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

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• 作者：Ivá ; n  ; M. Moya¹ ; ⁵ ; Lieve Umans² ; ⁵ ; ⁶ ; Elke Maas¹ ; Paulo  ; N.G. Pereira¹ ; Karen Beets¹ ; Annick Francis² ; ⁶ ; Ward Sents¹ ; Elizabeth  ; J. Robertson³ ; Christine  ; L. Mummery⁴ ; Danny Huylebroeck² ; ⁶ ; An Zwijsen¹ ; ^{an.zwijsen@cme.vib-kuleuven.be}
• 刊名：Developmental Cell
• 出版年：2012
• 出版时间：13 March, 2012
• 年：2012
• 卷：22
• 期：3
• 页码：501-514
• 全文大小：3184 K

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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 (m>Hes1m>, m>Hey1m>, m>Jagged1m>, m>VEGFR1m>, and m>Id1-3m>). 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/TGF¦Â-Smad1/5 and Notch signaling that orchestrates tip- versus stalk-cell selection and vessel plasticity.