adrenomedullin is a potent, endogenous vasodilator peptide synthesized and secreted by diverse locations such as adrenal glands, lungs, kidneys, vascular smooth muscle, and endothelium. Homozygous deletion of the adrenomedullin gene is embryonic lethal. We hypothesized that adrenomedullin has an important role in placental and fetal growth and development in rat pregnancy. The current study evaluated maternal systolic blood pressure, litter size, placental and pup weight, pup mortality, and placental pathology in pregnant rats following continuous in utero exposure to an adrenomedullin antagonist. Osmotic minipumps were inserted on Gestational Day 14 to continuously deliver either adrenomedullin, adrenomedullin antagonist, or vehicle control. Systolic blood pressure was recorded daily. Pregnant rats were killed on Gestational Day 15-18, 20, and/or 22 to evaluate placental development and fetal growth. The placentas were graded for the presence of necrosis in the decidua and fetal labyrinth as well as fetal vessel development in the labyrinth. A trend toward increased systolic blood pressure was noted between Gestational Days 17 and 20 in mothers treated with adrenomedullin antagonist, but the difference was not statistically significant. Antagonism of adrenomedullin function during rat pregnancy caused fetal growth restriction, decreased placental size, gross necrosis of placental margins and amniotic membranes, histologically deficient fetal vessel development in the labyrinth, and fetal edema. Adrenomedullin contributes to angiogenesis, functions as a growth factor, and helps regulate vascular tone during rat gestation.     

Chronic hypoxia increases fetoplacental vascular resistance and vasoconstrictor reactivity in the rat

An increase in fetoplacental vascular resistance caused by hypoxia is considered one of the key factors of placental hypoperfusion and fetal undernutrition leading to intrauterine growth restriction (IUGR), one of the serious problems in current neonatology. However, although acute hypoxia has been shown to cause fetoplacental vasoconstriction, the effects of more sustained hypoxic exposure are unknown. This study was designed to test the hypothesis that chronic hypoxia elicits elevations in fetoplacental resistance, that this effect is not completely reversible by acute reoxygenation, and that it is accompanied by increased acute vasoconstrictor reactivity of the fetoplacental vasculature. We measured fetoplacental vascular resistance as well as acute vasoconstrictor reactivity in isolated perfused placentae from rats exposed to hypoxia (10% O(2)) during the last week of a 3-wk pregnancy. We found that chronic hypoxia shifted the relationship between perfusion pressure and flow rate toward higher pressure values (by approximately 20%). This increased vascular resistance was refractory to a high dose of sodium nitroprusside, implying the involvement of other factors than increased vascular tone. Chronic hypoxia also increased vasoconstrictor responses to angiotensin II (by approximately 75%) and to acute hypoxic challenges (by >150%). We conclude that chronic prenatal hypoxia causes a sustained elevation of fetoplacental vascular resistance and vasoconstrictor reactivity that are likely to produce placental hypoperfusion and fetal undernutrition in vivo.     

Important aspects of placental-specific gene transfer

The placenta is a unique and highly complex organ that develops only during pregnancy and is essential for growth and survival of the developing fetus. The placenta provides the vital exchange of gases and wastes, the necessary nutrients for fetal development, acts as immune barrier that protects against maternal rejection, and produces numerous hormones and growth factors that promote fetal maturity to regulate pregnancy until parturition. Abnormal placental development is a major underlying cause of pregnancy-associated disorders that often result in preterm birth. Defects in placental stem cell propagation, growth, and differentiation are the major factors that affect embryonic and fetal well-being and dramatically increase the risk of pregnancy complications. Understanding the processes that regulate placentation is important in determining the underlying factors behind abnormal placental development. The ability to manipulate genes in a placenta-specific manner provides a unique tool to analyze development and eliminates potentially confounding results that can occur with traditional gene knockouts. Trophoblast stem cells and mouse embryos are not overly amenable to traditional gene transfer techniques. Most viral vectors, however, have a low infection rate and often lead to mosaic transgenesis. Although the traditional method of embryo transfer is intrauterine surgical implantation, the methodology reported here, combining lentiviral blastocyst infection and nonsurgical embryo transfer, leads to highly efficient and placental-specific gene transfer. Numerous advantages of our optimized procedures include increased investigator safety, a reduction in animal stress, rapid and noninvasive embryo transfer, and higher a rate of pregnancy and live birth.     

Regional blood flow distribution in fetal sheep with intrauterine growth retardation produced by decreased umbilical placental perfusion

To determine the capacity of the fetus to adapt to chronic O2 deficiency produced by decreased placental perfusion in the early development of growth retardation, we embolized the umbilical placental vascular bed of fetal sheep for a period of 9 days. Fetal umbilical placental embolization decreased arterial O2 content by 39%, decreased total placental blood flow by 33%, and produced a 20% reduction in mean fetal body weight. Neither the combined ventricular output nor the regional blood flow distribution was significantly different between the 8 growth-retarded and 7 normally grown fetuses despite the 39% decrease in fetal arterial O2 content. Thus a 33% reduction in total placental blood flow restricts normal fetal growth, but does not exceed the placental circulatory reserve capacity necessary to maintain normal basal metabolic oxygenation. Because the proportion of combined ventricular output to the placenta at rest is decreased in late IUGR fetuses but not in early IUGR fetuses, despite chronic oxygen deficiency, we conclude that the growth retarded fetus maintains a normal regional blood flow distribution until the placental circulatory reserve capacity is depleted.     

