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Stalk Cell Phenotype Depends on Integration of Notch and Smad1/5 Signaling Cascades

2012; Elsevier BV; Volume: 22; Issue: 3 Linguagem: Inglês

10.1016/j.devcel.2012.01.007

1878-1551

Iván M. Moya, Lieve Umans, Elke Maas, Paulo N. G. Pereira, Karen Beets, Annick Francis, Ward Sents, Elizabeth J. Robertson, Christine L. Mummery, Danny Huylebroeck, An Zwijsen,

TGF-β signaling in diseases

Summary 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.