title: Stalk cell phenotype depends on integration of Notch and Smad1/5 signaling cascades.
abstract: Gradients of vascular endothelial growth factor (VEGF) induce single endothelial cells to become leading tip cells of emerging angiogenic sprouts. Tip cells then suppress tip-cell features in adjacent stalk cells via Dll4/Notch-mediated lateral inhibition. We report here that Smad1/Smad5-mediated BMP signaling synergizes with Notch signaling during selection of tip and stalk cells. Endothelium-specific inactivation of Smad1/Smad5 in mouse embryos results in impaired Dll4/Notch signaling and increased numbers of tip-cell-like cells at the expense of stalk cells. Smad1/5 downregulation in cultured endothelial cells reduced the expression of several target genes of Notch and of other stalk-cell-enriched transcripts (Hes1, Hey1, Jagged1, VEGFR1, and Id1-3). Moreover, Id proteins act as competence factors for stalk cells and form complexes with Hes1, which augment Hes1 levels in the endothelium. Our findings provide in vivo evidence for a regulatory loop between BMP/TGFβ-Smad1/5 and Notch signaling that orchestrates tip- versus stalk-cell selection and vessel plasticity.
authors.affiliation: VIB11 Center for the Biology of Disease, Laboratory of Developmental Signaling, VIB and Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Iván M
authors.initials: IM
authors.lastname: Moya
authors.forename: Lieve
authors.initials: L
authors.lastname: Umans
authors.forename: Elke
authors.initials: E
authors.lastname: Maas
authors.forename: Paulo N G
authors.initials: PN
authors.lastname: Pereira
authors.forename: Karen
authors.initials: K
authors.lastname: Beets
authors.forename: Annick
authors.initials: A
authors.lastname: Francis
authors.forename: Ward
authors.initials: W
authors.lastname: Sents
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Robertson
authors.forename: Christine L
authors.initials: CL
authors.lastname: Mummery
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis; D002135:Calcium-Binding Proteins / Q000096:biosynthesis; D018797:Cell Cycle Proteins / Q000096:biosynthesis; D002478:Cells, Cultured; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000096:biosynthesis; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000096:biosynthesis; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis; D051796:Inhibitor of Differentiation Proteins / Q000096:biosynthesis; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic; D010641:Phenotype; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D000072056:Transcription Factor HES-1; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000096:biosynthesis
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D018398:Homeodomain Proteins; D051798:Inhibitor of Differentiation Protein 1; D051797:Inhibitor of Differentiation Protein 2; D051796:Inhibitor of Differentiation Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D051898:Smad1 Protein; D051902:Smad5 Protein; D000072056:Transcription Factor HES-1; D040281:Vascular Endothelial Growth Factor Receptor-1; C519665:DLL4 protein, mouse; C489734:Hes1 protein, mouse; C120420:Hey1 protein, mouse; C497455:Idb1 protein, mouse; C497452:Idb2 protein, mouse; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C497401:Smad1 protein, mouse; C497798:Smad5 protein, mouse; C067679:Idb3 protein, mouse