Research ArticlePRETERM LABOR

The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy

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Science Translational Medicine  23 Dec 2015:
Vol. 7, Issue 319, pp. 319ra204
DOI: 10.1126/scitranslmed.aad0376

TRPing up preterm labor

The biology of preterm labor, the leading cause of perinatal complications and deaths worldwide, is not yet well understood, and there is no effective treatment. Ying et al. have now uncovered the role of a calcium channel called TRPV4 (transient receptor potential vanilloid 4) in uterine contractility. The amount of TRPV4 gradually increases throughout gestation, explaining its ability to facilitate uterine contractions at term despite maintaining uterine quiescence earlier in pregnancy. The authors also demonstrated that blocking TRPV4 successfully prolonged pregnancy in two mouse models of preterm labor, suggesting that it may be a viable target for interventions to treat preterm labor in human patients.


The importance of gaining insight into the mechanisms underlying uterine quiescence and contractility is highlighted by the absence of an effective strategy to prevent or treat preterm labor, the greatest cause of perinatal mortality and morbidity worldwide. Although current evidence suggests that in myometrial smooth muscle cells (mSMCs) calcium homeostasis is modulated near term to promote uterine contractility, the efficacy of blocking voltage-operated calcium channels is limited by dose-related cardiovascular side effects. Thus, we considered whether uterine contractility might be modulated by calcium entry via transient receptor potential vanilloid 4 (TRPV4) channels. In mSMC, TRPV4 gene and protein expression increased with gestation, and TRPV4-mediated Ca2+ entry and contractility were increased in mSMC from pregnant compared to nonpregnant rats. Cell membrane TRPV4 expression was specifically increased, whereas the expression of β-arrestin-1 and β-arrestin-2, molecules that can sequester TRPV4 in the cytoplasm, decreased. Physical interaction of β-arrestin-2 and TRPV4 was apparent in nonpregnant, but absent in pregnant, mouse uterus. Moreover, direct pharmacologic activation of TRPV4 increased uterine contraction, but oxytocin-induced myometrial contraction was blocked by pharmacologic inhibition of TRPV4 and decreased in mice with global deletion of TRPV4. Finally, TRPV4 channel blockade prolonged pregnancy in two distinct in vivo murine models of preterm labor, whereas the absence of either β-arrestin-1 or β-arrestin-2 increased susceptibility to preterm labor. These data suggest that TRPV4 channel activity modulates uterine contractility and might represent a therapeutic target to address preterm labor.

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