1. Ras signaling directs endothelial specification of [VEGFR2.sup.+] vascular progenitor cells
- Author
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Kawasaki, Kyoko, Watabe, Tetsuro, Sase, Hitoshi, Hirashima, Masanori, Koide, Hiroshi, Morishita, Yasuyuki, Yuki, Keiko, Sasaoka, Toshikuni, Suda, Toshio, Katsuki, Motoya, Miyazono, Kohei, and Miyazawa, Keiji
- Subjects
Vascular endothelial growth factor -- Analysis ,Platelet-derived growth factor -- Analysis ,Endothelium -- Analysis ,Biological sciences - 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.sup.+]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 farnesyhransferase 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.sup.+] progenitor cells resulted in endothelial differentiationthrough the extracellular signal-related kinase (Erk) pathway. Both VEGF-A and PDGF-BB activated Ras in [VEGFR2.sup.+] 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.sup.+] vascular progenitor cells.
- Published
- 2008