Laboratory of Physiology and Pharmacology of Reproduction, Centre for Pharmacological and Botanical Studies (CONICET - School of Medicine, University of Buenos Aires), Buenos Aires, Argentina.
Laboratory of Physiopathology of Pregnancy and Labor, Centre for Pharmacological and Botanical Studies (CONICET - School of Medicine, University of Buenos Aires), Buenos Aires, Argentina.
J Cell Biochem. 2018 Jan;119(1):758-772. doi: 10.1002/jcb.26239. Epub 2017 Jul 31.
Successful implantation and placentation requires that extravillous cytotrophoblast acquires an endovascular phenotype and remodels uterine spiral arteries. Defects in this mechanism correlate with severe obstetric complications as implantation failure and preeclampsia. Lysophosphatidic acid (LPA) participates in embryo implantation and contributes to vascular physiology in different biological systems. However, the role of LPA on trophoblast endovascular transformation has not been studied. Due to difficulties in studying human pregnancy in vivo, we adopted a pharmacological approach in vitro to investigate LPA action in various aspects of trophoblast endovascular response, such as the formation of endothelial capillary-like structures, migration, and proliferation. The HTR-8/SVneo cell line established from human first trimester cytotrophoblast was used to model the acquisition of the endovascular phenotype by the invading trophoblast. LPA increased HTR-8/SVneo tube formation, migration (wound healing assay and phalloidin staining) and proliferation (MTT assay). LPA G protein-coupled receptors, LPA and LPA , were expressed in HTR-8/SVneo. By using selective antagonists, we showed that enhanced tubulogenesis was mediated by LPA . In addition, cyclooxygenase-2 and inducible nitric oxide synthase pathways participated in LPA-stimulated tubulogenesis. Inducible nitric oxide synthase was activated downstream cyclooxygenase-2. Furthermore, prostaglandin E2 and a nitric oxide donor (SNAP) increased trophoblast tube formation in a concentration-dependent manner. Finally, we observed that cyclooxygenase-2 and inducible nitric oxide synthase were localized in the nucleus, and LPA did not modify their cellular distribution. Our results show that LPA-triggered regulatory pathways promote trophoblast endovascular response in vitro, suggesting a new role for LPA during spiral artery remodeling at the maternal-fetal interface.
成功的着床和胎盘形成需要绒毛外滋养细胞获得血管内表型并重塑子宫螺旋动脉。这种机制的缺陷与严重的产科并发症有关，如着床失败和子痫前期。溶血磷脂酸（LPA）参与胚胎着床，并在不同的生物系统中对血管生理学起作用。然而，LPA 对滋养细胞血管内转化的作用尚未得到研究。由于在体内研究人类妊娠存在困难，我们采用药理学方法在体外研究 LPA 在滋养细胞血管内反应的各个方面的作用，如内皮毛细血管样结构的形成、迁移和增殖。我们从人早孕绒毛外滋养细胞建立的 HTR-8/SVneo 细胞系用于模拟侵袭性滋养细胞获得血管内表型。LPA 增加了 HTR-8/SVneo 的管形成、迁移（划痕愈合试验和鬼笔环肽染色）和增殖（MTT 试验）。HTR-8/SVneo 表达 LPA G 蛋白偶联受体 LPA 和 LPA。通过使用选择性拮抗剂，我们表明增强的管形成是由 LPA 介导的。此外，环氧合酶-2 和诱导型一氧化氮合酶途径参与了 LPA 刺激的管形成。诱导型一氧化氮合酶被环氧合酶-2 下游激活。此外，前列腺素 E2 和一氧化氮供体（SNAP）以浓度依赖的方式增加滋养细胞管形成。最后，我们观察到环氧合酶-2 和诱导型一氧化氮合酶定位于细胞核中，LPA 不改变它们的细胞分布。我们的结果表明，LPA 触发的调节途径促进了体外滋养细胞的血管内反应，提示 LPA 在母胎界面螺旋动脉重塑过程中发挥新的作用。
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