The role of the endocannabinoid system in gametogenesis, implantation and early pregnancy

doi:10.1093/humupd/dmm018 Human Reproduction Update, Vol.13, No.5 pp. 501–513, 2007 Advance Access publication June 21, 2007 The role of the endocannabinoid system in gametogenesis, implantation and early pregnancy A.H. Taylor, C. Ang, S.C. Bell and J.C. Konje1 1 Correspondence address. Tel: þ44-116-252-5826; Fax: þ44-116-252-5846; E-mail: Maternal use of marijuana, in which the exocannabinoid D9-tetrahydrocannabinol is the most active psychoactive ingredient, is known to have adverse effects on various aspects of reproduction including ovulation, spermatogenesis, implantation and pregnancy duration. Endogenous cannabinoids of which Anandamide is the prototype are widely distributed in the body especially in the reproductive tract and pregnancy tissues and act through the same receptors as the receptor as D9-tetrahydrocannabinol. Anandamide, has been reported to have pleiotropic effects on human reproduction and in experimental animal models. It appears to be the important neuro-cytokine mediator synchronizing the embryo-endometrial development for timed implantation, the development of the embryo into the blastocyst and transport of the embryo across the fallopian tubes. The mechanisms by which it exerts these effects are unclear but could be via direct actions on the various sites within the reproductive system or its differential actions on vascular tone dependent. In this review article we bring together the current knowledge on the role of endoccanabinoids in reproduction and postulate on the potential mechanisms on how these affect reproduction. In addition, we examine its role on the endothelium and vascular smooth muscle as a potential mechanism for adverse pregnancy outcome. Keywords: anandamide; cannabinoid; pregnancy; fetal growth restriction; vascular bed Introduction Pregnancy complications such as preterm labour, pre-eclampsia and fetal growth restriction (FGR) collectively make a significant contribution to perinatal morbidity and mortality. Although the pathophysiology has not been clearly defined, in most cases, the common phenomenon observed between these diseases is abnormal development and function of the placenta (Salafia, 1997; Pardi et al., 1997; Kim et al., 2002; McMaster et al., 2004). Normal placental development is dependent upon the differentiation and invasion of the trophoblast, the main cellular component of the placenta that originates from the trophoectoderm of the blastocyst in early pregnancy (Straszewski-Chavez et al., 2005). During this process of development and invasion, trophoblast cells rapidly divide to form the interface between mother and embryo. Other trophoblast subpopulations invade the decidua to remodel the uterine spiral arteries allowing the expansion of extra-embryonic tissues and increase in blood flow to the placenta and developing fetus. Any perturbation of this process, which is tightly regulated and influenced by several factors, may lead to pregnancy complications. Such factors include numerous angiogenic growth factors, cell adhesion molecules, cytokines and growth factors, extracellular matrix metalloproteases, hormones and transcription factors which have been studied extensively (Vuorela et al., 1997; Kayisli et al., 2002; Rajashekhar et al., 2005; Walter and Schonkypl, 2006). Another family of bioactive factors that have not been studied in depth, but thought to be involved in normal placentation is the endocannabinoids. In the light of recent evidence and increased interest in the role of endocannabinoids in early and late pregnancy problems, this review will re-examine the role of cannabinoids in pregnancy and in the development of the fetoplacental unit with special focus upon the effects of endocannabinoids on the endothelial and vascular smooth muscle cell as pertaining to efficient placental function. The endocannabinoid system Historical view Research on the chemistry and pharmacology of cannabinoids was well underway in the 19th century, during a time when cannabis was widely used in medicine (Mechoulam and Hanus, 2000). However, it was more than a century later, that its most psychoactive active component, D9-tetrahydrocannabinol (D9-THC), was isolated in its pure form and its chemical structure elucidated (Gaoni and Mechoulam, 1964, 1971). D9-THC (Fig. 1) is the principal biologically active component of marijuana and is the # The Author 2007. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: 501 Endocannabinoid Research Group (ERG) Reproductive Sciences Section, Department of Cancer Studies and Molecular Medicine, Robert Kilpatrick Clinical Sciences Building, University of Leicester, Leicester Royal Infirmary, PO Box 65, Leicester, Leicestershire LE2 7LX, UK Taylor et al. prototypical cannabinoid family member. This and related molecules (D8-THC, Fig. 1) were originally shown to exert their central psychoactive effects via the cannabinoid receptor, CB1, and their peripheral immunoregulatory effects via the CB2 receptor (Matsuda et al., 1990; Munro et al., 1993). Recently, it has been shown that some peripheral tissues contain both receptor isotypes and, in some cases, D9-THC may also activate the nociceptive receptor, vanilloid receptor 1 (VR1) (Zygmunt et al., 2000; Zygmunt et al., 2002). Metabolism—synthesis Endocannabinoids are generated ‘on demand’ from long chain polyunsaturated fatty acid precursors derived from arachidonic acid (Habayeb et al., 2002), through enhanced intracellular Ca2þ concentrations, e.g. from cell depolarization, or mobilization of intracellular Ca2þ stores following stimulation of Gq/11 502 Metabolism—transport and degradation Termination of endocannabinoid signalling at the cannabinoid receptors is thought to occur by transport of the compounds into the cell by a poorly characterized AEA transporter (Di Marzo et al., 2004; Moore et al., 2005; Bari et al., 2006), followed by the rapid degeneration of AEA by fatty acid amide hydrolase (FAAH) found on the internal membranes of AEA target cells (Di Marzo et al., 1994; Cravatt et al., 1996) (Figs. 2 and 3). It has also been suggested that FAAH may act as an AEA transporter and that FAAH not only absorbs AEA from the plasma, but may also export AEA under the appropriate conditions, i.e. estrogen stimulation of loaded endothelial cells (Maccarrone et al., Figure 1: The chemical structures of the main psychoactive ingredient in Cannabis sativa (THC) and the related cannabinoid (CB)-binding exocannabinoid, D8-THC Also shown are the chemical structures of the CB-binding endogenous cannabinoids, AEA and 2-AG protein-coupled receptors. The enzymes (N-arachidonyolphosphatidyl ethanolamine selective phospholipase D and sn-1 selective diacylglycerol lipases 1 and 2) that catalyse the last steps in the production of the two most studied endocannabinoids, arachidonyol-ethanolamine (anandamide, AEA, (...truncated)