Coordinated regulation of fetal and maternal prostaglandins directs successful birth and postnatal adaptation in the mouse

Abstract

Cyclooxygenase (COX)-derived prostaglandins (PGs) regulate numerous maternal-fetal interactions during pregnancy. PGs stimulate uterine contractions and prepare the cervix for parturition, whereas in the fetus, PGs maintain patency of the ductus arteriosus (DA), a vascular shunt that transmits oxygenated placental blood to the fetal systemic circulation. However, the origin and site of action of these PGs remain undefined. To address this, we analyzed mice lacking COX-1 (null mutation) or COX-2 (pharmacologic inhibition) or pups with a double null mutation. Our results show that COX-1 in the uterine epithelium is the major source of PGs during labor and that COX-1 ؊/؊ females experience parturition failure that is reversible by exogenous PGs. Using embryo transfer experiments, we also show that successful delivery occurs in COX-1 ؊/؊ recipient mothers carrying wild-type pups, establishing the sufficiency of fetal PGs for parturition. Although patency of the DA is PG dependent, neither COX-1 nor COX-2 expression was detected in the fetal or postnatal DA, and offspring with a double null mutation died shortly after birth with open DAs. These results suggest that DA patency depends on circulating PGs acting on specific PG receptors within the DA. Collectively, these findings demonstrate the coordinated regulation of fetal and maternal PGs at the time of birth but raise concern regarding the use of selective COX inhibitors for the management of preterm labor. T he timing of parturition is synchronized with fetal maturity to prevent premature birth (1). Prostaglandins (PGs) are associated with parturition, stimulating such diverse functions as uterine relaxation, contraction, and postpartum involution (2). Evidence that PGs participate in parturition stems from the observation of increased PG levels during labor, increased uterine contractility after PG administration, and delay in the onset of labor by inhibitors of PG synthesis (3-5).PGs are lipid mediators derived from the hydrolysis of cellular phospholipids. PG G͞H synthase or cyclooxygenase (COX) catalyzes the conversion of arachidonic acid to PGH 2 , the precursor to all prostanoids and thromboxanes. COX exists as two isoforms, COX-1 and COX-2, which share structural homology but arise from different loci (6). COX-1 is widely expressed and is considered a constitutive isoform. However, its expression in the mouse uterus is regulated by estrogen and progesterone (7). COX-1 Ϫ/Ϫ mice are a valuable model for studying labor, because they have delayed parturition and decreased pup survival (8, 9). In contrast, COX-2 is rapidly induced in response to various cellular stimuli and is critical for ovulation, fertilization, and embryo implantation (10, 11). Studies on parturition in COX-2 Ϫ/Ϫ mice are precluded by their infertility (10-12).The delivery of oxygenated blood from the placenta to the fetus depends on patency of the ductus arteriosus (DA), a vascular shunt coupling the main pulmonary artery with the aorta. This shunt bypasses the uninflated fetal lung and mu...

Cyclooxygenase-1-derived PGE2 promotes cell motility via the G-protein-coupled EP4 receptor during vertebrate gastrulation

“…Although Cox-2-null mice demonstrated numerous developmental defects (Dinchuk et al 1995), their embryogenesis proceeded normally. Given the vital role of prostaglandins in normal physiologic settings, it has been hypothesized that the maternal contribution of prostaglandins in the placenta allows the prostaglandindeficient embryos to develop normally (Reese et al 2000(Reese et al , 2001. Consistent with this notion, mammalian blastocysts produce high levels of PGE 2 and PGF 2␣ (Dey et al 1980;Davis et al 1983), and murine blastocysts cultured outside of the uterus do not survive in the presence of COX inhibitors (H. Wang and S.K.…”

“…A large body of evidence implicates PGE 2 as a lipid messenger that regulates a wide variety of important body functions in mammals, including pain and fever, maintenance of vascular tone, and cancer progression (Kobayashi and Narumiya 2002). However, deciphering the role of PGE 2 in early mammalian development has been limited by the maternal contribution of prostaglandins in utero (Reese et al 2000(Reese et al , 2001. As a result, the functional role for prostaglandins in early development remains virtually unknown.…”

Differential regulation of endocannabinoid synthesis and degradation in the uterus during embryo implantation

“…Wildtype and FAAH −/− mice were generated from heterozygous matings on 129/C57Bl6 mixed genetic background as previously described [36]. The cPLA2α −/− , COX-1 −/− , and COX-2 −/− mice were originally generated on 129/C57Bl6 mixed genetic background [37][38][39], and later these mutations were established on the CD-1 genetic background by backcrossing with CD1 wild-type mice (Charles River Laboratories) for 10 generations [35,40,41]. Polymerase chain reaction (PCR) analysis of tail genomic DNA determined the genotypes.…”

Identification of transcription factors at the site of implantation in the later stages of murine pregnancy

“…COX-2 is known to be critical for the early stages of pregnancy (Lim et al 1997). Since COX-2-deficient mice abort early in pregnancy, the necessity for COX-2 in the later stages of pregnancy remains controversial (Reese et al 2000, Tsuboi et al 2003. GILZ has been shown to play a putative role in the anti-inflammatory and immunosuppressive effects of glucocorticoids by interacting with Raf-1 and inhibiting the classic MAPK (mitogen-activated protein kinase) pathway (Ayroldi et al 2002).…”