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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37DA006668-19
Application #
8213726
Study Section
Special Emphasis Panel (NSS)
Program Officer
Purohit, Vishnudutt
Project Start
1990-07-01
Project End
2014-12-31
Budget Start
2012-01-01
Budget End
2014-12-31
Support Year
19
Fiscal Year
2012
Total Cost
$450,434
Indirect Cost
$150,145
Name
Cincinnati Children's Hospital Medical Center
Department
Type
DUNS #
071284913
City
Cincinnati
State
OH
Country
United States
Zip Code
45229
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Lanekoff, Ingela; Cha, Jeeyeon; Kyle, Jennifer E et al. (2016) Trp53 deficient mice predisposed to preterm birth display region-specific lipid alterations at the embryo implantation site. Sci Rep 6:33023
Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo et al. (2016) Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci U S A 113:E8079-E8088
Maccarrone, Mauro; Bab, Itai; Bíró, Tamás et al. (2015) Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci 36:277-96
Li, Yingju; Sun, Xiaofei; Dey, Sudhansu K (2015) Entosis allows timely elimination of the luminal epithelial barrier for embryo implantation. Cell Rep 11:358-65
Lanekoff, Ingela; Burnum-Johnson, Kristin; Thomas, Mathew et al. (2015) Three-dimensional imaging of lipids and metabolites in tissues by nanospray desorption electrospray ionization mass spectrometry. Anal Bioanal Chem 407:2063-71
Cha, Jeeyeon; Dey, Sudhansu K (2014) Cadence of procreation: orchestrating embryo-uterine interactions. Semin Cell Dev Biol 34:56-64
Daikoku, Takiko; Ogawa, Yuya; Terakawa, Jumpei et al. (2014) Lactoferrin-iCre: a new mouse line to study uterine epithelial gene function. Endocrinology 155:2718-24

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