A Role for the Transient Receptor Potential Vanilloid 4 Channel in Modulating Uterine Tone During Pregnancy

BACKGROUND The mechanisms responsible for the sustained myometrial smooth muscle cell (mSMC) contraction in active labor are incompletely understood. Transient receptor potential vanilloid (TRPV) channels are a novel class of non‐voltage gated membrane cation channels activated by swelling, stretch, and osmotic stimuli. Previously, we demonstrated that TRPV4 channel expression in mSMC increases with gestation in rats and mouse and that TRPV4 protein expression increases disproportionately more in the membrane than cytosolic fraction of mSMC. OBJECTIVE We hypotheses that TRPV4 channel plays a role in oxytocin induced increases in mSMC cytosolic calcium and modulates uterine contractility. DESIGN/METHODS Uterine muscle strips were isolated and stimulated with oxytocin, in the presence and absence of the TRPV4 channel antagonist HC 067047 and measured the contraction responses. Control wild‐type (WT) C57/B6, TRPV4 knockout (TRPV4 −/− ) mice were used. Contraction tracings were recorded using the POLYVIEW. The area under the curve was calculated for the final 3 minutes of each 9‐minute contraction tracing using the LabChart Reader Software. The area under the curve for each response was then normalized to the area under the curve for the spontaneous contraction pattern over the 5‐minutes period that immediately preceded the challenge. RESULTS To test the hypothesis that TRPV4 channel activity modulates the uterine contractile response to oxytocin, we studied the contractile response of uterine muscle strips from pregnant (day 18) WT mice exposed to increasing concentrations of oxytocin (1–1000 nM) from 1.08fold±0.96 to 3.30fold±0.39 (Area under curve, mean±SE) in the presence and absence of a specific TRPV4 channel antagonist HC 067047 (from 1.05fold±0.66 to 1.88fold±0.33), as well as the contractile response to the TRPV4 agonist, GSK1016790A. To further clarify the role of the TRPV4 channel in uterine contractility, we measured the contractile response of uterine strips derived from pregnant (day 18) TRPV4 null mice to oxytocin. Uterine strips from WT mice demonstrated a dose‐dependent contractile response to oxytocin that was attenuated by pharmacologic blockade of the TRPV4 channel. The TRPV4 channel agonist caused a dose‐dependent increase in uterine contractility. Uterine strips from TRPV4 null mice were less responsive to oxytocin than uterine strips from WT mice. CONCLUSIONS TRPV4 channel activity or expression increase oxytocin‐induced myometrial strips contraction.