Journal
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
Volume 28, Issue 7, Pages 1361-1368Publisher
SAGE PUBLICATIONS INC
DOI: 10.1038/jcbfm.2008.32
Keywords
angiogenesis; mouse brain endothelial cell; neural progenitor cell; rhEPO
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Funding
- NHLBI NIH HHS [R01 HL064766, R01HL 64766] Funding Source: Medline
- NINDS NIH HHS [P01 NS42345, P01 NS023393, P01 NS042345, R01 NS043324, P01 NS23393, R01NS43324] Funding Source: Medline
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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.
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