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Endocrinology Vol. 141, No. 1 315-324
Copyright © 2000 by The Endocrine Society

ARTICLES

Uterine Expression of Prostaglandin H2 Synthase in Late Pregnancy and during Parturition in Prostaglandin F Receptor-Deficient Mice1

Kazuhito Tsuboi, Yukihiko Sugimoto, Aya Iwane, Kei Yamamoto, Shozo Yamamoto and Atsushi Ichikawa

Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University (K.T., Y.S., A.Iw., A.Ic.), Kyoto 606-8501; and the Department of Biochemistry, University of Tokushima School of Medicine (K.Y., S.Y.), Tokushima 770-8503, Japan

Address all correspondence and requests for reprints to: Atsushi Ichikawa, Ph.D., Department of Physiological Chemistry, Faculty of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. E-mail: aichikaw{at}pharm.kyoto-u.ac.jp

PG production in uterine tissues is important for many physiological processes in late pregnancy, including parturition. We examined the expression of the PGH2 synthases, cyclooxygenase-1 (COX-1) and COX-2, in uterine tissues during late pregnancy, using PGF receptor-deficient (FP-/-) mice. Female FP-/- mice are unable to deliver normal fetuses at term, as they do not undergo luteolysis necessary for parturition. In wild-type mice, COX-1 messenger RNA (mRNA) was expressed in the endometrial epithelium, myometrium, and decidua throughout late pregnancy. The expression of COX-1 mRNA in the endometrial epithelium and myometrium decreased both in wild-type mice undergoing natural parturition and in FP-/- mice undergoing ovariectomy-induced parturition, but expression of COX-1 mRNA was enhanced in FP-/- mice at the expected term. In wild-type mice, COX-2 mRNA was not expressed in the myometrium before parturition, but was markedly induced during parturition. This induction of COX-2 was absent in FP-/- mice at the expected term, but was found during ovariectomy-induced parturition in these mice. Expression of COX-2 proteins was confirmed by immunohistochemical analysis. Thus, in uterine tissues, myometrial expression of COX-2 is closely associated with the occurrence of parturition, but uterine expression of COX-1 is induced much earlier and kept at a high level until parturition occurs. These results suggest that COX-1-derived PGs are responsible for the induction of luteolysis, and that COX-2-derived PGs play a role in the final pathway of parturition. . PGH2 synthase, generally referred to as cyclooxygenase (COX), is the rate-limiting enzyme in the biosynthetic pathway of various PGs from arachidonic acid (5). Of the two isozymes, COX-1 is generally considered to be the constitutive enzyme, playing housekeeping roles in many animal tissues. In contrast, COX-2 is thought to be more tightly regulated than COX-1, playing various physiological and pathological roles (6). Aspirin-like drugs, which inhibit enzymatic activities of the COX isozymes, are known to cause delayed parturition in many species (7). Indeed, a large amount of PGs, especially PGE2 and PGF2{alpha}, are produced and released in uterine tissues during parturition (8). As both PGE2 and PGF2{alpha} have potent uterotonic activity (9), these PGs have been thought to play roles in the physiological parturition process. However, the specific roles these PGs play in parturition remain unclear.

The actions of PGs are mediated by specific receptors on the surface of cells (10). To examine the physiological roles of the PGF receptor (FP) in parturition, we generated FP-deficient (FP-/-) mice (11). As reported previously, FP-/- mice are unable to deliver normal fetuses at term, although they are normal in other aspects of reproduction physiology. These mice did not show the normal decline of serum progesterone levels that precedes parturition. Ovariectomy on day 19 of pregnancy permitted successful delivery in these FP-/- mice, indicating that parturition is initiated when PGF2{alpha} interacts with FP in the ovary of pregnant mice, inducing luteolysis. It has just recently been reported that COX-1-deficient mice also show phenotypes of delayed parturition (12). This report stated that the significant increase in uterine PGF2{alpha} production on day 19 was lost in COX-1-deficient mice, and that the administration of PGF2{alpha} restored successful parturition. Hence, uterine induction of COX-1 before parturition appears important for inducing luteolysis. On the other hand, a number of reports have shown that a large amount of PG production and induction of COX-2 are detected in uterine tissues during parturition (8, 13). In humans, these events that occur in uterine tissues were found only during natural parturition and not upon cesarean section (14). Thus, it is likely that PGs produced by COX-2 take part in parturition through their uterotonic activity. From these results we speculated that uterine expression of the COX isozymes is regulated by different mechanisms, and that COX-1 and COX-2 preferentially contribute to the induction of luteolysis and myometrial contractility, respectively. To examine this possibility, we used FP-/- mice, because luteolysis is impaired in late pregnancy, and parturition can be artificially initiated by ovariectomy treatment. Here we show the uterine expression of COX-1 and COX-2 in FP-/- mice during late pregnancy and during ovariectomy-induced parturition. The results observed suggest that these two isozymes are regulated by parturition signals in very different ways.




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