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Adrenomedullin/cyclic AMP pathway induces notch activation and differentiation of arterial endothelial cells from vascular progenitors.
Arterioscler. Thromb. Vasc. Biol. 26, 1977-1984 (2006)
OBJECTIVE: The acquisition of arterial or venous identity is highlighted in vascular development. Previously, we have reported an embryonic stem (ES) cell differentiation system that exhibits early vascular development using vascular endothelial growth factor (VEGF) receptor-2 (VEGFR2)-positive cells as common vascular progenitors. In this study, we constructively induced differentiation of arterial and venous endothelial cells (ECs) in vitro to elucidate molecular mechanisms of arterial-venous specification. METHODS AND RESULTS: ECs were induced from VEGFR2+ progenitor cells with various conditions. VEGF was essential to induce ECs. Addition of 8bromo-cAMP or adrenomedullin (AM), an endogenous ligand-elevating cAMP, enhanced VEGF-induced EC differentiation. Whereas VEGF alone mainly induced venous ECs, 8bromo-cAMP (or AM) with VEGF supported substantial induction of arterial ECs. Stimulation of cAMP pathway induced Notch signal activation in ECs. The arterializing effect of VEGF and cAMP was abolished in recombination recognition sequence binding protein at the Jkappa site deficient ES cells lacking Notch signal activation or in ES cells treated with gamma-secretase inhibitor. Nevertheless, forced Notch activation by the constitutively active Notch1 alone did not induce arterial ECs. CONCLUSIONS: Adrenomedullin/cAMP is a novel signaling pathway to activate Notch signaling in differentiating ECs. Coordinated signaling of VEGF, Notch, and cAMP is required to induce arterial ECs from vascular progenitors.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
angiogenesis; developmental biology; embryonic stem cells; endothelium; vascular biology
Language
english
Publication Year
2006
HGF-reported in Year
0
ISSN (print) / ISBN
1079-5642
e-ISSN
1524-4636
Quellenangaben
Volume: 26,
Issue: 9,
Pages: 1977-1984
Publisher
Lippincott Williams & Wilkins
Reviewing status
Peer reviewed
Institute(s)
Institute of Stem Cell Research (ISF)
PSP Element(s)
G-550900-001
PubMed ID
16809546
Erfassungsdatum
2006-09-21