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Articles in PresS, published online ahead of print July 3, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00607.2001
Submitted on December 20, 2001
Accepted on June 25, 2002
1 Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
2 Toronto General Research Institute, Toronto, Ontario, Canada; Departments of Obstetrics and Gynecology and Physiology, University of Toronto, Toronto, Ontario, Canada
3 Program in Development and Fetal Health, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Departments of Obstetrics and Gynecology and Physiology, University of Toronto, Toronto, Ontario, Canada
* To whom correspondence should be addressed. E-mail: Lye{at}mshri.on.ca.
Evidence indicates that stretch of the uterus imposed by the growing fetus contributes to the onset of labor. Previously we have shown that mechanically stretching rat myometrial smooth muscle cells (SMCs) induces c-fos expression. To investigate this stretch-induced signaling we examined the involvement of the mitogen-activated protein kinase (MAPK) family. We show that stretching rat myometrial SMCs induces a rapid and transient phosphorylation (activation) of MAPKs: extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. Use of selective inhibitors for the ERK pathway (PD98059 and U0126), p38 (SB203580) and JNK pathway (curcumin) demonstrated that activation of all three MAPK signaling pathways was necessary for optimal stretch-induced c-fos expression. We also demonstrate that upstream tyrosine kinase activity is involved in the mechanotransduction pathway leading to stretch-induced MAPK activation and c-fos mRNA expression. To further examine the role of MAPKs in vivo we used a unilaterally pregnant rat model. MAPKs (ERK and p38) are expressed in the pregnant rat myometrium with maximal ERK and p38 phosphorylation occurring in the 24 hours immediately preceding labour. Importantly, the rise in MAPK phosphorylation was confined to the gravid horn and absent in the empty uterine horn, suggesting that mechanical strain imposed by the growing fetus controls MAPK activation in the myometrium. Collectively this data indicate that mechanical stretch modulates MAPK activity in the myometrium leading to c-fos expression.
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