title: Cellular and molecular responses of the uterus to embryo implantation can be elicited by locally applied growth factors.
abstract: The implantation of a blastocyst into a receptive uterus is associated with a series of events, namely the attachment reaction followed by decidualization of the stroma. Previous studies established that the gene encoding heparin-binding EGF-like growth factor (HB-EGF) is expressed in the luminal epithelium solely at the site of blastocyst apposition preceding the attachment reaction. We report here the expression during implantation of 21 genes encoding other signaling proteins, including those belonging to the Bone morphogenetic protein (BMP), fibroblast growth factor (FGF), WNT, and Hedgehog (HH) pathways. We find that the attachment reaction is associated with a localized stromal induction of genes encoding BMP-2, FGF-2, and WNT-4. Despite efforts by many investigators, a simple in vitro model of implantation is not yet available to study either the hierarchy of the events triggered in the uterus by the embryo or the function of individual signaling proteins. We have therefore approached these questions by introducing beads loaded with purified factors into the receptive uterus. We show that beads soaked in HB-EGF or insulin-like growth factor-1 (IGF-1), but not other proteins, induce many of the same discrete local responses elicited by the blastocyst, including increased localized vascular permeability, decidualization, and expression of Bmp2 at the sites of the beads. By contrast, the expression domains of Indian hedgehog (Ihh), patched, and noggin become restricted as decidualization proceeds. Significantly, beads containing BMP-2 do not themselves elicit an implantation response but affect the spacing of implantation sites induced by blastocysts cotransferred with the beads.
authors.affiliation: Department of Pediatrics, University of Kansas Medical Center, Ralph L. Smith Research Center, Kansas City, KS 66160-7338, USA.
authors.forename: B C
authors.initials: BC
authors.lastname: Paria
authors.forename: W
authors.initials: W
authors.lastname: Ma
authors.forename: J
authors.initials: J
authors.lastname: Tan
authors.forename: S
authors.initials: S
authors.lastname: Raja
authors.forename: S K
authors.initials: SK
authors.lastname: Das
authors.forename: S K
authors.initials: SK
authors.lastname: Dey
authors.forename: B L
authors.initials: BL
authors.lastname: Hogan
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics* / Q000494:pharmacology; D002352:Carrier Proteins; D003656:Decidua / Q000166:cytology / Q000502:physiology*; D010064:Embryo Implantation / Q000502:physiology*; D004627:Embryonic Induction; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D053823:Hedgehog Proteins; D066257:Heparin-binding EGF-like Growth Factor; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D000072079:Patched Receptors; D011247:Pregnancy; D011506:Proteins / Q000235:genetics; D011956:Receptors, Cell Surface; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D015534:Trans-Activators; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta; D014599:Uterus / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D000099176:Noggin Protein
chemical_list: D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D004815:Epidermal Growth Factor; D053823:Hedgehog Proteins; D066257:Heparin-binding EGF-like Growth Factor; D007334:Insulin-Like Growth Factor I; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D000072079:Patched Receptors; D011506:Proteins; D011956:Receptors, Cell Surface; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D000099176:Noggin Protein; C525719:Bmp2 protein, mouse; C587884:Hbegf protein, mouse