An Ang1-Tie2-PI3K axis in neural progenitor cells initiates survival responses against oxygen and glucose deprivation.
Neural progenitor cells (NPCs) have the potential to survive brain ischemia and participate in neurogenesis after stroke. However, it is not clear how survival responses are initiated in NPCs. Using embryonic mouse NPCs and the in vitro oxygen and glucose deprivation (OGD) model, we found that angiopoietin-1 (Ang1) could prevent NPCs from OGD-induced apoptosis, as evidenced by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling and annexin V labeling. Ang1 significantly elevated tunica intima endothelial kinase 2 (Tie2) autophosphorylation level, suggesting the existence of functional Tie2 receptors on NPCs. NPCs under OGD conditions exhibited reduction of Akt phosphorylation, decrease of the Bcl-2/Bax ratio, activation of caspase-3, cleavage of PARP, and downregulation of beta-catenin and nestin. Ang1 reversed the above changes concomitantly with significant rising of survival rates of NPCs under OGD, but all these effects of Ang1 could be blocked by either soluble extracellular domain of Tie2 Fc fusion protein (sTie2Fc) or the phosphoinositide 3-kinase (PI3K) inhibitor 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one (LY294002). Our findings suggest the existence of an Ang1-Tie2-PI3K signaling axis that is essential in initiation of survival responses in NPCs against cerebral ischemia and hypoxia.
Bai
Y
Y
Department of Cell Biology, School of Basic Medical Sciences, Peking University Health Science Center, 38 XueYuan Road, Beijing, 100191, China.
Meng
Z
Z
Cui
M
M
Zhang
X
X
Chen
F
F
Xiao
J
J
Shen
L
L
Zhang
Y
Y
D042683:Angiopoietin-1 / Q000502:physiology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism*; D005947:Glucose / Q000172:deficiency; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D055495:Neurogenesis / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D042787:Receptor, TIE-2 / Q000378:metabolism*; D015290:Second Messenger Systems / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D042683:Angiopoietin-1; D051017:Apoptosis Regulatory Proteins; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; C079086:Tek protein, mouse; D005947:Glucose