Faulty oxygen sensing disrupts angiomotin function in trophoblast cell migration and predisposes to preeclampsia
Faulty oxygen sensing disrupts angiomotin function in trophoblast cell migration and predisposes to preeclampsia
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DOI：
10.1172/jci.insight.127009
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发表时间：
2019-04-18
期刊：
影响因子：
8
通讯作者：
Caniggia, Isabella
中科院分区：
文献类型：
--
作者：
Farrell, Abby;Alahari, Sruthi;Caniggia, Isabella
人类胎盘的发育和成功的怀孕是义不容辞的精确氧依赖性控制滋养层细胞迁移/入侵。持续低氧导致滋养层浸润失败，促进螺旋动脉重塑不足，这是先兆子痫的特征。血管动素（AMOT）是一种多方面的支架蛋白，参与细胞极性和迁移，但其上游调控和人类胎盘中的意义仍然未知。在此，我们表明，AMOT主要表达在迁移绒毛外滋养层细胞（EVT）的中间和远端锚柱。妊娠10周后，当氧分压升高和EVT迁移/侵袭高峰时，其表达增加。延时成像证实AMOT 130-kDa亚型促进滋养层细胞JEG 3和HTR-8/SVneo细胞的迁移。然而，在先兆子痫中，AMOT表达降低，并且其在迁移性母胎界面EVT中的定位被破坏。我们证明，Jumonji C结构域蛋白6（JMJO 6），氧传感器，积极调节AMOT通过氧依赖赖氨酰羟基化。此外，体外和离体研究表明，转化生长因子-β（TGF-β）调节AMOT表达，其与极性蛋白PARS的相互作用，以及其从紧密连接到细胞骨架的亚细胞再分布。我们的数据揭示了人类胎盘中AMOT的氧和TGF-β驱动的迁移功能，并暗示其在滋养层迁移受损中的缺陷困扰着先兆子痫。
Human placenta development and a successful pregnancy is incumbent upon precise oxygen-dependent control of trophoblast migration/invasion. Persistent low oxygen leading to failed trophoblast invasion promotes inadequate spiral artery remodeling, a characteristic of preeclampsia. Angiomotin (AMOT) is a multifaceted scaffolding protein involved in cell polarity and migration, yet its upstream regulation and significance in the human placenta remain unknown. Herein, we show that AMOT is primarily expressed in migratory extravillous trophoblast cells (EVTs) of the intermediate and distal anchoring column. Its expression increases after 10 weeks of gestation when oxygen tension rises and EVT migration/invasion peaks. Time-lapse imaging confirmed that the AMOT 130-kDa isoform promotes migration of trophoblastic JEG3 and HTR-8/SVneo cells. In preeclampsia, however, AMOT expression is decreased and its localization to migratory fetomaternal interface EVTs is disrupted. We demonstrate that Jumonji C domain-containing protein 6 (JMJO6), an oxygen sensor, positively regulates AMOT via oxygen-dependent lysyl hydroxylation. Furthermore, in vitro and ex vivo studies show that transforming growth factor-beta (TGF-beta) regulates AMOT expression, its interaction with polarity protein PARS, and its subcellular redistribution from tight junctions to cytoskeleton. Our data reveal an oxygen- and TGF-beta-driven migratory function for AMOT in the human placenta, and implicate its deficiency in impaired trophoblast migration that plagues preeclampsia.