Impaired Gq signaling underlies oxytocin hyporesponsiveness in LPS and poly I:C-induced preterm labor in mice

Abstract

The regulation of oxytocin signaling in preterm labor remains poorly understood. In this study, we investigated uterine responsiveness to oxytocin in a combined lipopolysaccharide (LPS) and polyinosinic:polycytidylic acid (poly I:C)-induced preterm labor (PTL) model in mice and explored the underlying mechanisms. Administration of poly I:C followed by LPS triggered PTL within 8 h, accompanied by pronounced inflammatory cell infiltration in the amniotic fluid and uterine tissue. PTL was associated with upregulated expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), chemokines (CCL3, CCL4, CXCL1), and contraction-associated proteins (COX-2/Ptgs2, connexin 43/Gja1), along with increased cervical MMP-9 activity. Functionally, spontaneous uterine contractions and responses to 80 mM KCl were significantly elevated in both preterm non-laboring (PT NL) and preterm laboring (PT L) mice, whereas CaCl₂-induced contractions remained unchanged. In contrast, oxytocin-induced contractions were markedly suppressed across a wide concentration range (10^-12-10^-6 M) in both PT NL and PT L groups. Despite elevated oxytocin receptor expression and activation, the Gqα subunit showed significant reductions in both mRNA and protein levels in PT NL and PT L mice. Similarly, responsiveness to another Gq activator, PGF_2α, was diminished. These findings indicate that impaired Gq protein-mediated signaling, rather than oxytocin receptor downregulation, underlies oxytocin hyporesponsiveness in this inflammatory model of preterm labor, providing new insights into signaling dysregulation and potential mechanisms for therapeutic intervention.

Keywords: GRK6; Gq protein; LPS; Oxytocin; Poly I:C; Preterm labor; Uterus; β-arrestin.