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

Journal article

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: Moya, I; Umans, L; Maas, E; Pereira, P; Beets, K

• Journal: Developmental cell
• Volume: 22
• Issue: 3
• Pages: 501-514
• Publication date: 2012-03-01
• DOI: 10.1016/j.devcel.2012.01.007
• EISSN: 1878-1551
• ISSN: 1534-5807
• Language: English
• Keywords: Mice, Transgenic; Animals; Cell Cycle Proteins; Phenotype; Mice; Membrane Proteins; Smad5 Protein; Calcium-Binding Proteins; Intracellular Signaling Peptides and Proteins; Humans; Vascular Endothelial Growth Factor Receptor-1; Inhibitor of Differentiation Protein 2; Down-Regulation; Cells, Cultured; Signal Transduction; Basic Helix-Loop-Helix Transcription Factors; Mice, Knockout; Neovascularization, Physiologic; Smad1 Protein; Homeodomain Proteins; Inhibitor of Differentiation Protein 1; Inhibitor of Differentiation Proteins; Intercellular Signaling Peptides and Proteins