Stalk cell phenotype depends on integration of Notch and Smad1/5 signaling cascades

Dev Cell. 2012 Mar 13;22(3):501-14. doi: 10.1016/j.devcel.2012.01.007. Epub 2012 Feb 23.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis
  • Calcium-Binding Proteins / biosynthesis
  • Cell Cycle Proteins / biosynthesis
  • Cells, Cultured
  • Down-Regulation
  • Homeodomain Proteins / biosynthesis
  • Humans
  • Inhibitor of Differentiation Protein 1 / biosynthesis
  • Inhibitor of Differentiation Protein 2 / biosynthesis
  • Inhibitor of Differentiation Proteins / biosynthesis
  • Intercellular Signaling Peptides and Proteins / biosynthesis
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Jagged-1 Protein
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Neovascularization, Physiologic
  • Phenotype
  • Serrate-Jagged Proteins
  • Signal Transduction*
  • Smad1 Protein / genetics
  • Smad1 Protein / metabolism*
  • Smad5 Protein / genetics
  • Smad5 Protein / metabolism*
  • Transcription Factor HES-1
  • Vascular Endothelial Growth Factor Receptor-1 / biosynthesis

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Calcium-Binding Proteins
  • Cell Cycle Proteins
  • DLL4 protein, mouse
  • Hes1 protein, mouse
  • Hey1 protein, mouse
  • Homeodomain Proteins
  • Idb1 protein, mouse
  • Idb2 protein, mouse
  • Inhibitor of Differentiation Protein 1
  • Inhibitor of Differentiation Protein 2
  • Inhibitor of Differentiation Proteins
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • JAG1 protein, human
  • Jag1 protein, mouse
  • Jagged-1 Protein
  • Membrane Proteins
  • Serrate-Jagged Proteins
  • Smad1 Protein
  • Smad1 protein, mouse
  • Smad5 Protein
  • Smad5 protein, mouse
  • Transcription Factor HES-1
  • Idb3 protein, mouse
  • Vascular Endothelial Growth Factor Receptor-1