title: Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells.
abstract: Erythropoietin (EPO), a hypoxia-inducible cytokine, is required for survival, proliferation, and differentiation of erythroid progenitor cells. EPO can also stimulate proliferation and angiogenesis of endothelial cells that express EPO receptors (EPORs). In this study we investigated the EPO response of vascular endothelial cells at reduced oxygen tension (5% and 2%), in particular the effect of EPO on nitric oxide (NO) release. Endothelial nitric oxide synthase (eNOS) produces NO, which maintains blood pressure homeostasis and blood flow. We find that EPOR is inducible by EPO in primary human endothelial cells of vein (HUVECs) and artery (HUAECs) and cells from a human bone marrow microvascular endothelial line (TrHBMEC) to a much greater extent at low oxygen tension than in room air. We found a corresponding increase in eNOS expression and NO production in response to EPO during hypoxia. Stimulation of NO production was dose dependent on EPO concentration and was maximal at 5 U/mL. NO activates soluble guanosine cyclase to produce cyclic guanosine monophosphate (cGMP), and we observed that EPO induced cGMP activity. These results suggest that low oxygen tension increases endothelial cell capacity to produce NO in response to EPO by induction of both EPOR and eNOS. This effect of EPO on eNOS may be a physiologically relevant mechanism to counterbalance the hypertensive effects of increased hemoglobin-related NO destruction resulting from hypoxia-induced increased red cell mass.
authors.affiliation: Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1822, USA.
authors.forename: Bojana B
authors.initials: BB
authors.lastname: Beleslin-Cokic
authors.forename: Vladan P
authors.initials: VP
authors.lastname: Cokic
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Yu
authors.forename: Babette B
authors.initials: BB
authors.lastname: Weksler
authors.forename: Alan N
authors.initials: AN
authors.lastname: Schechter
authors.forename: Constance Tom
authors.initials: CT
authors.lastname: Noguchi
mesh_terms: D002318:Cardiovascular Diseases / Q000628:therapy; D002454:Cell Differentiation; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000473:pathology*; D004921:Erythropoietin / Q000494:pharmacology*; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry; D010100:Oxygen / Q000378:metabolism; D017467:Receptors, Erythropoietin / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells; D013997:Time Factors; D014466:Ultraviolet Rays
chemical_list: D006454:Hemoglobins; D009573:Nitrites; D009841:Oligonucleotides; D017467:Receptors, Erythropoietin; D004921:Erythropoietin; D009569:Nitric Oxide; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D006152:Cyclic GMP; D010100:Oxygen