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J. Biol. Chem., Vol. 280, Issue 25, 23429-23432, June 24, 2005

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N-Acylphosphatidylethanolamine-hydrolyzing Phospholipase D Is an Important Determinant of Uterine Anandamide Levels during Implantation^*

From the Departments of ^aPediatrics, ^kBiochemistry, ^eInstitute of Chemical Biology, ^gCancer Biology, ^hCell & Developmental Biology and ⁱPharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, the ^dDepartment of Biochemistry, Kagawa University School of Medicine, Kagawa 761-0793, Japan, and ^fThe Hormel Institute, University of Minnesota, Austin, Minnesota 55912

Implantation requires reciprocal interaction between blastocysts and a receptive uterus. In mice, one important player in this dialogue involves endocannabinoid signaling via cannabinoid receptor CB1. Anandamide is an endogenous cannabinoid ligand, and its levels are spatiotemporally regulated in the uterus during early pregnancy, showing lower levels in the receptive uterus and at the implantation site. However, the mechanism by which differential uterine anandamide gradients are established under different pregnancy status is not clearly understood. Using multiple approaches, we show here that uterine anandamide levels conducive to implantation are primarily regulated by spatiotemporal expression of Nape-Pld, the gene encoding N-acylphosphatidylethanolamine-hydrolyzing phospholipase D that generates anandamide. The expression is well correlated with its activity and anandamide levels. This study is clinically relevant, since elevated anandamide levels in peripheral circulation are associated with spontaneous pregnancy failure in women.

Received for publication, April 18, 2005 , and in revised form, May 9, 2005.

^* This work was supported in part by National Institutes of Health Grants DA06668, HD12304, HD33994, ES07814, and HD37830. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^b These authors contributed equally to this work.

^c Recipient of Solvay/Mortola Research Award from the Society for Gynecologic Investigation.

^j Recipient of Method to Extend Research in Time (MERIT) Awards from the National Institute on Drug Abuse (NIDA) and the National Institute of Child Health and Human Development (NICHD). To whom correspondence should be addressed. E-mail: sk.dey{at}vanderbilt.edu.

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