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Aberrant cannabinoid signaling impairs oviductal transport of embryos

Nature Medicine volume 10, pages 1074–1080 (2004)Cite this article

A Corrigendum to this article was published on 01 December 2004

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 β-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 β2-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.

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Figure 1: Impaired oviductal embryo transport causes pregnancy loss in Cnr1−/− mice.
Figure 2: Analysis of Mbldc1, Cnr1 and Cnr2 mRNAs in the oviduct.
Figure 3: Aberrant cannabinoid signaling causes impaired oviductal embryo transport in wild-type mice.
Figure 4: Lack of CB1 increases oviductal nor-adrenaline release.
Figure 5: Normal embryo development and transport in Cnr1−/− mice are restored by prostaglandins and β-AR signaling, respectively.

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Acknowledgements

We thank T. Bonner and A. Zimmer for providing us initially with the Cnr mutant mice for establishing colonies in our animal facilities. This work was supported in part by the National Institutes of Health (NIH) Grants (DA06668, HD12304, HD37830 & CA77839) and National Foundation for Cancer Research. S.K. Dey is recipient of Method to Extend Research in Time (MERIT) Awards from the National Institute on Drug Abuse (NIDA) and the National Institute of Child Health and Human Development (NICHD). H. Wang is a Lalor Foundation Fellow.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, 37232, Tennessee, USA

    Haibin Wang, Yong Guo, Sanjoy K Das & Sudhansu K Dey

  2. Department of Medicine, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, 37232, Tennessee, USA

    Dingzhi Wang & Raymond N DuBois

  3. Department of Biochemistry, Division of Reproductive and Developmental Biology, Institute of Chemical Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, 37232, Tennessee, USA

    Philip J Kingsley & Lawrence J Marnett

  4. Department of Cancer Biology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, 37232, Tennessee, USA

    Sanjoy K Das & Raymond N DuBois

  5. Department of Pharmacology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, 37232, Tennessee, USA

    Raymond N DuBois & Sudhansu K Dey

  6. Departments of Cell and Developmental Biology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, 37232, Tennessee, USA

    Sudhansu K Dey

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Supplementary information

Supplementary Fig. 1

CB1 deficiency causes pregnancy loss in mice (PDF 139 kb)

Supplementary Table 1

Treatment with phenylephrine alone or in combination with butoxamine in wild-type pregnant mice leads to oviductal retention of embryos (PDF 18 kb)

Supplementary Table 2

Supplementation with progesterone or estrogen fails to restore normal embryo transport in Cnr1−/− mice (PDF 18 kb)

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Wang, H., Guo, Y., Wang, D. et al. Aberrant cannabinoid signaling impairs oviductal transport of embryos. Nat Med 10, 1074–1080 (2004). https://doi.org/10.1038/nm1104

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