*2.6. NOTCH Signaling Pathway*

NOTCH signaling pathway is involved in the regulation of various cellular processes such as cell proliferation, invasion, adhesion, survival, apoptosis and differentiation [164–167]. All four NOTCH receptors, the ligands Jagged1 (JAG1) and Delta-like (DLL) 4 and the target genes hairy enhancer of split (HES) and Hes-related 1 (HEY1) are known to be expressed by the endometrium [168–171]. Several ligands and receptors of the NOTCH signaling pathway are expressed in both the inner cell mass (ICM) and trophectoderm of the human blastocyst [172–174]. NOTCH1 plays an important role in the process of decidualization, by inducing pro-survival signals in the endometrium, thus avoiding apoptosis normally occurring at the end of the menstrual cycle. Hess et al. showed that blastocyst-conditioned medium induces an increase in the expression of NOTCH family members in decidual cells, suggesting a role for this pathway in decidualization [175]. Moreover, it has recently been shown that NOTCH signaling pathway is dysregulated in the endometrium of women with unexplained recurrent pregnancy loss [176]. Activation of NOTCH1 pathway in the endometrium is stimulated by CG and progesterone and leads to increased expression of α-SMA and Forkhead box protein O1 (FOXO1) [1,128,177]. FOXO1, in turns, induces expression of PRL and IGFBP1 and it is essential for the decidualization process [178–182]. NOTCH1 is involved in the inhibition of cAMP/protein kinase A (PKA) signaling pathway [183], so that NOTCH1 has to be downregulated to allow cAMP response of stromal cells. Similar to what described for α-SMA and LHCGR expression, a downregulation of NOTCH1 is necessary for the induction of IGFBP1 and the completion of decidualization [111,120,128].
