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

Harald H.O Schmid,Yong Guo,Haibin Wang,Natsuo Ueda,Sanjoy K Das,Sudhansu K Dey,Yasuo Okamoto,Lawrence J Marnett,Philip J Kingsley

doi:10.1074/jbc.c500168200

Abstract

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.

Highlights

Implantation requires reciprocal interaction between blastocysts and a receptive uterus
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
On day 5 with the onset of implantation, we observed an interesting expression pattern; while Nape-pld expression is very low in the luminal epithelium close to the implanting blastocyst, the expression is much higher in the luminal epithelium further to the blastocyst within the same implantation chamber and as expected at the interimplantation site (Fig. 1A)

Summary

Introduction

Implantation requires reciprocal interaction between blastocysts and a receptive uterus. Biochemical and physiological approaches, we demonstrate here that uterine NAPE-PLD expression and activity change in a spatiotemporal manner determining anandamide levels at the implantation site and during various states of uterine receptivity for implantation. Nape-pld Shows Spatiotemporal Expression in the Periimplantation Uterus—As described above, endocannabinoid signaling is primarily mediated by interactions between uterine anandamide and embryonic CB1, directing embryo development and implantation in a stage and dose dependent manner in mice.

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