Kisspeptin/KISS1R signaling potentiates extravillous trophoblast adhesion to type-I collagen in a PKC- and ERK1/2-dependent manner.

During the first trimester of human pregnancy, cytotrophoblasts proliferate within the tips of the chorionic villi to form cell columns that anchor the placenta to the uterus. This migration coincides with a widespread change in the adhesion molecule repertoire of these trophoblasts. Kisspeptin and its receptor, KISS1R, are best known as potent triggers of gonadotropin-releasing hormone secretion. The kisspeptin/KISS1R signaling system is also highly expressed in the human placenta, where it was demonstrated to inhibit extra-villous trophoblast (EVT) migration and invasion in vitro. Here we show that kisspeptin, in a dose- and time-dependent manner, induces increased adhesion of human EVTs to type-I collagen, a major component of the human placenta. This increased adhesion was both rapid and transient, suggesting that it likely occurred through the activation of KISS1R secondary effectors such as PKC and ERK, which underwent rapid and transient kisspeptin-dependent activation in EVTs. We then showed that inhibition of both PKC and ERK1/2 attenuated the kisspeptin-dependent increase in EVT adhesion, suggesting that these molecules are key positive regulators of trophoblast adhesion. We therefore propose that kisspeptin/KISS1R signaling potentiates EVT adhesion to type-I collagen via "inside-out signaling." Furthermore, kisspeptin treatment increased mouse blastocyst adhesion to collagen I, suggesting that kisspeptin signaling is a key regulator of trophoblast function during implantation as well as early placentation.