title: E-selectin expression and stimulation by inflammatory mediators are developmentally regulated during embryogenesis.
abstract: Leukocyte recruitment during inflammation is specified, in part, by the spatial distribution and temporal regulation of endothelial adhesion molecules. In this study we investigated the developmental onset of E-selectin and intercellular adhesion molecule-1 (ICAM-1) basal expression and inducibility by inflammatory mediators as indices of lineage-restricted endothelial adhesion molecule expression. We studied both murine embryos and embryoid bodies (EB), derived from differentiated embryonic stem cells, to examine a broad range of endothelial ontogeny. Our results reveal that E-selectin and ICAM-1 are differentially regulated during development and that three stages define the ontogeny of the E-selectin-inducible response. The earliest endothelial lineage cells in Day 4 and Day 5 EB did not express E-selectin in the basal state or after stimulation. A second stage, observed between embryonic Day 9.5 (E9.5) and E11.5 to E12.5 in cultured embryo cells and transiently at Day 6 of EB differentiation, was characterized by basal expression that was not stimulated by inflammatory mediators. A third stage was characterized by both basal and inducible expression of E-selectin and was observed beginning at E12.5 to E13.5 in cultured embryo cells and at Day 7 in EB. In contrast ICAM-1 was stimulated at all of the embryonic stages examined and before the onset of E-selectin inducibility in both embryos and EB. E-selectin expression in embryos was also stimulated by introducing endotoxin into the embryonic, but not the maternal, peritoneum. This suggests that embryos are protected from inflammatory insults present in the maternal circulation. The developmentally regulated acquisition of E-selectin inducibility during embryogenesis likely involves changes in signal transduction cascades, transcription factors, and/or chromatin accessibility that specify inducible expression within the endothelial lineage and further restrict inducibility to particular endothelial subpopulations.
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. milstone@rascal.med.harvard.edu
authors.forename: D S
authors.initials: DS
authors.lastname: Milstone
authors.forename: P E
authors.initials: PE
authors.lastname: O'Donnell
authors.forename: G
authors.initials: G
authors.lastname: Stavrakis
authors.forename: R M
authors.initials: RM
authors.lastname: Mortensen
authors.forename: V M
authors.initials: VM
authors.lastname: Davis
mesh_terms: D000818:Animals; D019040:E-Selectin / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000187:drug effects; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics; D011247:Pregnancy; D011518:Proto-Oncogene Proteins / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D017978:Receptors, Growth Factor / Q000235:genetics; D040262:Receptors, Vascular Endothelial Growth Factor; D011994:Recombinant Proteins / Q000494:pharmacology; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1
chemical_list: D019040:E-Selectin; D007375:Interleukin-1; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1