title: Prostacyclin receptor up-regulates the expression of angiogenic genes in human endometrium via cross talk with epidermal growth factor Receptor and the extracellular signaling receptor kinase 1/2 pathway.
abstract: Prostacyclin (PGI) is a member of the prostanoid family of lipid mediators that mediates its effects through a seven-transmembrane G protein-coupled receptor (IP receptor). Recent studies have ascertained a role for prostanoid-receptor signaling in angiogenesis. In this study we examined the temporal-spatial expression of the IP receptor within normal human endometrium and additionally explored the signaling pathways mediating the role of IP receptor in activation of target angiogenic genes. Quantitative RT-PCR analysis demonstrated the highest endometrial expression of the IP receptor during the menstrual phase compared with all other stages of the menstrual cycle. Immunohistochemical analysis localized the site of IP receptor expression to the glandular epithelial compartment with stromal and perivascular cell immunoreactivity. Expression of the immunoreactive IP receptor protein was greatest during the proliferative and early secretory phases of the menstrual cycle. To explore the role of the IP receptor in glandular epithelial cells, we used the Ishikawa endometrial epithelial cell line. Stimulation of Ishikawa cells and human endometrial biopsy explants with 100 nm iloprost (a PGI analog) rapidly activated ERK1/2 signaling and induced the expression of proangiogenic genes, basic fibroblast growth factor, angiopoietin-1, and angiopoietin-2, in an epidermal growth factor receptor (EGFR)-dependent manner. Furthermore, EGFR colocalized with IP receptor in the glandular epithelial compartment. These data suggest that PGI-IP interaction within glandular epithelial cells can promote the expression of proangiogenic genes in human endometrium via cross talk with the EGFR.
authors.affiliation: Medical Research Council Human Reproductive Science Unit, Centre for Reproductive Biology, Queen's Medical Research Institute, Edinburgh, Scotland, UK.
authors.forename: Oliver P Milling
authors.initials: OP
authors.lastname: Smith
authors.forename: Sharon
authors.initials: S
authors.lastname: Battersby
authors.forename: Kurt J
authors.initials: KJ
authors.lastname: Sales
authors.forename: Hilary O D
authors.initials: HO
authors.lastname: Critchley
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
mesh_terms: D042683:Angiopoietin-1 / Q000235:genetics; D042702:Angiopoietin-2 / Q000235:genetics; D045744:Cell Line, Tumor; D004717:Endometrium / Q000378:metabolism*; D066246:ErbB Receptors / Q000502:physiology*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000235:genetics; D005786:Gene Expression Regulation; D006801:Humans; D016285:Iloprost / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D010766:Phosphorylation; D044006:Receptors, Epoprostenol / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: C467630:ANGPT1 protein, human; D042683:Angiopoietin-1; D042702:Angiopoietin-2; D044006:Receptors, Epoprostenol; D016222:Fibroblast Growth Factor 2; D066246:ErbB Receptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D016285:Iloprost