Cannabinoid and planar cell polarity signaling converges to direct placentation

Significance During placentation, some trophoblast cells, termed spiral artery trophoblast giant cells (SpA-TGCs), invade the maternal decidua and replace arterial endothelial cells to increase blood supply to the placenta; how this directional trophoblast migration occurs remains unknown. We show here that planar cell polarity (PCP) signaling mediated by VANGL2 in SpA-TGCs plays a key role in trophoblast movement and successful placentation. Mice with SpA-TGC progenitors deficient in Vangl2 had pregnancy termination in mid-gestation due to increased random cell protrusion and compromised cell migration. We also found endocannabinoid signaling intersects with PCP signaling in directing trophoblast migration by direct association of CB1 and VANGL2. These results demonstrated that trophoblast invasion in placentation requires organized PCP. 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.

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