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Published online April 7, 2008
doi:10.1083/jcb.200709127
The Journal of Cell Biology, Vol. 181, No. 1, 131-141
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Kawasaki et al.
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Article

 Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells

Kyoko Kawasaki1, Tetsuro Watabe1, Hitoshi Sase1, Masanori Hirashima2, Hiroshi Koide3, Yasuyuki Morishita1, Keiko Yuki1, Toshikuni Sasaoka4, Toshio Suda2, Motoya Katsuki4, Kohei Miyazono1, and Keiji Miyazawa1

1 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Bunkyo, Tokyo 113-0033, Japan
2 Department of Cell Differentiation, The Sakaguchi Laboratory, School of Medicine, Keio University, Shinjuku, Tokyo 160-8582, Japan
3 Department of Stem Cell Biology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 930-8640, Japan
4 National Institute for Basic Biology, Okazaki, Aichi 444-8585, Japan

Correspondence to Keiji Miyazawa: keiji-miyazawa{at}umin.ac.jp

Vascular endothelial growth factor receptor 2 (VEGFR2) transmits signals of crucial importance to vasculogenesis, including proliferation, migration, and differentiation of vascular progenitor cells. Embryonic stem cell–derived VEGFR2+ mesodermal cells differentiate into mural lineage in the presence of platelet derived growth factor (PDGF)–BB or serum but into endothelial lineage in response to VEGF-A. We found that inhibition of H-Ras function by a farnesyltransferase inhibitor or a knockdown technique results in selective suppression of VEGF-A–induced endothelial specification. Experiments with ex vivo whole-embryo culture as well as analysis of H-ras–/– mice also supported this conclusion. Furthermore, expression of a constitutively active H-Ras[G12V] in VEGFR2+ progenitor cells resulted in endothelial differentiation through the extracellular signal-related kinase (Erk) pathway. Both VEGF-A and PDGF-BB activated Ras in VEGFR2+ progenitor cells 5 min after treatment. However, VEGF-A, but not PDGF-BB, activated Ras 6–9 h after treatment, preceding the induction of endothelial markers. VEGF-A thus activates temporally distinct Ras–Erk signaling to direct endothelial specification of VEGFR2+ vascular progenitor cells.

Abbreviations used in this paper: AcLDL, acetylated low-density lipoprotein; {alpha}SMA+, {alpha}–smooth muscle actin positive; E, embryonic day; ESC, embryonic stem cells; Erk, extracellular signal-related kinase; HMEC, human microvascular endothelial cell; miRNA, microRNA; PECAM1+, platelet-endothelial cell adhesion molecule-1 positive; VEGFR2+, vascular endothelial growth factor receptor 2 positive.


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