Published online before print June 29, 2006, doi: 10.1161/01.ATV.0000234978.10658.41
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© 2006 American Heart Association, Inc.
Vascular Biology |
Adrenomedullin/Cyclic AMP Pathway Induces Notch Activation and Differentiation of Arterial Endothelial Cells From Vascular Progenitors
From the Laboratory of Stem Cell Differentiation (T.Y.-K., A.N., G.N., F.K., K.Y., M.H.-K., E.I., J.K.Y.), Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, Japan; Department of Medicine and Clinical Science (T.Y.-K., H.I., K.N.), Kyoto University Graduate School of Medicine, Japan; Institute of Stem Cell Research (T.S.), GSF-National Research Center for Environment and Health, Germany; Department of Medical Systems Control (T.A., T.N.), Institute for Frontier Medical Sciences, Kyoto University, Japan; Institute of Biochemistry (U.J.), University of Kiel, Germany; Laboratory for Stem Cell Biology (S.-I.N.), Center for Developmental Biology, RIKEN, Japan; PRESTO (J.K.Y.), Japan Science and Technology Agency, Japan.
Correspondence to Jun K. Yamashita, Laboratory of Stem Cell Differentiation, Stem Cell Research Center, Institute for Frontier Medical Sciences, Kyoto University, 53 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507 Japan. E-mail juny{at}frontier.kyoto-u.ac.jp
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 J
site deficient ES cells lacking Notch signal activation or in ES cells treated with 
-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.
Previously, we have reported an embryonic stem cell differentiation system for blood vessels. In this study, we induced arterial and venous endothelial cells (ECs) in vitro and demonstrated that adrenomedullin/cAMP is a novel pathway to activate Notch signaling in ECs and is required to induce arterial ECs from vascular progenitors.
Key Words: angiogenesis • developmental biology • embryonic stem cells • endothelium • vascular biology
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Arterioscler. Thromb. Vasc. Biol. 2006 26: 1934-1935.
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