Preferable existence of polyunsaturated lysophosphatidic acids in human follicular fluid from patients programmed with in vitro fertilization.

Lysophosphatidic acid (LPA) exerts diverse physiological effects on various types of animal cells, including reproductive cells, through its binding to six LPA receptors. We previously found that LPA promoted maturation of the nucleus and cytoplasm of mouse and hamster oocytes surrounded by cumulus cells in vitro. Using gas-liquid chromatography, we previously reported detection of several species of LPA by analyzing the fatty acid methyl esters derived from thin layer chromatography-purified LPA in lipid extract from incubated follicular fluids programmed with in vitro fertilization. In this study using liquid chromatography- tandem mass spectrometry, we directly detected high levels of linoleoyl, arachidonoyl, and docosahexaenoyl LPAs in human follicular fluid. This unique molecular species composition of LPA was suggested to be due to a balance between the low LPA-degrading activity and high LPA-producing activity of autotaxin in human follicular fluid. Our results suggest that polyunsaturated LPAs produced by autotaxin in human follicular fluid exert unknown physiological effects on cumulus cells.

Lysophosphatidic acid stimulates hyaluronan production by mouse cumulus-oocyte complexes.

Purpose: In mammals, cumulus expansion due to increased synthesis of hyaluronan was suggested to correlate with modification of the gap junction between cumulus cells and the oocyte, leading to cumulus expansion. We examined whether lysophosphatidic acid, a lipid mediator detected in mammalian body fluids, stimulates significant production of hyaluronan and thus affects mouse cumulus expansion in vitro. Methods: Cumulus-oocyte complexes isolated from the gonadotropin-treated ovaries of B6C3F1 mice were exposed to lysophosphatidic acid in the presence and absence of 0.3 % fetal bovine serum for measurement of cumulus expansion and released hyaluronan, respectively. Results: Exogenously added lysophosphatidic acid concentration-dependently stimulated production of hyaluronan in the cumulus cell-oocyte complex, and the stimulatory effect of lysophosphatidic acid on hyaluronan production was mediated through the signal pathways, including LPA receptor-Gi coupling, EGF receptor transactivation, and activations of phosphatidylinositol-specific phospholipase C, protein kinase C and mitogen-activated protein kinases. LPA increased mRNA expression of tumor necrosis α-induced protein 6, a hyaluronan-binding protein, and expansion of cumulus cell-oocyte complex. Conclusions: Lysophosphatidic acid in follicular fluids may participate in physiological cumulus expansion before ovulation by stimulating production of hyaluronan and proteins that enable the association of hyaluronan with cumulus cells and oocytes.