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Ras signaling directs endothelial specification of VEGFR2+ vascular progenitor cells
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.
SMA+, –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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