Uterine Gαq/11 signaling, in a progesterone-dependent manner, critically regulates the acquisition of uterine receptivity in the female mouse

A nonreceptive uterus is a major cause of embryo implantation failure. This study examined the importance of the Gαq/11-coupled class of GPCRs as regulators of uterine receptivity. Mice were created lacking uterine Gαq and Gα11; as a result, signaling by all uterine Gαq/11-coupled receptors was disrupted. Reproductive profiling of the knockout females revealed that on d 4 of pregnancy, despite adequate serum progesterone (P4) levels and normal P4 receptor (PR) expression, there was no evidence of PR signaling. This resulted in the down-regulation of heart and neural crest derivatives expressed 2, Kruppel-like factor 15, and cyclin G1 and the subsequent persistent proliferation of the luminal epithelium. Aquaporin (Aqp) 11 was also potently down-regulated, whereas Aqp5/AQP5 expression persisted, resulting in the inhibition of luminal closure. Hypertrophy of the myometrial longitudinal muscle was also dramatically diminished, likely contributing to the observed implantation failure. Further analyses reveale...