Li Yan, Zhu Hua, Klausen Christian, Peng Bo, Leung Peter C K
Department of Obstetrics and Gynaecology, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada V5Z 4H4.
Endocrinology. 2015 Nov;156(11):4257-68. doi: 10.1210/en.2015-1228. Epub 2015 Aug 20.
Remodeling of maternal spiral arteries during pregnancy requires a subpopulation of extravillous cytotrophoblasts (EVTs) to differentiate into endovascular EVTs. Activin A, which is abundantly expressed at the maternal-fetal interface, has been shown to promote trophoblast invasion, but its role in endovascular differentiation remains unknown. Vascular endothelial growth factor-A (VEGF-A) is well recognized as a key regulator in trophoblast endovascular differentiation. Whether and how activin A might regulate VEGF-A production in human trophoblasts and its relationship to endovascular differentiation have yet to be determined. In the present study, we found that activin A increased VEGF-A production in primary and immortalized (HTR8/SVneo) human EVT cells. In addition, activin A enhanced HTR8/SVneo endothelial-like tube formation, and these effects were attenuated by pretreatment with small interfering RNA targeting VEGF-A or the VEGF receptor 1/2 inhibitor SU4312. Pretreatment with the activin/TGF-β type 1 receptor (ALK4/5/7) inhibitor SB431542 abolished the stimulatory effects of activin A on phosphorylated mothers against decapentaplegic (SMAD)-2/3 phosphorylation, VEGF-A production, and endothelial-like tube formation. Moreover, small interfering RNA-mediated down-regulation of SMAD2, SMAD3, or common SMAD4 abolished the effects of activin A on VEGF-A production and endothelial-like tube formation. In conclusion, activin A may promote human trophoblast cell endothelial-like tube formation by up-regulating VEGF-A production in an SMAD2/3-SMAD4-dependent manner. These findings provide insight into the cellular and molecular events regulated by activin A during human implantation.
孕期母体外周螺旋动脉重塑需要一群绒毛外细胞滋养层细胞（EVT）分化为血管内EVT。激活素A在母胎界面大量表达，已被证明可促进滋养层细胞侵袭，但其在血管内分化中的作用尚不清楚。血管内皮生长因子-A（VEGF-A）是滋养层细胞血管内分化的关键调节因子，激活素A是否以及如何调节人滋养层细胞中VEGF-A的产生及其与血管内分化的关系尚待确定。在本研究中，我们发现激活素A可增加原代和永生化（HTR8/SVneo）人EVT细胞中VEGF-A的产生。此外，激活素A增强了HTR8/SVneo细胞内皮样管的形成，而这些作用可被靶向VEGF-A的小干扰RNA或VEGF受体1/2抑制剂SU4312预处理所减弱。激活素/TGF-β1型受体（ALK4/5/7）抑制剂SB431542预处理可消除激活素A对磷酸化的母亲针对截瘫（SMAD）-2/3磷酸化、VEGF-A产生和内皮样管形成的刺激作用。此外，小干扰RNA介导的SMAD2、SMAD3或共同的SMAD4下调可消除激活素A对VEGF-A产生和内皮样管形成的影响。总之，激活素A可能通过以SMAD2/3-SMAD4依赖的方式上调VEGF-A的产生来促进人滋养层细胞内皮样管的形成。这些发现为激活素A在人类着床过程中调节的细胞和分子事件提供了见解。
