title: Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures.
abstract: During vertebrate angiogenesis, Notch regulates the cell-fate decision between vascular tip cells versus stalk cells. Canonical Notch signaling depends on sequential proteolytic events, whereby interaction of Notch with membrane-anchored ligands triggers proteolytic processing, first by Adam10 and then presenilins. This liberates the Notch intracellular domain, allowing it to enter the nucleus and activate Notch-dependent genes. Here we report that conditional inactivation of Adam10 in endothelial cells (A10ΔEC) recapitulates the increased branching and density of the retinal vasculature that is also caused by interfering with Notch signaling. Moreover, A10ΔEC mice have additional vascular abnormalities, including aberrant subcapsular hepatic veins, enlarged glomeruli, intestinal polyps containing endothelial cell masses, abnormal endochondral ossification, leading to stunted long bone growth and increased pathologic neovascularization following oxygen-induced retinopathy. Our findings support a model in which Adam10 is a crucial regulator of endothelial cell-fate decisions, most likely because of its essential role in canonical Notch signaling.
authors.affiliation: Arthritis and Tissue Degeneration Program, Hospital for Special Surgery, New York, NY, USA.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Glomski
authors.forename: Sébastien
authors.initials: S
authors.lastname: Monette
authors.forename: Katia
authors.initials: K
authors.lastname: Manova
authors.forename: Bart
authors.initials: B
authors.lastname: De Strooper
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.forename: Carl P
authors.initials: CP
authors.lastname: Blobel
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000818:Animals; D001808:Blood Vessels / Q000196:embryology* / Q000254:growth & development*; D015153:Blotting, Western; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000502:physiology*; D051880:Receptors, Notch / Q000378:metabolism; D012160:Retina / Q000254:growth & development; D012171:Retinal Vessels / Q000254:growth & development; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse