Mice Missing Cnr1 and Cnr2 Show Implantation Defects.

Cannabinoid/endocannabinoid signaling is primarily mediated by cannabinoid receptor type 1 (CB1; encoded by Cnr1) and/or type 2 (CB2; encoded by Cnr2). Here, we show that Cnr1-/-Cnr2-/- mice are subfertile as a result of compromised implantation. Upon implantation, the epithelium is smooth and adhered to the blastocyst trophectoderm within the implantation chamber (crypt) in wild-type mice, whereas the epithelium in Cnr1-/-Cnr2-/- mice is ruffled, which compromises appropriate blastocyst-uterine interactions. The suboptimal implantation leads to higher incidence of pregnancy failure in Cnr1-/-Cnr2-/- mice. Histological analysis revealed heightened edema around the implantation chamber in these deleted females. With the use of a reporter mouse line, we observed that CB2 is present on endothelial cells of uterine blood vessels, and its absence leads to blood vessel leakage during implantation. These results suggest that appropriately regulated uterine edema is important to optimal implantation.

[1]  M. T. Grande,et al.  Cannabinoid CB2 receptors in the mouse brain: relevance for Alzheimer’s disease , 2018, Journal of Neuroinflammation.

[2]  S. Dey,et al.  Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation , 2018, Nature Communications.

[3]  S. Dey,et al.  Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation , 2016, Proceedings of the National Academy of Sciences.

[4]  M. J. Uddin,et al.  Antipsychotic-like Effects of M4 Positive Allosteric Modulators Are Mediated by CB2 Receptor-Dependent Inhibition of Dopamine Release , 2016, Neuron.

[5]  John H. Zhang,et al.  Cannabinoid Receptor Type 2 Agonist Attenuates Acute Neurogenic Pulmonary Edema by Preventing Neutrophil Migration after Subarachnoid Hemorrhage in Rats. , 2016, Acta neurochirurgica. Supplement.

[6]  D. Otte,et al.  Expression Analysis of CB2-GFP BAC Transgenic Mice , 2015, PloS one.

[7]  H. Feng,et al.  Cannabinoid CB2 receptor stimulation attenuates brain edema and neurological deficits in a germinal matrix hemorrhage rat model , 2015, Brain Research.

[8]  D. Vestweber,et al.  Integrin β1 controls VE-cadherin localization and blood vessel stability , 2015, Nature Communications.

[9]  Zheng-Xiong Xi,et al.  Cannabinoid CB2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice , 2014, Proceedings of the National Academy of Sciences.

[10]  H. Clevers,et al.  Ovarian LGR5 is critical for successful pregnancy , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  S. Rafii,et al.  Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development. , 2012, Developmental cell.

[12]  E. Marczylo,et al.  Ectopic pregnancy is associated with high anandamide levels and aberrant expression of FAAH and CB1 in fallopian tubes. , 2012, The Journal of clinical endocrinology and metabolism.

[13]  S. Dey,et al.  Endocannabinoid signaling in female reproduction. , 2012, ACS chemical neuroscience.

[14]  R. Ye,et al.  Role of G protein-coupled receptors in inflammation , 2012, Acta Pharmacologica Sinica.

[15]  S. Dey,et al.  Conditional deletion of Msx homeobox genes in the uterus inhibits blastocyst implantation by altering uterine receptivity. , 2011, Developmental cell.

[16]  D. Selley,et al.  The CB2 cannabinoid receptor-selective agonist O-3223 reduces pain and inflammation without apparent cannabinoid behavioral effects , 2011, Neuropharmacology.

[17]  C. Nicco,et al.  Antiproliferative effects of cannabinoid agonists on deep infiltrating endometriosis. , 2010, The American journal of pathology.

[18]  K. Mackie,et al.  CB2: a cannabinoid receptor with an identity crisis , 2010, British journal of pharmacology.

[19]  M. Habiba,et al.  Histomorphometric evaluation of cannabinoid receptor and anandamide modulating enzyme expression in the human endometrium through the menstrual cycle , 2010, Histochemistry and Cell Biology.

[20]  M. Dusch,et al.  Predominant CB2 receptor expression in endothelial cells of glioblastoma in humans , 2009, Brain Research Bulletin.

[21]  E. Mekada,et al.  Maternal heparin-binding-EGF deficiency limits pregnancy success in mice , 2007, Proceedings of the National Academy of Sciences.

[22]  K. Mackie,et al.  CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. , 2007, American journal of physiology. Heart and circulatory physiology.

