Aberrant cannabinoid signaling impairs oviductal transport of embryos

Abstract

Ectopic pregnancy is a major reproductive health issue. Although other underlying causes remain largely unknown, one cause of ectopic pregnancy is embryo retention in the fallopian tube. Here we show that genetic or pharmacologic silencing of cannabinoid receptor CB1 causes retention of a large number of embryos in the mouse oviduct, eventually leading to pregnancy failure. This is reversed by isoproterenol, a beta-adrenergic receptor agonist. Impaired oviductal embryo transport is also observed in wild-type mice treated with methanandamide. Collectively, the results suggest that aberrant cannabinoid signaling impedes coordinated oviductal smooth muscle contraction and relaxation crucial to normal oviductal embryo transport. Colocalization of CB1 and beta2-adrenergic receptors in the oviduct muscularis implies that a basal endocannabinoid tone in collaboration with adrenergic receptors coordinates oviductal motility for normal journey of embryos into the uterus. Besides uncovering a new regulatory mechanism, this study could be clinically relevant to ectopic pregnancy.

Endocannabinoid Signaling in Female Reproduction

“…This effect can be counterbalanced by administration of isoproterenol, a β2-AR agonist, which restored normal embryo transport in Cnr1 −/− mice. 33 In WT mice, treatment of methanandamide decreased the release of noradrenaline, and it was blocked by a CNR1 specific antagonist. Similarly, circular muscles maintained a relaxation phase in Faah −/− mice, where AEA levels were higher than in WT mice.…”

“…31 In the oviduct and uterus, only CNR1, but not CNR2, is detected. 32,33 In addition to the presence of these two receptors, FAAH and NAPE-PLD are also present in the preimplantation embryos from the 2-cell stage to the blastocyst stage. FAAH is mainly detected in the outer cell layers of morula and in the trophectoderm of blastocysts.…”

“…37 This abnormal embryo development may be the consequence of oviductal and/or embryonic Cnr1 deficiency. Observations that heterozygous embryos recovered from Cnr1 −/− females mated with WT males showed normal embryo development 33 indicating that embryonic CNR1, but not maternal CNR1, directs appropriate embryo development. 38 These findings suggest that either silenced or augmented CNR1 signaling leads to abnormal embryo development.…”

“…33 Additionally, normal oviductal transport in WT mice was disrupted by treatment with a CNR1 specific blocker, while CNR2 antagonists had no effect. 33 Higher cannabinoid signaling also affects oviductal embryo transport. Faah −/− mice with higher oviductal AEA levels than those in WT oviducts have similar oviductal retention of embryos.…”

Endocannabinoid signaling directs differentiation of trophoblast cell lineages and placentation

“…For instance, pregnancy success in both mice and humans requires regulated AEA signaling (15)(16)(17). Whereas Cnr1 −/− mice show oviductal retention of embryos (18), women with ectopic pregnancy have reduced CNR1 expression in the Fallopian tubes (19).…”