The Role of Erk1/2 in Uterine Contractility and Preterm Labor in Rats

The present study tested the hypothesis that ERK activation is an essential step in the onset of labor in a rat model of preterm labor. The administration of RU486, an antiprogesterone agent, to rats induced preterm delivery 22.2±0.24 hrs after treatment. Changes in basal signaling events were studied in myometrial tissue taken from CO2 euthanized rats. Rats treated with RU486 displayed a dramatically increased in vitro uterine contractility compared to gestational stage matched, sham treated rats. In vitro contractility was not significantly different from that during spontaneous labor. During RU486-induced preterm labor, as previously described for spontaneous labor, ERK phosphorylation levels increased as did phosphorylation of caldesmon (CaD) at Ser, an ERK phosphorylation site. Also, a small but significant increase in myosin light chain phosphorylation (LC20-P) was seen at a constant intracellular pCa of 7. When rats were chronically treated with an agent that prevents ERK activation, U0126, the onset of RU486-induced preterm labor was delayed in a statistically significant manner. Chronic in vivo treatment with U0126 also significantly inhibited the RU486-induced increase in in vitro contractility, ERK and CaD phosphorylation, but did not alter the RU486-induced increase in LC20-P level. These data indicate that ERK activation is a component of the multiple events leading to the development of labor in this rat model. We suggest that the ERK pathway could possibly be used to identify targets for the development of a novel class of tocolytic agents.