Synchronized embryonic development to the blastocyst stage, preparation of the receptive uterus and reciprocal embryo-uterine interactions are critical to implantation. Mechanisms that coordinate these events are not clearly understood. N-arachidonoylethanolamine (anandamide) and 2-arachidonoyglycerol (2-AG) function as endogenous ligands (endocannabinoids) for cannabinoid receptors (CB1 and CB2). CB1 and CB2 are G protein-coupled receptors. Their activation inhibits adenylyl cyclase and of N- or P/Q-type Ca++ channels, but induces activation of mitogen-activated protein kinase (MAPK). Our recent observation of expression of functional CB1 in mouse embryos, uterine anandamide synthesis, and dose-dependent anandamide effects on embryo development and implantation suggests that endocannabinoid signaling is important for these processes. Moreover, levels of uterine anandamide and blastocyst CB1 are coordinately downregulated prior to implantation, but remain high during delayed implantation. These results suggest that lower, but not higher levels, of anandamide and CB1 are beneficial for implantation. Indeed, we noted that a low dose of anandamide stimulates blastocyst growth, but a higher dose inhibits this growth. The mechanisms of these biphasic effects still remain elusive. Collectively, the results suggest that endocannabinoid signaling has a biphasic role during pregnancy. We propose that while uterine endocannabinoids and blastocyst CB1 at specific levels play a physiological role in synchronizing embryonic development and uterine receptivity for implantation, their aberrant levels interfere with these processes, and that endocannabinoids mediate these biphasic effects using different signaling pathways.
Our specific aims are to study in mice: (1) Are the levels of uterine 2-AG regulated in a similar fashion as anandamide? (2) Do ovarian steroids regulate uterine fatty acid amide hydrolase (FAAH) expression? (3) Do cyclooxygenase-2 (COX-2) and FAAH interact in regulating uterine endocannabinoid levels? (4) Does biphasic role of endocannabinoids on embryo development and implantation involve different signaling pathways? (5) Are implantation and pregnancy maintenance altered in the absence of cannabinoid receptors? Our proposed genetic, molecular and physiological approaches using mice as an animal model will provide valuable information for better understanding of risks and benefits of cannabinoid signaling during human pregnancy.
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