Erythropoietin prevents blood brain barrier damage induced by focal cerebral ischemia in mice.
Recombinant human erythropoietin (rhEPO), a neurovascular protective agent, therapeutically supports angiogenesis after stroke by enhancing endogenous up-regulation of vascular endothelial growth factor (VEGF). Increased VEGF expression has been characterized to negatively impact the integrity of the blood brain barrier (BBB), causing brain edema and secondary injury. The present study investigated the rhEPO-induced BBB protection after stroke and how it might be achieved by affecting VEGF pathway. rhEPO treatment (5,000 U/kg, i.p., 30 min before stroke and once a day for three days after stroke) reduced Evans blue leakage and brain edema after ischemia. The expression of the BBB integrity markers, occludin, alpha-catenin and beta-catenin, in the brain was preserved in animals received rhEPO. rhEPO up-regulated VEGF expression; however, the expression of VEGF receptor-2 (fetal liver kinase receptor, Flk-1) was significantly reduced in rhEPO-treated animals three days after stroke. We propose that, disregarding increased VEGF levels, rhEPO protects against ischemia-induced BBB damage at least partly by down-regulating Flk-1 expression and the response to VEGF signaling in the acute phase after stroke.
Li
Ying
Y
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, 165 Ashley Ave., Charleston, SC 29425, USA.
Lu
Zhong-Yang
ZY
Ogle
Molly
M
Wei
Ling
L
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000473:pathology*; D001929:Brain Edema / Q000517:prevention & control; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D004921:Erythropoietin / Q000627:therapeutic use*; D005070:Evans Blue; D005455:Fluorescent Antibody Technique; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D018613:Microscopy, Confocal; D062793:Occludin; D011994:Recombinant Proteins; D020521:Stroke / Q000473:pathology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis / Q000235:genetics
D008565:Membrane Proteins; C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D011994:Recombinant Proteins; D004921:Erythropoietin; D005070:Evans Blue; D040301:Vascular Endothelial Growth Factor Receptor-2