Understanding the mechanism of oxytocin-induced uterine contractility is critical for addressing conditions at both extremes of the uterine contractility spectrum, preterm labour and uterine atony. We hypothesized that oxytocin induces extracellular calcium influx and uterine contraction through activation of the transient receptor potential vanilloid 4 (TRPV4) channel. To test this hypothesis, uterine tissue was obtained with informed consent from pregnant patients undergoing term, non-labouring caesarean delivery. In human myometrial tissue and smooth muscle cells in primary culture (mSMCs), TRPV4 and oxytocin receptor (OXTR) proteins colocalize at distances less than 40 nm. In mSMCs, both pharmacological blockade of TRPV4 and TRPV4 depletion via small interfering RNA prevent oxytocin-induced calcium influx and contraction. In contrast, voltage-gated calcium channel blockade does not diminish oxytocin-induced calcium transients. Pharmacological blockade of OXTR has no effect on TRPV4 agonist-induced calcium influx or contractility. In uterine tissue from patients with oxytocin-resistant uterine atony, there is a marked reduction in glycosylated OXTR expression and in proximity ligation between OXTR and TRPV4 compared with tissue from control patients with optimal postpartum contractility. Taken together, these findings demonstrate that in the gravid uterine smooth muscle, TRPV4 activation is required for oxytocin-induced uterine contraction. They also suggest reduced OXTR-TRPV4 protein-protein interaction as a novel pathophysiological mechanism underlying uterine atony in non-labouring parturients. These findings highlight the physiological importance of oxytocin signalling via the TRPV4 channel and may motivate the development of targeted, TRPV4-focused treatments to modulate uterine contractility. KEY POINTS: Oxytocin-induced contraction in smooth muscle cells from term pregnant human myometrium requires activation of the TRPV4 calcium channel. TRPV4 and oxytocin receptor (OXTR) colocalize at <40 nM and interact functionally in myometrial smooth muscle cells. TRPV4 antagonism or siRNA-mediated TRPV4 knockdown abolishes oxytocin-induced calcium influx and contractility. In patients with oxytocin-resistant uterine atony, glycosylated OXTR quantity and TRPV4-OXTR colocalization are markedly reduced. These findings identify TRPV4 as a critical mediator of uterine contractility. TRPV4 antagonists may have a role as novel therapeutic agents for preventing or treating preterm labour.
Fornes et al. (Sat,) studied this question.