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.
View: Text | PDF
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

×

Figure 3

SRC-1/-2 dhet or WT females bred to dhet or 1-KO/2-het males, respectively, manifest decreased myometrial PGF2α synthesis and delayed ovarian luteolysis.

Options: View larger image (or click on image) Download as PowerPoint
SRC-1/-2 dhet or WT females bred to dhet or 1-KO/2-het males, respectiv...
(A) Akr1b3 mRNA and (B) protein in myometrium from WT females × WT males (n = 5), WT females × 1-KO/2-het males (n = 4), and dhet females × dhet males (n = 5). Immunoblots and densitometric scans normalized to β-actin are shown. (C) PGDH mRNA and (D) protein in myometrium of WT females × WT males (n = 5), WT females × 1-KO/2-het males (n = 4), and dhet females × dhet males (n = 5). Immunoblots and densitometric scans normalized to β-actin are shown. (E) PGF2α levels in myometrial homogenates normalized to protein for WT females × WT males (n = 12), WT females × 1-KO/2-het males (n = 8) and dhet females × dhet males (n = 15). 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) Maternal serum P4, measured by ELISA for WT females × WT males (n = 12), WT females × 1-KO/2-het males (n = 8), and dhet females × dhet males (n = 14). (G) StAR protein in ovaries. Representative immunoblot of StAR, and densitometric scans of StAR immunoblots normalized to β-actin (n = 8 per group). (H) At 17 and 19 dpc, StAR immunostaining in corpus luteum of SRC-1/-2 dhet females × SRC-1/-2 dhet males (dhet) was more intense than that of WT. Three independent experiments conducted. Original magnification, ×200. Data are mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001 (ANOVA).