Erythropoietin, known for its role in erythroid differentiation, is required for normal blood as well as heart and brain development. Erythropoietin stimulates progenitor cells from multiple origins: hematopoietic, endothelial, muscle and neural. In culture erythropoietin stimulate muscle satellite cells to proliferate and inhibit differentiation and fusion into myotubes. Erythropoietin promotes expression of the early muscle transcription factors, MyoD and Myf5, and inhibits the expression of myogenin, required for fusion into myotubes. High levels of erythropoietin receptor are expressed in embryonic brain in regions associated with proliferating neural progenitor cells. Lack of erythropoietin receptor affects brain development as early as embryonic day 10.5. Neural progenitor cells from erythropoietin receptor null mice appear normal at embryonic day 9.5. At embryonic day 10.5, there is a reduction in neuron generation and increased sensitivity to hypoxia. Neurons harvested from the erythropoietin receptor null mice do not survive 24 hour exposure to hypoxia. In contrast, erythropoietin stimulated proliferation of normal neural progenitor cells and provided a neuroprotective effect to hypoxia. Increased sensitivity to erythropoietin at low oxygen is explained in part by induction of the erythropoietin receptor by hypoxia and erythropoietin. In endothelial cells erythropoietin induces its receptor at low oxygen tension. In immortalized human bone marrow endothelial cells, TrHBMEC, human umbilical vein endothelial cells and human umbilical artery endothelial cells, erythropoietin stimulation also increases endothelial nitric oxide synthase and nitric oxide production, with the greatest effect observed for the human umbilical vein endothelial cells. These effects are not mediated through action of vascular endothelial growth factor. These results suggest that endothelial stimulation by erythropoietin may produce nitric oxide to balance the hypertensive effect of nitric oxide binding to the increased hemoglobin mass by erythropoietin stimulation of erythropoiesis in the bone marrow. Regulation of erythropoietin receptor in these cells representative of the multi-organ response of erythropoietin appears to be analogous to that in hematopoietic cells and requires the GATA- and SP1 motifs for high level of expression. The multi-organ response to erythropoietin appears to be determined in part by regulation of expression of its receptor and suggest that induction of erythropoietin receptor during hypoxia is an important aspect of erythropoietin response to stimulate proliferation and/or survival.
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