Induction of nitric oxide by erythropoietin is mediated by the {beta} common receptor and requires interaction with VEGF receptor 2

• Published in: Blood 2010-01, Vol.115 (4), p.896-905
• Main Authors: Sautina, Larysa, Sautin, Yuri, Beem, Elaine, Zhou, Zhuo, Schuler, Anna, Brennan, Jennafer, Zharikov, Sergey I, Diao, Yanpeng, Bungert, Jorg, Segal, Mark S
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; Dimerization; Erythropoietin - metabolism; Erythropoietin - pharmacology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Phosphorylation - physiology; Protein Subunits - chemistry; Protein Subunits - genetics; Protein Subunits - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Receptor Cross-Talk - physiology; Receptors, Erythropoietin - chemistry; Receptors, Erythropoietin - genetics; Receptors, Erythropoietin - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 1528-0020
• DOI: 10.1182/blood-2009-04-216432

Vascular endothelial growth factor (VEGF) and erythropoietin (EPO) have profound effects on the endothelium and endothelial progenitor cells (EPCs), which originate from the bone marrow and differentiate into endothelial cells. Both EPO and VEGF have demonstrated an ability to increase the number and performance properties of EPCs. EPC behavior is highly dependent on nitric oxide (NO), and both VEGF and EPO can stimulate intracellular NO. EPO can bind to the homodimeric EPO receptor (EPO-R) and the heterodimeric receptor, EPO-R and the common beta receptor (betaC-R). Although VEGF has several receptors, VEGF-R2 appears most critical to EPC function. We demonstrate that EPO induction of NO is dependent on the betaC-R and VEGF-R2, that VEGF induction of NO is dependent on the expression of the betaC-R, and that the betaC-R and VEGF-R2 interact. This is the first definitive functional and structural evidence of an interaction between the 2 receptors and has implications for the side effects of EPO.