Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells

Abstract

. Mitogen-activated protein kinases mediate stretch-induced c-fos mRNA expression in myometrial smooth muscle cells. Am J Physiol Cell Physiol 283: C1530-C1539, 2002. First published July 3, 2002 10.1152 10. /ajpcell.00607.2001 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 NH 2-terminal kinase (JNK), and p38. The use of selective inhibitors for the ERK pathway (PD-98059 and U-0126), p38 (SB-203580), 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 h immediately preceding labor. Importantly, the rise in MAPK phosphorylation was confined to the gravid horn and was 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.

Estrogen receptor (ER) expression and function in the pregnant human myometrium: estradiol via ERα activates ERK1/2 signaling in term myometrium

“…Myometrial ERK2 phosphorylation increased significantly with advancing GA in accordance with previously reported results in the pregnant rat uterus (Oldenhof et al 2002, Serrano-Sanchez et al 2008. We observed no change in ERK1/2 phosphorylation in the myometrium with labor, which agrees with a previous report on the rat myometrium (Oldenhof et al 2002) but differs from that of Li et al (2003) who reported increased ERK2 phosphorylation in the rat uterus during labor.…”

“…We observed no change in ERK1/2 phosphorylation in the myometrium with labor, which agrees with a previous report on the rat myometrium (Oldenhof et al 2002) but differs from that of Li et al (2003) who reported increased ERK2 phosphorylation in the rat uterus during labor. While total ERK protein levels do not appear to change in the rat myometrium with pregnancy or labor (Li et al 2003), we saw a decrease in total ERK in human myometrium with advancing gestation.…”

“…In pregnant rats, the abundance of activated ERK in myometrial cells increases with gestation (Oldenhof et al 2002, Serrano-Sanchez et al 2008 and labor onset (Li et al 2003). In animals induced to deliver preterm (PT) by administration of the progesterone receptor antagonist RU486, concurrent inhibition of ERK signaling delayed preterm labor and decreased myometrial contractility (Li et al 2004).…”

Monocyte Chemoattractant Protein-1 (CCL-2) Integrates Mechanical and Endocrine Signals That Mediate Term and Preterm Labor

“…The stretch unit consists of a computer-controlled vacuum unit and a base plate to hold the 6-well culture dishes, which is placed in a humidified incubator with 5% CO 2 at 37°C. Static strain was applied by deforming the membrane with 150 mm Hg of vacuum pressure, which produces a maximal 25% stretch equal to the average 10% elongation (29). Control cells were cultured under identical conditions but remained stationary.…”

Gene and protein expression in the myometrium in pregnancy and labor

“…Mechanical stretch of the rat uterus stimulates myometrial cell hypertrophy (Douglas et al 1988) via a mechanism involving integrin/focal adhesion/MAPK cascades (Macphee & Lye 2000). Activation of MAPKs is necessary for optimal stretch-induced c-fos expression (Oldenhof et al 2002). In addition, the spatial expression of MAPK p38 and ERK-1/2 in conjunction with ATF2 isoforms within the human uterine corpus during pregnancy and labor is likely to be important in preparation of the uterus for labor (Otun et al 2005).…”