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Blood, 1 October 2004, Vol. 104, No. 7, pp. 2073-2080. Prepublished online as a Blood First Edition Paper on June 17, 2004; DOI 10.1182/blood-2004-02-0744. This Article Full Text Full Text (PDF) All Versions of this Article: 2004-02-0744v1 104/7/2073    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Beleslin-Cokic, B. B. Articles by Noguchi, C. T. Search for Related Content PubMed PubMed Citation Articles by Beleslin-Cokic, B. B. Articles by Noguchi, C. T. Related Collections Hematopoiesis and Stem Cells Hemostasis, Thrombosis, and Vascular Biology Red Cells Gene Expression Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells Bojana B. Beleslin-Cokic, Vladan P. Cokic, Xiaobing Yu, Babette B. Weksler, Alan N. Schechter, and Constance Tom Noguchi From the Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD; and the Division of Hematology/Oncology, Weill Medical College of Cornell University, New York, NY. 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. (Blood. 2004;104:2073-2080) CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: M. Martini, L. Teofili, T. Cenci, F. Giona, L. Torti, M. Rea, R. Foa, G. Leone, and L. M. Larocca A novel heterozygous HIF2AM535I mutation reinforces the role of oxygen sensing pathway disturbances in the pathogenesis of familial erythrocytosis Haematologica, July 1, 2008; 93(7): 1068 - 1071. [Abstract] [Full Text] [PDF] L. V. d'Uscio and Z. S. 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