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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.

Original publication




Journal article


Dev Cell

Publication Date





501 - 514


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