cGMP-dependent protein kinase II determines β-catenin accumulation that is essential for uterine decidualization in mice

Abstract

In the early phase of pregnancy, decidualization is an indispensable event after mammal embryo implantation, accompanied by proliferation and differentiation of uterine stromal cells. Type II cGMP-dependent protein kinase (Prkg2) belongs to the family of serine/threonine kinase, which plays multiple roles in cellular signaling pathways to control proliferation and differentiation. However, the regulatory function and molecular mechanism of Prkg2 in decidualization are still unknown. In this study, we show that Prkg2 has a gradually increased expression pattern during peri-implantation and artificial decidualization, and the expression of Prkg2 is induced by estrogen and progesterone in the ovariectomized mouse uteri and primary cultured uterine stromal cells, the process of which is blocked by treating with estrogen receptor (ER) antagonist (ICI-182,780) and progesterone receptor (PR) antagonist (RU-486). Inhibition of Prkg2 activity by HA-100 promotes uterine stromal cell proliferation but compromises decidualization with decreased expression of prolactin family 8, subfamily a, member 2. In addition, the functional regulation of decidualization by Prkg2 is accomplished by its induced phosphorylation of glycogen synthase kinase-3β (GSK-3β) at serine-9, which results in accumulation of β-catenin in the decidual cells. Taken together, our findings demonstrate that estrogen and progesterone upregulate the expression of Prkg2 in uterine stromal cells depending on ER and PR; Prkg2 promotes phosphorylation of GSK-3β at serine-9 and inactivates it, leading to the accumulation of β-catenin and promoting the process of decidualization. In addition to revealing the regulatory mechanism of Prkg2 that ensures the success of uterine decidualization, our findings will contribute to the understanding in the maintenance of early pregnancy.

Sildenafil Citrate Downregulates PDE5A mRNA Expression in Women with Recurrent Pregnancy Loss without Altering Angiogenic Factors—A Preliminary Study

“…It also improves NK activity [ 36 ]. The shortage of cGMP in the cells of RPL patients may disturb NO release and, subsequently, cause an inadequate cytotrophoblast invasion of the uterine spiral arteries and endometrium growth, as well as embryonic cell proliferation decrease [ 12 , 47 , 48 , 49 ]. The downregulation of PDE5 gene expression by SC may restore the required level of cGMP and improve NO production demanded during trophoblast implantation.…”

Novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

“…PRKG2 , the closest gene to the lead female-associated variant, is induced by estrogen and progesterone. 115 Interestingly, estrogen has been reported as having protective effects in glaucoma. 116 Fourteen additional loci show significant effect size differences between ancestries, three of which also have significant difference in effect between males and females.…”

Genome-wide association meta-analysis identifies novel ancestry-specific primary open-angle glaucoma loci and shared biology with vascular mechanisms and cell proliferation

“…PRKG2, the closest gene to the lead female associated variant, is induced by estrogen and progesterone. 147 Interestingly, estrogen has been reported as having protective effects in glaucoma. 148 14 additional loci show significant effect size differences between ancestries, three of which also have significant difference in effect between males and females.…”