Activation of vascular endothelial growth factor receptor-2 in bone marrow leads to accumulation of myeloid cells: role of granulocyte-macrophage colony-stimulating factor.
Vascular endothelial growth factor (VEGF) is a secreted cytokine that plays a major role in the formation and maintenance of the hemopoietic and vascular compartments. VEGF and its receptors, VEGFR-1 and VEGFR-2, have been found to be expressed on subsets of normal and malignant hemopoietic cells, but the role of the individual receptors in hemopoiesis requires further study. Using a VEGFR-2 fusion protein that can be dimerized with a synthetic drug, we were able to specifically examine the effects of VEGFR-2 signaling in hemopoietic cells in vivo. Mice transplanted with bone marrow transduced with this inducible VEGFR-2 fusion protein demonstrated expansion of myeloid cells (Gr-1+, CD11b+). Levels of myeloid progenitors were also increased following VEGFR-2 activation, through autocrine and paracrine mechanisms, as measured by clonogenic progenitor assays. VEGFR-2 activation induced expression of GM-CSF and increased serum levels in vivo. Abrogation of GM-CSF activity, either with neutralizing Abs or by using GM-CSF-null hemopoietic cells, inhibited VEGFR-2-mediated myeloid progenitor activity. Our findings indicate that VEGF signaling through VEGFR-2 promotes myelopoiesis through GM-CSF-dependent and -independent mechanisms.
Larrivée
Bruno
B
Department of Experimental Medicine, University of British Columbia, Vancouver, Canada.
Pollet
Ingrid
I
Karsan
Aly
A
D000818:Animals; D001854:Bone Marrow Cells / Q000502:physiology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000502:physiology*; D038042:Myelopoiesis; D019707:Receptors, Chemokine / Q000032:analysis; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000502:physiology*
C503133:Gr-1 protein, mouse; D019707:Receptors, Chemokine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D040301:Vascular Endothelial Growth Factor Receptor-2