Wang Haibin, Xie Huirong, Sun Xiaofei, Kingsley Philip J, Marnett Lawrence J, Cravatt Benjamin F, Dey Sudhansu K
Department of Pediatrics, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Prostaglandins Other Lipid Mediat. 2007 Feb;83(1-2):62-74. doi: 10.1016/j.prostaglandins.2006.09.009. Epub 2006 Nov 28.
Preimplantation embryo development to the blastocyst stage and uterine differentiation to the receptive state are prerequisites for embryo implantation. Burgeoning evidence suggests that endocannabinoid signaling is critical to early pregnancy events. Anandamide (N-arachidonoylethanolamine) and 2-AG (2-arachidonoylglycerol) are two major endocannabinoids that bind to and activate G-protein coupled cannabinoid receptors CB1 and CB2. We have previously shown that a physiological tone of anandamide is critical to preimplantation events in mice, since either silencing or amplification of anandamide signaling causes retarded development and oviductal retention of embryos via CB1, leading to deferred implantation and compromised pregnancy outcome. Whether 2-AG, which also influences many biological functions, has any effects on early pregnancy remains unknown. Furthermore, mechanisms by which differential uterine endocannabinoid gradients are established under changing pregnancy state is not clearly understood. We show here that 2-AG is present at levels one order of magnitude higher than those of anandamide in the mouse uterus, but with similar patterns as anandamide, i.e. lower levels at implantation sites and higher at interimplantation sites. We also provide evidence that region- and stage-specific uterine expression of N-acylphosphatidylethanolamine-specific phospholipase D (NAPE-PLD) and fatty acid amide hydrolase (FAAH), and sn-1-diacylglycerol (DAG) lipase alpha (DAGLalpha) and monoacylglycerol lipase (MAGL) for synthesis and hydrolysis of anandamide and 2-AG, respectively, creates endocannabinoid gradients conducive to implantation. Our genetic evidence suggests that FAAH is the major degrading enzyme for anandamide, whereas COX-2, MAGL and to some extent COX-1 participate in metabolizing 2-AG in the pregnant uterus. The results suggest that aberrant functioning of these pathways impacting uterine anandamide and/or 2-AG levels would compromise pregnancy outcome.
植入前胚胎发育至囊胚阶段以及子宫分化至接受状态是胚胎着床的先决条件。越来越多的证据表明，内源性大麻素信号传导对早期妊娠事件至关重要。花生四烯酸乙醇胺（N-花生四烯酰乙醇胺）和2-花生四烯酸甘油酯（2-AG）是两种主要的内源性大麻素，它们与G蛋白偶联的大麻素受体CB1和CB2结合并激活它们。我们之前已经表明，花生四烯酸乙醇胺的生理水平对小鼠植入前事件至关重要，因为花生四烯酸乙醇胺信号传导的沉默或增强都会通过CB1导致胚胎发育迟缓并滞留在输卵管中，从而导致着床延迟和妊娠结局受损。同样影响许多生物学功能的2-AG对早期妊娠是否有任何影响仍不清楚。此外，在不断变化的妊娠状态下建立不同子宫内源性大麻素梯度的机制尚不清楚。我们在此表明，在小鼠子宫中，2-AG的水平比花生四烯酸乙醇胺高一个数量级，但模式与花生四烯酸乙醇胺相似，即在着床部位水平较低，在着床间隙部位水平较高。我们还提供证据表明，N-酰基磷脂酰乙醇胺特异性磷脂酶D（NAPE-PLD）和脂肪酸酰胺水解酶（FAAH）以及分别用于合成和水解花生四烯酸乙醇胺和2-AG的sn-1-二酰基甘油（DAG）脂肪酶α（DAGLα）和单酰基甘油脂肪酶（MAGL）在子宫中的区域和阶段特异性表达会产生有利于着床的内源性大麻素梯度。我们的遗传学证据表明，FAAH是花生四烯酸乙醇胺的主要降解酶，而COX-2、MAGL以及在一定程度上COX-1参与妊娠子宫中2-AG的代谢。结果表明，这些影响子宫花生四烯酸乙醇胺和/或2-AG水平的途径功能异常会损害妊娠结局。
