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.

Figures

Figure 1

The etiology of prostaglandins in parturition. (A and B) In situ hybridization of 35S-labeled COX-1 (A) and COX-2 (B) in wild-type uteri on the morning of expected delivery (×10). Top includes implantation and interimplantation segments with the intact amniotic sac. Sections of the labyrinthine (L), spongiotrophoblast (S), and giant cell (GC), layers of the placenta and uterine luminal epithelium (LE) myometrium (M) and decidual (D) of the uterus are shown, along with fetal epidermis (E), amniotic membrane (Am), and yolk sac (Y). Sense probes were negative at sites of specific hybridization. (C) Prostaglandin concentrations of wild-type and COX-1−/− uteri on the morning of expected delivery, determined by GC mass spectrometry. *, P < 0.005. (D) Delayed parturition in 51 COX-1−/− litters on two genetic backgrounds. Mice with a 129/Bl6 background delivered later with less surviving pups, whereas CD-1 background mice had more severe lethality when parturition was delayed (129/Bl6 = dashed, R2 = 0.48; CD-1 = solid, R2 = 0.90). Overlapping points exist which represent the outcome of more than one litter.

Figure 2

The contribution of COX-1, COX-2, and fetal PGs to parturition. (A) Response of COX-1−/− females to prostaglandin administration during delayed parturition. The length of gestation (bars) and pup survival (○) in wild-type and vehicle-treated COX-1−/− females are shown. *, P < 0.01, **, P < 0.001, compared with vehicle-treated COX-1−/−. Single s.c. injections were given on the evening of expected delivery and responses monitored by infrared videorecording. Alterations in gestational length are shown with corresponding survival rates. (B) Response of wild-type females to selective COX-2 inhibition on the morning of expected delivery. *, P < 0.05, compared with vehicle. Drug or vehicle was administered twice daily by gavage feeding and responses monitored by infrared videorecording. (C) Effect of fetal-derived PGs on parturition. The outcome of pregnancy after transfer of wild-type blastocysts to COX-1−/− and wild-type pseudopregnant females is shown. Parturition failure was reduced and pup survival was improved in COX-1−/− mothers with wild-type pups compared with COX-1−/− mothers with COX-1−/− or COX-1+/− litters. *, P < 0.05, compared with COX-1−/− mother with COX-1−/− pups. ET, embryo transfer.

Figure 3

Prostaglandin effects on the fetal ductus arteriosus. (A–C) DA closure in untreated wild-type pups after delivery; immediate newborn period (A), 30 min–1 h (B), and 1–3 h of age (C) (×40). Arrowhead indicates closing DA. (D) Effect of COX inhibitors on in utero DA patency. Wild-type pups exposed to indomethacin or celecoxib before delivery were scored for the degree of DA constriction. (E–H) Brightfield (E and F) and darkfield (G and H) in situ hybridization images of 35S-labeled COX-1 (G) and COX-2 (H) mRNA in the fetal ductus arteriosus before delivery on the morning of day 19 (×40). Atria (A), ventricle (V), main pulmonary artery (MPA), branch pulmonary artery (BPA), ductus arteriosus (DA), and aorta (AO) are shown.