title: Neural progenitor cells treated with EPO induce angiogenesis through the production of VEGF.
abstract: Recombinant human erythropoietin (rhEPO) induces neurogenesis and angiogenesis. Using a coculture system of mouse brain endothelial cells (MBECs) and neural progenitor cells derived from the subventricular zone of adult mouse, we investigated the hypothesis that neural progenitor cells treated with rhEPO promote angiogenesis. Treatment of neural progenitor cells with rhEPO significantly increased their expression and secretion of vascular endothelial growth factor (VEGF) and activated phosphatidylinositol 3-kinase/Akt (PI3K/Akt) and extracellular signal-regulated kinase (ERK1/2). Selective inhibition of the Akt and ERK1/2 signaling pathways significantly attenuated the rhEPO-induced VEGF expression in neural progenitor cells. The supernatant harvested from neural progenitor cells treated with rhEPO significantly increased the capillary-like tube formation of MBECs. SU1498, a specific VEGF type-2 receptor (VEGFR2) antagonist, abolished the supernatant-enhanced angiogenesis. In addition, coculture of MBECs with neural progenitor cells treated with rhEPO substantially increased VEGFR2 mRNA and protein levels in MBECs. These in vitro results suggest that EPO enhances VEGF secretion in neural progenitor cells through activation of the PI3K/Akt and ERK1/2 signaling pathways and that neural progenitor cells treated with rhEPO upregulate VEGFR2 expression in cerebral endothelial cells, which along with VEGF secreted by neural progenitor cells promotes angiogenesis.
authors.affiliation: Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Michael
authors.initials: M
authors.lastname: Chopp
authors.forename: Sara R
authors.initials: SR
authors.lastname: Gregg
authors.forename: Rui Lan
authors.initials: RL
authors.lastname: Zhang
authors.forename: Hua
authors.initials: H
authors.lastname: Teng
authors.forename: Angela
authors.initials: A
authors.lastname: Jiang
authors.forename: Yifan
authors.initials: Y
authors.lastname: Feng
authors.forename: Zheng Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D018920:Coculture Techniques; D042783:Endothelial Cells; D004921:Erythropoietin / Q000494:pharmacology*; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics*
chemical_list: D042461:Vascular Endothelial Growth Factor A; D004921:Erythropoietin; D040301:Vascular Endothelial Growth Factor Receptor-2