Directed trophoblast migration toward the maternal mesometrial pole is critical for placentation and pregnancy success. Trophoblasts replace maternal arterial endothelial cells to increase blood supply to the placenta. Inferior trophoblast invasion results in pregnancy complications including preeclampsia, intrauterine growth restriction, miscarriage, and preterm delivery. The maternal chemotactic factors that direct trophoblast migration and the mechanism by which trophoblasts respond to these factors are not clearly understood. Here, we show that invasive trophoblasts deficient in Vangl2, a core planar cell polarity (PCP) component, fail to invade in maternal decidua, and this deficiency results in middle-gestational fetal demise. Previously, we have shown that tightly regulated endocannabinoids via G protein–coupled cannabinoid receptor CB1 are critical to the invasion of trophoblasts called spiral artery trophoblast giant cells (SpA-TGCs). We find that CB1 directly interacts with VANGL2. Trophoblast stem cells devoid of Cnr1 and/or Vangl2 show compromised cell migration. To study roles of VANGL2 and CB1 in trophoblast invasion in vivo, we conditionally deleted Cnr1 (coding CB1) and Vangl2 in progenitors of SpA-TGCs using trophoblast-specific protein alpha (Tpbpa)-Cre. We observed that signaling mediated by VANGL2 and CB1 restrains trophoblasts from random migration by keeping small GTPases quiescent. Our results show that organized PCP in trophoblasts is indispensable for their directed movement and that CB1 exerts its function by direct interaction with membrane proteins other than its canonical G protein–coupled receptor role.

定向滋养细胞向母体子宫系膜极迁移对于胎盘形成和妊娠成功至关重要。滋养细胞取代母体动脉内皮细胞以增加胎盘的血液供应。下位滋养细胞侵入会导致妊娠并发症，包括先兆子痫、宫内生长受限、流产和早产。指导滋养细胞迁移的母体趋化因子以及滋养细胞对这些因子的反应机制尚不清楚。在这里，我们表明缺乏Vangl2 的侵袭性滋养细胞, 核心平面细胞极性 (PCP) 成分，无法侵入母体蜕膜，这种缺陷导致妊娠中期胎儿死亡。此前，我们已经表明，通过 G 蛋白偶联大麻素受体 CB1 严格调节的内源性大麻素对于称为螺旋动脉滋养层巨细胞 (SpA-TGC) 的滋养层细胞的侵袭至关重要。我们发现 CB1 直接与 VANGL2 相互作用。缺乏Cnr1和/或Vangl2的滋养层干细胞显示受损的细胞迁移。为了研究VANGL2和 CB1 在体内滋养层细胞侵袭中的作用，我们使用滋养层细胞特异性蛋白 alpha ( Tpbpa)-Cre。我们观察到由 VANGL2 和 CB1 介导的信号通过保持小 GTP 酶静止来抑制滋养细胞的随机迁移。我们的结果表明，滋养细胞中有组织的 PCP 对于它们的定向运动是不可或缺的，并且 CB1 通过与膜蛋白的直接相互作用而不是其典型的 G 蛋白偶联受体作用发挥其功能。