Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition
Lu Gao, … , Bert W. O’Malley, Carole R. Mendelson
Lu Gao, … , Bert W. O’Malley, Carole R. Mendelson
Published June 22, 2015
Citation Information: J Clin Invest. 2015;125(7):2808-2824. https://doi.org/10.1172/JCI78544.
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Research Article Reproductive biology

Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

Abstract

The precise mechanisms that lead to parturition are incompletely defined. Surfactant protein-A (SP-A), which is secreted by fetal lungs into amniotic fluid (AF) near term, likely provides a signal for parturition; however, SP-A–deficient mice have only a relatively modest delay (~12 hours) in parturition, suggesting additional factors. Here, we evaluated the contribution of steroid receptor coactivators 1 and 2 (SRC-1 and SRC-2), which upregulate SP-A transcription, to the parturition process. As mice lacking both SRC-1 and SRC-2 die at birth due to respiratory distress, we crossed double-heterozygous males and females. Parturition was severely delayed (~38 hours) in heterozygous dams harboring SRC-1/-2–deficient embryos. These mothers exhibited decreased myometrial NF-κB activation, PGF2α, and expression of contraction-associated genes; impaired luteolysis; and elevated circulating progesterone. These manifestations also occurred in WT females bearing SRC-1/-2 double-deficient embryos, indicating that a fetal-specific defect delayed labor. SP-A, as well as the enzyme lysophosphatidylcholine acyltransferase-1 (LPCAT1), required for synthesis of surfactant dipalmitoylphosphatidylcholine, and the proinflammatory glycerophospholipid platelet-activating factor (PAF) were markedly reduced in SRC-1/-2–deficient fetal lungs near term. Injection of PAF or SP-A into AF at 17.5 days post coitum enhanced uterine NF-κB activation and contractile gene expression, promoted luteolysis, and rescued delayed parturition in SRC-1/-2–deficient embryo-bearing dams. These findings reveal that fetal lungs produce signals to initiate labor when mature and that SRC-1/-2–dependent production of SP-A and PAF is crucial for this process.

Authors

Lu Gao, Elizabeth H. Rabbitt, Jennifer C. Condon, Nora E. Renthal, John M. Johnston, Matthew A. Mitsche, Pierre Chambon, Jianming Xu, Bert W. O’Malley, Carole R. Mendelson

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Figure 7

Rescue of parturition delay in SRC-1/SRC-2 dhet females bred to SRC-1/-2 dhet males is associated with increased myometrial PGF2α synthesis and decreased ovarian P4 production.

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Rescue of parturition delay in SRC-1/SRC-2 dhet females bred to SRC-1/-2...
(A) Akr1b3 mRNA (n = 6 per group) and (B) protein (n = 3 for WT, PBS, and SP-A; n = 4 for PAF) in myometrium. The same immunoblot of β-actin was used for normalization of PGDH (D), which was probed on the same blot. (C) PGDH mRNA (n = 6 per group) and (D) protein (n = 3 for WT, PBS, and SP-A; n = 4 for PAF) in myometrium. (E) PGF2α levels in myometrial homogenates for WT or SRC-1/-2 mice injected i.a. with PBS, SP-A, or PAF (n = 8 per group). In the box-and-whisker plot, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate 10th and 90th percentiles. (F) StAR protein in ovaries of WT (n = 3) or SRC-1/-2 dhet females × SRC-1/-2 dhet males injected i.a. with PBS (n = 3), SP-A (n = 3), or PAF (n = 4). (G) Maternal serum P4 levels, measured by ELISA, of 18.5 dpc WT females × WT males or SRC-1/-2 dhet females × SRC-1/-2 dhet males injected i.a. with PBS, SP-A, or PAF (n = 8 per group). (H) Proposed cooperative roles of SRC-1 and SRC-2 in the initiation of labor through regulation of SP-A and Lpcat1 gene expression. Data are the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, compared with WT; #P < 0.05, ##P < 0.01, ###P < 0.001, ####P < 0.0001 compared with PBS injection (ANOVA).