Loss of TRPV4 decreases NFκB-mediated myometrial inflammation and prevents preterm labor.

Inflammation is a key initiating event in both spontaneous term and preterm labor. However, the link between inflammation and the onset of labor remains incompletely understood. We identified the transient receptor potential vanilloid 4 (TRPV4) channel as a critical regulator of myometrial calcium (Ca2+) entry and contractility. In this study, we aimed to determine if the TRPV4 channel regulates uterine inflammation and its subsequent effects on myometrial contractility in experimental preterm labor. We demonstrated that global loss of TRPV4 protected mice against inflammation-induced preterm labor, decreased baseline myometrial contractility, and diminished lipopolysaccharide-stimulated increases in oxytocin-mediated contraction. Pharmacological inhibition of TRPV4 in human myometrial smooth muscle cells (SMC) blunted lipopolysaccharide (LPS)-induced activation of nuclear factor kappa-B (NFκB) and pro-inflammatory cytokine expression. In contrast, pharmacologic activation of TRPV4 augmented LPS-induced NFκB activation. Further, TRPV4-mediated NFκB activation was dependent on extracellular Ca2+ entry in myometrial SMC. Together, these data show that extracellular Ca2+ entry via TRPV4 potentiates NFκB-mediated inflammation and increases susceptibility to preterm labor. The ability of TRPV4 to modulate both myometrial inflammation and contractility, processes central to the onset of preterm and term labor, suggests that the TRPV4 channel may represent a novel therapeutic target for the treatment of premature birth.