Survival and size are differentially regulated by placental and fetal PKBalpha/AKT1 in mice

The importance of placental circulation is exemplified by the correlation of placental size and blood flow with fetal weight and survival during normal and compromised human pregnancies in such conditions as preeclampsia and intrauterine growth restriction (IUGR). Using noninvasive magnetic resonance imaging, we evaluated the role of PKBalpha/AKT1, a major mediator of angiogenesis, on placental vascular function. PKBalpha/AKT1 deficiency reduced maternal blood volume fraction without affecting the integrity of the fetomaternal blood barrier. In addition to angiogenesis, PKBalpha/AKT1 regulates additional processes related to survival and growth. In accordance with reports in adult mice, we demonstrated a role for PKBalpha/AKT1 in regulating chondrocyte organization in fetal long bones. Using tetraploid complementation experiments with PKBalpha/AKT1-expressing placentas, we found that although placental PKBalpha/AKT1 restored fetal survival, fetal PKBalpha/AKT1 regulated fetal size, because tetraploid complementation did not prevent intrauterine growth retardation. Histological examination of rescued fetuses showed reduced liver blood vessel and renal glomeruli capillary density in PKBalpha/Akt1 null fetuses, both of which were restored by tetraploid complementation. However, bone development was still impaired in tetraploid-rescued PKBalpha/Akt1 null fetuses. Although PKBalpha/AKT1-expressing placentas restored chondrocyte cell number in the hypertrophic layer of humeri, fetal PKBalpha/AKT1 was found to be necessary for chondrocyte columnar organization. Remarkably, a dose-dependent phenotype was exhibited for PKBalpha/AKT1 when examining PKBalpha/Akt1 heterozygous fetuses as well as those complemented by tetraploid placentas. The differential role of PKBalpha/AKT1 on mouse fetal survival and growth may shed light on its roles in human IUGR.     

The placental problem: Linking abnormal cytotrophoblast differentiation to the maternal symptoms of preeclampsia

The placenta is a remarkable organ. In normal pregnancy its specialized cells (termed cytotrophoblasts) differentiate into various specialized subpopulations that play pivotal roles in governing fetal growth and development. One cytotrophoblast subset acquires tumor-like properties that allow the cells to invade the decidua and myometrium, a process that attaches the placenta to the uterus. The same subset also adopts a vascular phenotype that allows these fetal cells to breach and subsequently line uterine blood vessels, a process that channels maternal blood to the rest of the placenta. In the pregnancy complication preeclampsia, which is characterized by the sudden onset of maternal hypertension, proteinuria and edema, cytotrophoblast invasion is shallow and vascular transformation incomplete. These findings, together with very recent evidence from animal models, suggest that preeclampsia is associated with abnormal placental production of vasculogenic/angiogenic substances that reach the maternal circulation with the potential to produce at least a subset of the clinical signs of this syndrome. The current challenge is to build on this knowledge to design clinically useful tests for predicting, diagnosing and treating this dangerous disorder.     

How to study placental vascular development?

Both exogenous and endogenous factors during pregnancy may impact placental vascular development and cause different malformations of placental vessels. In humans, consequences of abnormal vascular development have been associated with different pregnancy-related pathologies ranging from miscarriage to intrauterine growth restriction or preeclampsia. Pregnancy-associated exposure to bacterial or viral infections or pharmacologic or toxic agents may also influence vascular development of the placenta and lead to preterm labor and delivery. Several steps of vascular adaptation on both the fetal and maternal side are necessary and include such events as uterine vasodilation, remodeling by extravillous trophoblast, as well as vasculogenesis and angiogenesis within the placenta. Ubiquitous as well as pregnancy-specific angiogenic factors are involved. Morphologic and stereologic approaches, as well as experiments in established laboratory animals, cannot be applied to large domestic animals or humans without hesitation. Thus, further studies into the different aspects of this process will require an appropriate in vitro model of placental vascular development. Reflecting the core of placental vascular development, the in vitro model should facilitate the interactions between trophoblast and stromal cells with endothelial progenitor cells. The effects of viral or bacterial infection as well as pharmacologic or toxic agents may be studied more closely in the process. This report reviews major aspects of vascular development in the placenta and describes the establishment of a three-dimensional in vitro model of human placental vascular development.     

Factors affecting gas transfer across the placenta and the oxygen supply to the fetus

The factors that affect placental gas exchange are reviewed, with particular reference to recent measurements of the effect of changes in one or more of these factors on O2 delivery to the fetus and on fetal O2 uptake. Fetal or maternal placental blood flows and blood O2 capacities can be altered by 50% without any major change occurring in fetal O2 uptake: umbilical venous O2 content and fetal O2 delivery fall, but the O2 consumption of the fetus is maintained by increasing the fractional extraction of O2 from the blood. There is evidence that the fetus can also cope with a reduction in blood O2 affinity resulting from replacement of fetal with maternal blood. The critical level of O2 delivery is about 0.6 mmol.min-1.kg-1 in the fetal sheep. When O2 delivery is reduced below this level, by decreasing maternal placental blood flow, raising or lowering fetal haematocrit, decreasing maternal O2 capacity, or decreasing fetal O2 affinity, fetal O2 uptake tends to fall. The resultant tissue hypoxia and inability to maintain oxidative metabolism is reflected in a lowering of arterial blood pH and base excess. Whilst the results of short-term experiments suggest that there exists a large reserve for placental O2 transfer and fetal O2 supply, there is evidence that fetal O2 uptake is more tightly linked to O2 delivery when the latter is reduced for a period of days or weeks. In the long term, restriction of the supply of O2 and nutrients leads to a reduced rate of fetal growth and a reprogramming of tissue development.