The role of the mTOR signaling pathway in myometrial differentiation

The mTOR (mammalian Target Of Rapamycin) signaling pathway regulates cellular growth and proliferation in many tissues. We hypothesized that mTOR was a mediator of myometrial hyperplasia during gestation. The activation status of mTOR and its upstream regulators and downstream effectors, as well as the proliferative activity of the uterine myocytes, was analyzed throughout normal pregnancy in rats. An ovariectomized (OVX) rat model was used to analyze the modulation of the mTOR pathway and proliferative activity of the uterine myocytes by estrogen. The mTOR pathway was up-regulated in the rat myometrium during the proliferative phase of pregnancy, while inhibition of mTOR signaling by rapamycin blocked the proliferation. Rapamycim also blocked the estrogen-induced and IGF-1 mediated up-regulation of the mTOR pathway and reduced the number of proliferating cells in the OVX rats. These data clearly demonstrate that the mTOR pathway mediates the estrogen-induced proliferation of rat myometrial smooth muscle cells during pregnancy.