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.

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

“…A recent report BLOOD, 28 JANUARY 2010 ⅐ VOLUME 115, NUMBER 4 For personal use only. on May 12, 2018. by guest www.bloodjournal.org From demonstrated that EPO-induced angiogenesis was via the induction of VEGF in neural progenitor cells 27 ; however, we found that an anti-VEGF antibody added to the human CD34 ϩ EPCs had minimal effect on NO induction ( Figure 3B), even though the concentration of anti-VEGF antibody was able to block stimulation of NO of exogenously added VEGF (data not shown). Thus, EPO stimulation of NO was strictly dependent on the VEGF-R2 receptor.…”

Menstrual Blood Cells Display Stem Cell–Like Phenotypic Markers and Exert Neuroprotection Following Transplantation in Experimental Stroke

“…Indeed, examination of trophic factor levels in the media of OGD-exposed cultured menstrual blood-derived stem cells reveals the up-regulation of VEGF, BDNF, NT-3, but not GDNF. Recent reports have implicated this set of trophic factors as mediating therapeutic benefi ts of transplanted stem cells in a variety of CNS disorders, including stroke [42][43][44][45][46][47]. In view of clinical product development, there may be less safety and toxicity concerns for peptide delivery compared to cell therapy.…”

High-Dose Erythropoietin and Hypothermia for Hypoxic-Ischemic Encephalopathy: A Phase II Trial

“…41 Epo exhibits antiapoptotic and antiinflammatory effects acutely after neonatal brain injury [42][43][44][45][46] and promotes neurogenesis, plasticity, and tissue remodeling after hypoxia-ischemia. 15,[47][48][49][50] In animal models of neonatal stroke, Epo increases proliferation, migration, and differentiation of neuronal precursors, resulting in increased neurogenesis in the injured basal ganglia and cortex. 47,51,52 Although therapeutic hypothermia has improved the outlook of infants with HIE, 53,54 there remains a pressing need for neuroprotective therapies that will further reduce the high rate of neurologic disabilities.…”