Secretion of brain-derived neurotrophic factor from brain microvascular endothelial cells.
The cerebral microvasculature has recently been identified as a source of factors that can influence the generation and survival of neurons, including brain-derived neurotrophic factor (BDNF). However, relatively little is known about signals that regulate secretion of endothelial cell derived BDNF. To approach this issue the present study examined BDNF secretion from brain endothelial cells in response to reduced oxygen availability (hypoxia), using the mouse brain microvascular endothelial cell line, bEnd.3. We found that exposure of bEnd.3 cells to either sustained or intermittent hypoxia (IH) stimulates BDNF expression and release and that IH is the more potent stimulus. IH-induced BDNF release can be partially inhibited by either N-acetyl-L-cysteine, a scavenger of reactive oxygen species, or by the stable superoxide dismutase mimetic manganese(III)tetrakis1-methyl-4-pyridylporphyrin, indicating that oxyradical formation contributes to enhanced secretion of BDNF. In addition, we found that IH-induced BDNF release requires Ca2+ mobilization from internal stores through ryanodine- and inositol (1,4,5-triphosphate) IP3 receptors and is completely blocked by SKF 96365, a nonselective inhibitor of transient receptor potential (TRP) channels. These data demonstrate that bEnd.3 cells respond to oxidative stress by increasing BDNF secretion and, in addition, highlight TRP channels as potential therapeutic targets for enhancing BDNF availability from the cerebral microvasculature.
Department of Neurosciences, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106, USA.
Hong
H
Wang
Nicole
N
Ward
Mark
M
Boswell
David M
DM
Katz
D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism; D006801:Humans; D002534:Hypoxia, Brain / Q000378:metabolism; D007202:Indicators and Reagents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D019837:Ryanodine Receptor Calcium Release Channel / Q000187:drug effects
D019208:Brain-Derived Neurotrophic Factor; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D016166:Free Radical Scavengers; D005609:Free Radicals; C506926:ITPR1 protein, human; D007202:Indicators and Reagents; D053496:Inositol 1,4,5-Trisphosphate Receptors; D017382:Reactive Oxygen Species; D018160:Receptors, Cytoplasmic and Nuclear; D019837:Ryanodine Receptor Calcium Release Channel; D002118:Calcium