Prostaglandin-nuclear receptor-angiogenic signaling axis during embryo implantation with special emphasis on the uterine cPLA2α-Cox2-PPARδ-Vegf network.
Research has long indicated that prostaglandins (PGs) play a role in female reproduction, but the exact processes involved are not well understood. Our lab is working to better understand the roles played by various Cox-2 derived PGs in the uterus. We discovered that Cox-2-derived PGI plays a critical role in embryo implantation, through activation of PPARδ.
Cytokine-growth factor-homeobox-morphogen signaling axis in embryo implantation involving the Lif-Hb-Egf-Hoxa10 / Msx1-Ihh / Bmp / Wnt network in the uterus.
Successful implantation relies on intricate coordination between the blastocyst and the uterus. Our lab has examined the roles different growth factor pathways play in this process. We showed that uterine HB-EGF plays a role in implantation (implantation was compromised in mice conditionally deleted of uterine HB-EGF), and determined that amphiregulin could prevent loss of pregnancy in this scenario. We showed that implantation was compromised in mice conditionally deleted of uterine HB-EGF, though amphiregulin could prevent loss of pregnancy.
Immunophilin / co-chaperone-nuclear signaling involving FKBP52-PR during implantation in the mouse uterus.
FKBP52, an immunophilin co-chaperone for PR, is critical for embryo implantation. Deficiency of FKBP52 results in implantation failure. This failure can be rescued in certain genetic backgrounds by progesterone supplementation. Since FKBP52, but not PR, is expressed in the placenta, FKBP52 could have functions independent of PR. Our laboratory is currently working to define these alternative functions in pregnancy maintenance.
Ligand-receptor signaling with endocannabinoids during peri-implantation events in mice, in the context of anandamide interacting with G-protein coupled receptors CB1 and CB2.
Endocannabinoids, a group of endogenously produced cannabinoid-like lipid molecules that activate G-protein coupled cannabinoid receptors, have been shown to play a critical role in various female reproductive events. There are two cannabinoid receptors: CB1, which is found in the testes and uterus, and CB2, which is found in the spleen and immune cells. More is understood about the role CB1 plays in the early stages of pregnancy than CB2. Embryos exposed to elevated levels of endocannabinoids or synthetic or natural cannabinoids show severe growth retardation, but can be rescued by the administration of a CB1, but not CB2, antagonist. Additionally, it appears that the absence of CB1 leads to oviductal retention of embryos, as does excessive exposure to THC. Endocannabinoid levels, primarily anandamide, are also tightly regulated during embryo implantation. Although the specifics of endocannabinoid signaling are not known, it appears a fine balance of endocannabinoid levels is needed to ensure successful pregnancy.