Abbott B D, Buckalew A R
Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Dev Dyn. 2000 Dec;219(4):526-38. doi: 10.1002/1097-0177(2000)9999:9999<::AID-DVDY1080>3.0.CO;2-N.
The aryl hydrocarbon receptor nuclear translocator (ARNT) is a transcriptional regulator that heterodimerizes with Per-ARNT-Sim (PAS) proteins. ARNT also dimerizes with hypoxia inducible factor1alpha (HIF1alpha), inducing expression of vascular endothelial cell growth factor (VEGF) to promote angiogenesis. The angiogenesis/vasculogenesis pathway is required for embryonic survival and includes several receptors (VEGFR1, VEGFR2, Tie2) and ligands (VEGF, Ang1, Ang2, neuropillin). Transgenic knockout of ARNT in mice is lethal due to abnormal placentation. This study examines the VEGF pathway in GD9.5 embryos of wild-type (+/+), heterozygous (+/-), or knockout (-/-) ARNT genotype. All genotypes expressed abundant VEGF in trophoblastic giant cells. However, -/- conceptuses had less VEGFR2 in placental labyrinth and trophoblastic giant cells. Ang1 and Tie2 decreased in trophoblastic giant cells and Ang2 was decreased in placental endothelial cells. Abnormal development of the labyrinth correlated with decreased binding of VEGF and decreased expression of VEGFR2. In addition, VEGFR2 seemed to be the primary VEGF binding receptor in the labyrinth and blood lacunae of the placenta, as binding could be eliminated by masking the VEGFR2 receptor with inactive antibody complex. VEGFR1 may be primarily responsible for binding of VEGF to yolk sac and embryonic tissues, as masking VEGFR2 did not reduce VEGF binding in those areas, and it is interesting that major structural defects were also not found in those regions. In summary, in the ARNT knockout conceptus, the impact of ARNT deficiency on placental expression of VEGFR2 seems to provide an explanation for the failure of the placental labyrinth to progress, whereas the vascularization of the yolk sac and embryo appear relatively unaffected on GD9.5. Published 2000 Wiley-Liss, Inc.
芳烃受体核转运蛋白（ARNT）是一种转录调节因子，可与Per-ARNT-Sim（PAS）蛋白形成异二聚体。ARNT还可与缺氧诱导因子1α（HIF1α）形成二聚体，诱导血管内皮细胞生长因子（VEGF）表达以促进血管生成。血管生成/血管发生途径是胚胎存活所必需的，包括几种受体（VEGFR1、VEGFR2、Tie2）和配体（VEGF、Ang1、Ang2、神经纤毛蛋白）。小鼠中ARNT的转基因敲除由于胎盘形成异常而致死。本研究检测了野生型（+/+）、杂合子（+/-）或敲除（-/-）ARNT基因型的妊娠第9.5天胚胎中的VEGF途径。所有基因型在滋养层巨细胞中均表达丰富的VEGF。然而，纯合子胚胎的胎盘迷路和滋养层巨细胞中VEGFR2较少。滋养层巨细胞中Ang1和Tie2减少，胎盘内皮细胞中Ang2减少。迷路的异常发育与VEGF结合减少和VEGFR2表达降低相关。此外，VEGFR2似乎是胎盘中迷路和血腔中主要的VEGF结合受体，因为用无活性抗体复合物掩盖VEGFR2受体可消除结合。VEGFR1可能主要负责VEGF与卵黄囊和胚胎组织的结合，因为掩盖VEGFR2不会降低这些区域的VEGF结合，有趣的是，这些区域也未发现主要结构缺陷。总之，在ARNT敲除胚胎中，ARNT缺乏对胎盘VEGFR2表达的影响似乎为胎盘迷路发育失败提供了解释，而卵黄囊和胚胎的血管化在妊娠第9.5天似乎相对未受影响。2000年由Wiley-Liss公司出版。
