Rajakumar A, Whitelock K A, Weissfeld L A, Daftary A R, Markovic N, Conrad K P
Department of Obstetrics, University of Pittsburgh School of Medicine and Magee-Womens Research Institute, Pittsburgh, PA 15213, USA.
Biol Reprod. 2001 Feb;64(2):499-506. doi: 10.1093/biolreprod/64.2.499.
Transcription factors orchestrate the development of extraembryonic tissues. Because placental hypoxia likely plays an important role in both normal and abnormal placentation, we have been investigating the hypoxia-inducible transcription factors (HIFs) in the human placenta. In this report, we focus on the placentas from women with preeclampsia. Because the placenta is a large, heterogeneous organ, we employed a systematic and unbiased approach to placental sampling, and our results are based on the analyses of eight biopsy sites per placenta. We observed no significant differences in HIF-1alpha or -2alpha mRNA expression between normal term and preeclamptic placentas. Nor was HIF protein expression significantly different, with the notable exception of HIF-2alpha, which, on average, was increased by 1.7-fold in the preeclamptic placentas (P: < 0.03 vs. normal term placentas). Considering all 48 paired placental biopsy sites (eight sites each for six normal term and six preeclamptic placentas), HIF-2alpha protein levels in the preeclamptic placentas exceeded those in the normal term placentas in 39, or 81%, of the paired sites (P: < 0.0013). The HIF-2alpha immunoreactivity was mainly located in the nuclei of the syncytiotrophoblast and fetoplacental vascular endothelium in the preeclamptic villous placenta. To control for the earlier gestational age of the preeclamptic placentas, an additional group of placentas from preterm deliveries without preeclampsia were also evaluated. The HIF protein expression was comparable in these preterm specimens and the normal term placentas. We conclude that protein expression of HIF-2alpha, but not of HIF-1alpha or -1beta, is selectively increased in the preeclamptic placenta. The molecular mechanism(s) of this abnormality as well as the genes affected downstream are currently under investigation. To our knowledge, this is the first report of abnormal HIF-2alpha expression in human disease other than cancer.
转录因子协调胚外组织的发育。由于胎盘缺氧可能在正常和异常胎盘形成过程中都发挥重要作用，我们一直在研究人胎盘中的缺氧诱导转录因子（HIFs）。在本报告中，我们重点关注子痫前期女性的胎盘。由于胎盘是一个庞大且异质性的器官，我们采用了系统且无偏倚的胎盘采样方法，我们的结果基于对每个胎盘八个活检部位的分析。我们观察到足月胎盘与子痫前期胎盘之间HIF-1α或-2α mRNA表达无显著差异。HIF蛋白表达也无显著差异，但HIF-2α是个明显的例外，其在子痫前期胎盘中平均增加了1.7倍（与足月胎盘相比，P < 0.03）。考虑所有48对胎盘活检部位（六个足月胎盘和六个子痫前期胎盘各八个部位），子痫前期胎盘的HIF-2α蛋白水平在39对，即81%的配对部位中超过足月胎盘（P < 0.0013）。HIF-2α免疫反应性主要位于子痫前期绒毛胎盘的合体滋养层细胞核和胎儿胎盘血管内皮中。为了排除子痫前期胎盘孕周较早的影响，我们还评估了另一组无子痫前期的早产胎盘。这些早产标本与足月胎盘的HIF蛋白表达相当。我们得出结论，子痫前期胎盘中HIF-2α的蛋白表达选择性增加，而HIF-1α或-1β则不然。这种异常的分子机制以及下游受影响的基因目前正在研究中。据我们所知，这是除癌症外人类疾病中HIF-2α异常表达的首次报道。
