Rajakumar A, Conrad K P
Departments of Obstetrics, Gynecology and Reproductive Sciences and of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.
Biol Reprod. 2000 Aug;63(2):559-69. doi: 10.1095/biolreprod63.2.559.
Placental hypoxia likely plays an important role in both normal placental development and pathology. Yet, the molecular mechanisms of hypoxia signaling in this organ are virtually unexplored. Therefore, we investigated the expression of the hypoxia inducible transcription factors (HIF) in normal human placentas spanning the first trimester to term. Several key observations emerged: 1) HIF-1 alpha and -2 alpha mRNA were present in placentas of all gestational ages but with greater variability during early pregnancy; 2) overall, HIF-1 alpha mRNA was expressed at a constant level in all placentas, whereas HIF-2 alpha mRNA increased significantly with gestational age; 3) both HIF-1 alpha and -2 alpha protein decreased significantly with gestational age; and 4) HIF-1 alpha and -2 alpha immunoreactivity were overlapping in cellular distribution being expressed by the syncytiotrophoblast, villous cytotrophoblast, and fetoplacental vasculature with both nuclear and cytoplasmic localization. Next, we studied the regulation of these transcription factors by oxygen using placental villous explants in culture from first-trimester and term placentas. The major findings were 1) HIF-1 alpha and -2 alpha protein, but not mRNA, was induced by hypoxia in the placental villous explants; 2) HIF-1 alpha DNA-binding activity was also stimulated by hypoxia; and 3) glucose transporter-1 mRNA (a known target of HIF) was also increased by hypoxia in placental villous explants. We suggest that physiological hypoxia contributes to the increased expression of HIF-1 alpha and -2 alpha protein in early placentas and that regulation of these transcription factors by hypoxia in the human placenta occurs at the level of protein and not mRNA.
胎盘缺氧可能在正常胎盘发育和病理过程中都发挥着重要作用。然而，该器官中缺氧信号传导的分子机制实际上尚未得到探索。因此，我们研究了从孕早期到足月的正常人类胎盘中缺氧诱导转录因子（HIF）的表达。出现了几个关键观察结果：1）HIF-1α和-2αmRNA存在于所有孕周的胎盘中，但在孕早期变异性更大；2）总体而言，HIF-1αmRNA在所有胎盘中以恒定水平表达，而HIF-2αmRNA随孕周显著增加；3）HIF-1α和-2α蛋白均随孕周显著降低；4）HIF-1α和-2α免疫反应性在细胞分布上重叠，由合体滋养层、绒毛细胞滋养层和胎儿胎盘血管表达，具有核和细胞质定位。接下来，我们使用来自孕早期和足月胎盘的培养胎盘绒毛外植体研究了氧气对这些转录因子的调节。主要发现为：1）缺氧诱导胎盘绒毛外植体中HIF-1α和-2α蛋白而非mRNA的表达；2）缺氧也刺激HIF-1αDNA结合活性；3）葡萄糖转运蛋白-1mRNA（HIF的已知靶点）在胎盘绒毛外植体中也因缺氧而增加。我们认为生理缺氧有助于早期胎盘中HIF-1α和-2α蛋白表达的增加，并且人类胎盘中缺氧对这些转录因子的调节发生在蛋白质水平而非mRNA水平。
