3.4.3. Endometrial Control of Blastocyst Invasion

In all the placental species the extent of endometrial decidualization is proportional to the invasiveness of the embryo. The human placenta is the most invasive one known so far, and it has been suggested that the unique invasiveness of the human trophoblast could be due to its high production of hyperglycosylated CG isoform, which is maximal in the first weeks of pregnancy [282,283].

In order to limit the extent of trophoblast invasion, both trophoblast and endometrium balance the expression of growth factors, cytokines, and enzymes. As an example, maternal endometrium increases the production of tissue inhibitors of MMPs (TIMPs), due to a spatial and temporal regulation of cytokines and growth factors, such as IL-10 [284], TGFβ and IL-1α [268]. While IL-1α significantly increases the activity of MMP-9 and MCSF increases MMP-9 immunoreactivity, TGFβ inhibits total gelatinolytic activity, MMP-9 activity and immunoreactivity [268]. TIMP-3, which is up-regulated by progesterone, plays a major role in restricting trophoblast invasion by limiting ECM degradation, and its expression has been detected in the fetal extravillous trophoblast, as well as in the maternal endometrial cells [285,286]. On the contrary, by in situ hybridization in implanting mouse embryos no expression was observed for TIMP-1 or TIMP-2 in the embryo proper, trophoblasts, or in the decidua. Weak signals were demonstrated for TIMP-1 only in the circular layer of myometrial smooth muscle and in some uterine stroma cells distant from the site of embryo implantation. Moreover, the expression of TIMP-1 and TIMP-2 is not dependent on the stage of the menstrual cycle [286]. Trophoblast invasion is promoted by the action of the plasminogen activator (PA) system since it is able to promote trophoblast invasion, by converting plasminogen into the active serine protease plasmin, which in turn, degrades ECM [287]. In endometrial cells, TGFβ regulates trophoblast invasion up-regulating the expression of plasminogen activator inhibitor-1 (PAI-1), which is the main inhibitor of urokinase-type plasminogen activator (uPA) [288–290], and decorin, a decidua-derived TGFβ binding proteoglycan, which inhibits proliferation, migration and invasion of trophoblast cells [291]. The blastocyst is completely embedded in the uterine stroma 8 days after fertilization and the site of entry is covered by fibrin, over which the uterine epithelial cells grow [233,292,293].
