The effect of recombinant human erythropoietin on neurovasculature repair after focal ischemic stroke in neonatal rats.
Cerebral ischemia disrupts the neurovascular unit, involving death of neuronal, glial, and endothelial cells (ECs) in the core and penumbra regions. Whereas the neuroprotective effect of recombinant human erythropoietin (rhEPO) has been widely investigated, its effects on ECs remain elusive. We now report the effects of rhEPO treatment on EC death and neurovasculature repair following a focal ischemic stroke in postnatal day 7 neonatal rats. rhEPO (5000 U/kg i.p.) was administered 60 min after ischemia and for the next 3 days. Western blot analysis revealed increased expression of neurovascular remodeling proteins, including Tie-1, angiopoietin-2, and basic fibroblast growth factor in rhEPO-treated pups. rhEPO treatment significantly reduced EC death in the ischemic penumbra region 12 to 72 h after ischemia examined by immunostaining of terminal deoxynucleotidyl transferase dUTP nick-end labeling and EC marker glucose transporter-1 (GLUT-1). Treatment with rhEPO increased proliferation of ECs and neuronal cells, revealed by costaining of 5-bromo-2'-deoxyuridine with GLUT-1 or with the neuronal marker protein (NeuN) 7 to 21 days after stroke. Specifically, rhEPO increased number of NeuN-positive cells in close proximity to proliferating microvessels. These results suggest for the first time that, in addition to its protection on neural cells, EPO protects ECs and promotes the neurovascular unit repair, which may contribute to its therapeutic benefits after neonatal ischemic stroke.
Keogh
Christine L
CL
Department of Pathology and Laboratory Medicine, 165 Ashley Ave. Medical University of South Carolina, Charleston, SC 29425, USA.
Yu
Shan Ping
SP
Wei
Ling
L
D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002339:Carotid Arteries / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D002536:Cerebral Arteries / Q000601:surgery; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004921:Erythropoietin / Q000494:pharmacology* / Q000627:therapeutic use; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008026:Ligation; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D009420:Nervous System / Q000098:blood supply / Q000187:drug effects* / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D042810:Receptor, TIE-1 / Q000378:metabolism; D011994:Recombinant Proteins; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D042702:Angiopoietin-2; D051272:Glucose Transporter Type 1; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D016222:Fibroblast Growth Factor 2; D004921:Erythropoietin; D042810:Receptor, TIE-1