Uterine contractions depend on KIT-positive interstitial cells in the mouse: genetic and pharmacological evidence.
In the gastrointestinal tract, interstitial cells of Cajal (ICCs) generate a pacemaker activity. They produce electric slow waves that trigger and coordinate gut smooth muscle contractions. Interstitial cells of Cajal's slender shape is revealed by KIT immunostaining. Based on several features, including KIT expression and KIT dependence, ICC-like cells were identified in nongastrointestinal tissues. Here, we investigated in the mouse whether uterine contractions depend on ICC-like cells' activity. By labeling KIT-expressing cells, we found putative ICC-like cells in the uterus, observed as KIT-positive interstitial, long spindle-shaped cells with fine branched cytoplasm processes, distributed in muscular layers and in subepithelial connective tissue. We then checked the potential KIT dependence of ex vivo contractile activity of the uterus by combining genetic and pharmacological approaches, using the Kit W-v hypomorphic mutation, and imatinib as a KIT noncompetitive inhibitor. We found a significant reduction in frequency of longitudinal uterine contractions in Kit W-v/Kit W-v compared with Kit+/+ mice, whereas amplitude was unaffected. There was no difference in frequency or amplitude of circular uterine contractions between Kit W-v/Kit W-v and Kit+/+ mice. Ex vivo treatment of Kit+/+ uterine horns with imatinib resulted in a dose-dependent reduction of the frequency and amplitude of longitudinal myometrial contractions. Amplitude and frequency of circular contractions were unaffected in presence of imatinib. These concurrent results suggest that longitudinal contractions of the uterus depend on a KIT signaling pathway of ICC-like cells. The existence of ICC-like cells in the myometrium may enhance our understanding of uterine spontaneous contractile activity and suggest new approaches for treatment of uterine contractility disorders.
Allix
Sébastien
S
Institut National de la Recherche Agronomique, UMR955 de Génétique Moléculaire et Cellulaire, Ecole Nationale Vétérinaire d'Alfort, 94704 Maisons-Alfort, France.
Reyes-Gomez
Edouard
E
Aubin-Houzelstein
Geneviève
G
Noël
Delphine
D
Tiret
Laurent
L
Panthier
Jean-Jacques
JJ
Bernex
Florence
F
D000818:Animals; D001549:Benzamides; D004305:Dose-Response Relationship, Drug; D004386:Duodenum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004594:Electrophysiology; D005260:Female; D000068877:Imatinib Mesylate; D008407:Mast Cells / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009215:Myometrium / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014590:Uterine Contraction / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D014599:Uterus / Q000187:drug effects / Q000378:metabolism
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit