Title

Notch pathway targets proangiogenic regulator Sox17 to restrict angiogenesis.

Document Type

Article

Publication Date

7-7-2014

Institution/Department

MMCRI

Journal Title

Circulation research

MeSH Headings

Animals, Carcinoma, Lewis Lung, Cell Differentiation, Cell Movement, Cytoskeleton, Embryo, Mammalian, Embryonic Stem Cells, Endothelial Cells, Gene Expression Regulation, HMGB Proteins, Human Umbilical Vein Endothelial Cells, Humans, Intercellular Junctions, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Morphogenesis, Neovascularization, Pathologic, Neovascularization, Physiologic, Protein Structure, Tertiary, RNA, Small Interfering, Receptor, Notch1, Receptors, Notch, Recombinant Fusion Proteins, Retinal Vessels, SOXF Transcription Factors, Signal Transduction, Specific Pathogen-Free Organisms, Transcription, Genetic

ISSN

1524-4571

Abstract

RATIONALE: The Notch pathway stabilizes sprouting angiogenesis by favoring stalk cells over tip cells at the vascular front. Because tip and stalk cells have different properties in morphology and function, their transcriptional regulation remains to be distinguished. Transcription factor Sox17 is specifically expressed in endothelial cells, but its expression and role at the vascular front remain largely unknown.

OBJECTIVE: To specify the role of Sox17 and its relationship with the Notch pathway in sprouting angiogenesis.

METHODS AND RESULTS: Endothelial-specific Sox17 deletion reduces sprouting angiogenesis in mouse embryonic and postnatal vascular development, whereas Sox17 overexpression increases it. Sox17 promotes endothelial migration by destabilizing endothelial junctions and rearranging cytoskeletal structure and upregulates expression of several genes preferentially expressed in tip cells. Interestingly, Sox17 expression is suppressed in stalk cells in which Notch signaling is relatively high. Notch activation by overexpressing Notch intracellular domain reduces Sox17 expression both in primary endothelial cells and in retinal angiogenesis, whereas Notch inhibition by delta-like ligand 4 (Dll4) blockade increases it. The Notch pathway regulates Sox17 expression mainly at the post-transcriptional level. Furthermore, endothelial Sox17 ablation rescues vascular network from excessive tip cell formation and hyperbranching under Notch inhibition in developmental and tumor angiogenesis.

CONCLUSIONS: Our findings demonstrate that the Notch pathway restricts sprouting angiogenesis by reducing the expression of proangiogenic regulator Sox17.

First Page

215

Last Page

226

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