Regulation of Angiogenesis and Decidualization by Sex Steroid Hormones in Human Endometrium

The human endometrium undergoes remarkable cyclic growth and regeneration in response to the female sex steroids estrogen (E) and progesterone. Local autocrine and paracrine molecules that vary periodically during the menstrual cycle have been suggested to play various roles in uterine function. Endometrial growth and repair after menstruation are associated with profound angiogenesis. Several mediators regulate angiogenesis, including, vascular endothelial growth factor (VEGF), soluble VEGF receptor 1 (sVEGFR-1) as a VEGF antagonist, and stromal cell-derived factor 1 (SDF-1/CXCL12). <database size limit exceeded - text deleted> Real-time PCR analyses revealed a significant increase in PC6 mRNA levels in ESCs treated with E plus P during decidualization. On the other hand, E alone did not increase PC6 mRNA expression. Using an antisense morpholino approach, PRL production, a typical marker for decidualization, was significantly attenuated in decidualized ESCs following treatment with PC6 morpholino antisense oligonucleotides in comparison to controls. These results suggest that PC6 plays a key role for decidualization in human endometrium. With the use of real-time PCR, we have studied the expression levels of VEGF, SDF-1, IL-15, Fibulin-1, and PC6 mRNA in receptive phase endometria from 31 idiopathic infertile patients. The patients were categorized as follows: Group A had never been pregnant; Group B had become pregnant after intercourse and IUI; Group C had become pregnant after IVF and ICSI. There were no statistically significant differences regarding the expression of VEGF, SDF-1, and PC6 mRNA in all groups. The levels of IL-15 and Fibulin-1 mRNA were significantly decreased in Group B with regard to Group A and C. Significantly decreased levels of these transcripts in human endometria may be associated with implantation failure. Our findings contribute not only on the insight into mechanisms of key reproductive processes such as decidualization and the establishment and maintenance of early pregnancy, but also on future clinical applications for implantation failure.