Abstract：
The placenta, as a \"transit station\" between mother and fetus, has functions delivering nutrients, excreting metabolic wastes and secreting hormones. A healthy placenta is essential for fetal growth and development while the melatonergic system seems to play a critical physiological role in this organ since melatonin, its synthetic enzymes and receptors are present in the placenta. In current study, Mtnr1a and Mtnr1b knockout mice were constructed to explore the potential roles of melatonergic system played on the placental function and intrauterine growth retardation (IUGR). The result showed that Mtnr1a knockout had little effect on placental function while Mtnr1b knockout reduced placental efficiency and increased IUGR. Considering the extremely high incidence of IURG in sows, the pregnant sows were treated with melatonin. This treatment reduced the incidence of IUGR. All the evidence suggests that the intact melatonergic system in placenta is required for its function. Mechanistical studies uncovered that Mtnr1b knockout increased placental oxidative stress and apoptosis but reduced the angiogenesis. The RNA sequencing combined with histochemistry study identified the reduced angiogenesis and placental vascular density in Mtnr1b knockout mice. These alterations were mediated by the disrupted STAT3/VEGFR2/PI3K/AKT pathway, i.e., Mtnr1b knockout reduced the phosphorylation of STAT3 which is the promotor of VEGFR2. The downregulated VEGFR2 and its downstream elements of PI3K and AKT expressions, then, jeopardizes the angiogenesis and placental development.
摘要：
胎盘,作为母亲和胎儿之间的“中转站”，具有输送营养的功能，排泄代谢废物和分泌激素。健康的胎盘对胎儿的生长发育至关重要，而褪黑激素系统似乎在该器官中起着至关重要的生理作用，因为褪黑激素，它的合成酶和受体存在于胎盘中。在目前的研究中,构建Mtnr1a和Mtnr1b基因敲除小鼠，以探讨褪黑系统对胎盘功能和宫内发育迟缓（IUGR）的潜在作用。结果表明，Mtnr1a基因敲除对胎盘功能影响不大，而Mtnr1b基因敲除降低胎盘效率，增加IUGR。考虑到IURG在母猪中的发病率极高，怀孕的母猪用褪黑激素治疗。这种治疗降低了IUGR的发生率。所有证据表明，胎盘中完整的褪黑能系统是其功能所必需的。机制研究发现，Mtnr1b敲除增加胎盘氧化应激和细胞凋亡，但减少血管生成。RNA测序结合组织化学研究发现Mtnr1b基因敲除小鼠的血管生成和胎盘血管密度降低。这些改变是由被破坏的STAT3/VEGFR2/PI3K/AKT通路介导的，即，Mtnr1b敲除降低了作为VEGFR2启动子的STAT3的磷酸化。下调VEGFR2及其下游元件PI3K和AKT的表达,然后,危及血管生成和胎盘发育。
