Role of cAMP/PKA/CREB pathway and β-arrestin 1 in LH induced luteolysis in pregnant rats

Luteal dysfunction in pregnant women is associated with early pregnancy loss, making the study of structure and function of the corpus luteum (CL) critical. Luteinizing hormone (LH) plays a crucial role in the mammalian female reproduction majorly by regulating luteal development. In rats, the luteotropic roles of LH have been widely investigated but its role in the process of luteolysis has received little attention. In this study, we explored the luteolytic actions of LH during different stages of pregnancy in rats. Repeated administration of LH during the late and mid-stages of pregnancy led to functional luteolysis during both stages, while structural luteolysis was observed only during the late-stage. We analyzed the involvement of cAMP/PKA/CREB pathway, MAP kinases and beta-arrestins to elucidate the molecular mechanism of LH-mediated luteolysis. The results indicate that the repeated administration of LH causes LH/CGR desensitization along with an increase in beta-arrestin 1 expression, while luteal expression of MAP kinases remained unaffected. Further, siRNA-mediated depletion of beta-arrestin 1 in primary luteal-cell cultures prevents initiation of the luteolysis process to some extent during both the stages of pregnancy, underscoring its role in LH mediated-luteolysis. In conclusion, the luteolytic actions of LH appear to involve more than one signaling pathway and cAMP/PKA/CREB pathway appears to be the key regulator. This is the first report to show a positive correlation between beta-arrestin 1 and 20 alpha-hsd expression. These findings have implications for our understanding of the molecular pathways that regulate luteolysis.

Automated summary

This study investigated the luteolytic actions of LH in rats during different stages of pregnancy, revealing that LH mediates luteolysis through multiple signaling pathways, with the cAMP/PKA/CREB pathway playing a key role. Additionally, a positive correlation between beta-arrestin 1 and 20α-HSD expression was found for the first time in this study, indicating its potential role in LH-mediated luteolysis.