Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells

Kyoko Kawasaki, Tetsuro Watabe, Hitoshi Sase, Masanori Hirashima, Hiroshi Koide, Yasuyuki Morishita, Keiko Yuki, Toshikuni Sasaoka, Toshio Suda, Motoya Katsuki, Kohei Miyazono, Keiji Miyazawa

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)131-141
Number of pages11
JournalJournal of Cell Biology
Volume181
Issue number1
DOIs
Publication statusPublished - 2008 Apr 7

    Fingerprint

ASJC Scopus subject areas

  • Cell Biology

Cite this

Kawasaki, K., Watabe, T., Sase, H., Hirashima, M., Koide, H., Morishita, Y., Yuki, K., Sasaoka, T., Suda, T., Katsuki, M., Miyazono, K., & Miyazawa, K. (2008). Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells. Journal of Cell Biology, 181(1), 131-141. https://doi.org/10.1083/jcb.200709127