Lysophosphatidic acid stimulates rat uterine contraction in vitro

Abstract

Lysophosphatidic acid (LPA) has been implicated in the uterine endometrial functions of implantation and decidualization; however, not much is known about its myometrial contractile function. Herein we characterized the uterotonic effects of LPA in non-pregnant (estrus) and peri-parturient rats in vitro. LPA dose-dependently (0.01-10 μM) stimulated the amplitude and integral, but not the frequency, of the uterine strip contraction of estrous rats. The stimulatory effect of LPA was enhanced 1 day before parturition but was lost 1 day postpartum. LPA did not cause the de novo synthesis of prostaglandin (PG) F₂α but stimulated contractions cooperatively with the PG. LPA-induced contractions were significantly inhibited by an LPA1/2/3 antagonist in the uteri of estrous rats but not in term rats. This study characterized the uterotonic effect of a natural LPA that occurs at physiological concentrations, changes with reproductive states, and is independent of mediation by the newly synthesized PG.

Keywords: Contraction; Lysophosphatidic acid; Prostaglandin F2α; Uterus.

Fig. 1.

Spontaneous contraction of uterine strips ex vivo. The upper (left column) and lower (right column) segments were sampled on estrus (cycling), PRG22, or PP1, and their spontaneous contraction were determined. Typical kymographs of each stage are shown in the top panel. Numerical data for indices of contraction (integral, amplitude, and frequency) are shown as mean ± SEM (n = 4–8). Different alphabetical letters within each figure indicate the significant differences (P < 0.05).

Fig. 2.

Lysophosphatidic acid (LPA) effect on uterine contraction in vitro. Uterine strips isolated from rats in estrus, PRG22, or PP1 (from the top to the bottom) were measured for their contraction before or after treatment with cumulative doses of LPA (0.01–10 mM) for 10 min each. Typical kymographs are shown in the left columns. Indices of contraction (integral, amplitude, and frequency), normalized to those before LPA addition, are shown in the right column. Data were expressed as mean ± SEM (n = 5, estrus; n = 6, PRG22; n = 7, PP1). Different alphabetical letters in each index of the figure indicate the significant differences (P < 0.05).

Fig. 3.

Sphingosine-1-phosphate (S1P) effect on uterine contraction in vitro. Uterine strips isolated on estrus or PRG22 were measured for their contraction before or after treatment with cumulative doses of S1P (0.1–10 mM) for 10 min. The integral, amplitude and frequency of contractions were normalized to those before S1P addition. Data are expressed as mean ± SEM (n = 9, estrus; n = 5, PRG22). Different alphabetical letters within each index indicate significant differences (P < 0.05).

Fig. 4.

Additive effect of lysophosphatidic acid (LPA) with PGF₂α or oxytocin on uterine contraction. The contraction of uterine strips isolated from rats on PRG22 was measured after the initial treatment with PGF₂α (100 nM) or oxytocin (10 nM), followed by the subsequent treatment with cumulative doses of LPA (10–1000 nM) for 10 min each. The integral of contraction was normalized to that of the no treatment group. Data are expressed as mean ± SEM (n = 6). Different alphabetical letters within the same row indicate significant differences (P < 0.05).