[23]  P. McGuire,et al.  Proteolytic Degradation of VE-Cadherin Alters the Blood-Retinal Barrier in Diabetes , 2007, Diabetes.

[24]  C. Ledent,et al.  Direct suppression of CNS autoimmune inflammation via the cannabinoid receptor CB1 on neurons and CB2 on autoreactive T cells , 2007, Nature Medicine.

[25]  J. Crabbe,et al.  Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades , 2006, Proceedings of the National Academy of Sciences.

[26]  M. Tsai,et al.  Indian hedgehog is a major mediator of progesterone signaling in the mouse uterus , 2006, Nature Genetics.

[27]  H. Zhang,et al.  Fatty acid amide hydrolase deficiency limits early pregnancy events. , 2006, The Journal of clinical investigation.

[28]  G. Uhl,et al.  Cannabinoid CB2 receptors: Immunohistochemical localization in rat brain , 2006, Brain Research.

[29]  K. Mackie,et al.  Identification functional characterization of brainstem cannabinoid CB2 receptors. , 2022 .

[30]  S. Dey,et al.  Variation in commercial rodent diets induces disparate molecular and physiological changes in the mouse uterus. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[31]  L. Marnett,et al.  Aberrant cannabinoid signaling impairs oviductal transport of embryos , 2004, Nature Medicine.

[32]  A. Barbáchano,et al.  Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: An immunohistochemical study , 2004, Synapse.

[33]  Jeff Reese,et al.  Molecular cues to implantation. , 2004, Endocrine reviews.

[34]  Alberto Rábano,et al.  Cannabinoid CB2 Receptors and Fatty Acid Amide Hydrolase Are Selectively Overexpressed in Neuritic Plaque-Associated Glia in Alzheimer's Disease Brains , 2003, The Journal of Neuroscience.

[35]  R. Roberts,et al.  Differential G protein-coupled cannabinoid receptor signaling by anandamide directs blastocyst activation for implantation , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[36]  A. Finazzi-Agro’,et al.  Low fatty acid amide hydrolase and high anandamide levels are associated with failure to achieve an ongoing pregnancy after IVF and embryo transfer. , 2002, Molecular human reproduction.

[37]  G. Cabral,et al.  Differential expression of the CB2 cannabinoid receptor by rodent macrophages and macrophage-like cells in relation to cell activation. , 2002, International immunopharmacology.

[38]  G. Csaba,et al.  Mice lacking histidine decarboxylase exhibit abnormal mast cells , 2001, FEBS letters.

[39]  T. Bonner,et al.  Dysregulated Cannabinoid Signaling Disrupts Uterine Receptivity for Embryo Implantation* , 2001, The Journal of Biological Chemistry.

[40]  E. Berdyshev,et al.  Cannabinoid receptors and the regulation of immune response. , 2000, Chemistry and physics of lipids.

[41]  Takashi Kobayashi,et al.  Abnormal functional and morphological regulation of the gastric mucosa in histamine H2 receptor-deficient mice. , 2000, The Journal of clinical investigation.

[42]  A. Finazzi-Agro’,et al.  Relation between decreased anandamide hydrolase concentrations in human lymphocytes and miscarriage , 2000, The Lancet.

[43]  T. Bonner,et al.  Cannabinoid-induced mesenteric vasodilation through an endothelial site distinct from CB1 or CB2 receptors. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[44]  S. Dey,et al.  Differential Uterine Expression of Estrogen and Progesterone Receptors Correlates with Uterine Preparation for Implantation and Decidualization in the Mouse1. , 1999, Endocrinology.

[45]  J. Morrow,et al.  Cyclo-oxygenase-2-derived prostacyclin mediates embryo implantation in the mouse via PPARdelta. , 1999, Genes & development.

[46]  M. Herkenham,et al.  Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[47]  S. Dey,et al.  Multiple Female Reproductive Failures in Cyclooxygenase 2–Deficient Mice , 1997, Cell.

[48]  S. Dey,et al.  Changes in anandamide levels in mouse uterus are associated with uterine receptivity for embryo implantation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[49]  S. Dey,et al.  The preimplantation mouse embryo is a target for cannabinoid ligand-receptor signaling. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[50]  G. O'neill,et al.  Activation of the human peripheral cannabinoid receptor results in inhibition of adenylyl cyclase. , 1995, Molecular pharmacology.

[51]  S. Dey,et al.  Cannabinoid ligand-receptor signaling in the mouse uterus. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[52]  S. Dey,et al.  Requirement for Progesterone Priming and Its Long-Term Effects on Implantation in the Mouse , 1990, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.