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Cyclic Mechanical Stretch Augments Prostacyclin Production in Cultured Human Uterine Myometrial Cells from Pregnant Women: Possible Involvement of Up-Regulation of Prostacyclin Synthase Expression

Department of Gynecology and Obstetrics (D.K., N.S., H.I., S.Y., M.Y., K.K., M.T., S.F.), Kyoto University Graduate School of Medicine, 606-8507 Kyoto, Japan; and Department of Pharmacology (C.Y., T.T.), National Cardiovascular Center Research Institute, 565-8565 Osaka, Japan

Address all correspondence and requests for reprints to: Norimasa Sagawa, M.D., Ph.D., Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, 606-8507 Kyoto, Japan. E-mail: fetus{at}kuhp.kyoto-u.ac.jp.

Abstract

Prostacyclin (PGI₂), a potent smooth muscle relaxant, is a major prostaglandin secreted from human myometrium. The concentrations of PGI₂ metabolites in the maternal plasma were reported to be elevated during pregnancy, especially in labor. To clarify the mechanism in PGI₂ secretion from the myometrium, we first investigated the protein expression of cytosolic phospholipase A₂, cyclooxygenase (COX)-1, COX-2, and prostacyclin synthase (PGIS) in the human uterine myometrium at various gestational ages before labor. To elucidate the involvement of labor in the increase in PGI₂ production during labor, we next examined the effect of labor-like cyclic mechanical stretch on PGI₂ production by cultured human myometrial cells.

Pregnancy specifically increased COX-1 and PGIS protein expression in the myometrial tissues before labor (P < 0.01 for both). Cyclic mechanical stretch augmented PGIS promoter activity, via activation of activator protein-1 site, and PGIS mRNA and protein expression in cultured human myometrial cells and resulted in a 3.5-fold increase in the concentration of 6-keto-prostaglandin F₁, the stable metabolite of PGI₂, in the culture medium (P < 0.05). However, stretch did not affect the levels of prostaglandin E₂, prostaglandin F₂, or thromboxane A₂ secreted into the same culture media. These results suggest that cyclic mechanical stretch during labor may contribute to the increase in the PGI₂ concentration in the maternal plasma during parturition.

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