title: The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy.
abstract: 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 Ca(2+) 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.
authors.affiliation: Center for Excellence in Pulmonary Biology, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Ying
authors.affiliation: Pôle Mère, Département de Gynécologie Obstétrique, Centre Hospitalier de Calais, Calais 62100, France.
authors.forename: Margaux
authors.initials: M
authors.lastname: Becard
authors.affiliation: Departments of Pediatrics and Obstetrics and Gynecology, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Deirdre
authors.initials: D
authors.lastname: Lyell
authors.affiliation: Department of Urology, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Urology, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Linda
authors.initials: L
authors.lastname: Shortliffe
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Nevada, Reno, CA 89557, USA.
authors.forename: Cristiana Iosef
authors.initials: CI
authors.lastname: Husted
authors.affiliation: Center for Excellence in Pulmonary Biology, Stanford University Medical School, Stanford, CA 94305, USA. Divisions of Pulmonary, Asthma and Sleep Medicine, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Alvira
authors.affiliation: Center for Excellence in Pulmonary Biology, Stanford University Medical School, Stanford, CA 94305, USA. Divisions of Pulmonary, Asthma and Sleep Medicine, Stanford University Medical School, Stanford, CA 94305, USA. Division of Critical Care Medicine, Stanford University Medical School, Stanford, CA 94305, USA.
authors.forename: David N
authors.initials: DN
authors.lastname: Cornfield
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005782:Gels; D017353:Gene Deletion; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D008070:Lipopolysaccharides; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009215:Myometrium / Q000166:cytology; D007752:Obstetric Labor, Premature; D010121:Oxytocin / Q000494:pharmacology; D011247:Pregnancy; D011485:Protein Binding / Q000187:drug effects; D017207:Rats, Sprague-Dawley; D050916:TRPV Cation Channels / Q000378:metabolism*; D014590:Uterine Contraction / Q000187:drug effects; D014599:Uterus / Q000187:drug effects / Q000502:physiology*; D000071557:beta-Arrestins / Q000378:metabolism
chemical_list: D005782:Gels; D008070:Lipopolysaccharides; D050916:TRPV Cation Channels; D000071557:beta-Arrestins; D010121:Oxytocin; D003094:Collagen; D002118:Calcium