Adrenomedullin/cyclic AMP pathway induces notch activation and differentiation of arterial endothelial cells from vascular progenitors

Takami Yurugi-Kobayashi, Hiroshi Itoh, Timm Schroeder, Akiko Nakano, Genta Narazaki, Fumiyo Kita, Kentoku Yanagi, Mina Hiraoka-Kanie, Emi Inoue, Toshiaki Ara, Takashi Nagasawa, Ursula Just, Kazuwa Nakao, Shin Ichi Nishikawa, Jun K. Yamashita

Research output: Contribution to journalArticlepeer-review

109 Citations (Scopus)


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 Jκ site deficient ES cells lacking Notch signal activation or in ES cells treated with γ-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.

Original languageEnglish
Pages (from-to)1977-1984
Number of pages8
JournalArteriosclerosis, Thrombosis, and Vascular Biology
Issue number9
Publication statusPublished - 2006 Sept
Externally publishedYes


  • Angiogenesis
  • Developmental biology
  • Embryonic stem cells
  • Endothelium
  • Vascular biology

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine


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