Lysophosphatidic acid and sphingosine 1-phosphate metabolic pathways and their receptors are differentially regulated during decidualization of human endometrial stromal cells

In the luteal phase, human endometrial stromal cells (HESCs) undergo proliferation, migration and differentiation during the decidualization process under the control of the ovarian steroids progesterone and estrogen. Proper decidualization of stromal cells is required for blastocyst implantation and the development of pregnancy. The proliferation, migration and differentiation of HESCs in decidualization do not require the presence of a blastocyst but are greatly accelerated during implantation. Lysophosphatidic acid (LPA) and sphingosine-I-phosphate (S I P) are potent bioactive lysophospholipids that have critical roles in various physiological and pathophysiological processes, including inflammation, angiogenesis and cancer. The expression of the enzymes involved in LPA and SI P turnover and their receptors in HESCs during decidualization has not been characterized yet. We found that the LPAR(1) and LPAR(6) and SIPR3 receptors are highly expressed in HESCs. LPAR(1), autotaxin (ATX), an LPA producing enzyme and lipid phosphate phosphatase 3 were up-regulated during decidualization. Interestingly, the expression of all SI P receptor subtypes and LPA receptors (LPAR(2-6)) mRNA was down-regulated after decidualization. We found that SPHK1 is highly expressed in HESCs, and is up-regulated during decidualization. SIP phosphatase SGPP1 and SIP lyase SGPL1 are highly expressed in HESCs. SGPP1 mRNA expression was significantly up-regulated in decidualized HESCs. In conclusion, this study shows the first time that specific LPA and SIP receptors and their metabolizing enzymes are highly regulated in HESCs during decidualization. Furthermore, we suggest that LPAR(1) receptor-mediated signaling in HESCs may be crucial in decidualization process. SPHK1 activity and high turnover of SIP and LPA might be essential for precise regulation of their signaling during decidualization of human endometrium and implantation.