title: Ischemic tolerance is associated with VEGF-C and VEGFR-3 signaling in the mouse hippocampus.
abstract: The functions of vascular endothelial growth factor C (VEGF-C) and the VEGF receptor 3 (VEGFR-3) in the nervous system are not well known. In this study, we examined the role of VEGF-C and VEGFR-3 in ischemic preconditioning (IPC)-induced tolerance in the mouse hippocampus. Adult male C57BL/6 mice were subjected to either severe ischemia (SI) induced by 40 min of bilateral common carotid artery occlusion (BCCAO) with or without IPC (5-min BCCAO) or IPC only. Cerebral blood flow was measured during ischemic periods using laser Doppler flowmetry. Neuronal damage was assessed histologically, and VEGF-C and VEGFR-3 expression levels were assessed through immunostaining. Fluoro-Jade B-labeled cells were abundant in the CA1 area 7 days after SI without IPC (sham+SI group), whereas cells were rarely labeled in mice subjected to IPC followed by SI (IPC+SI group). Similarly, the number of neuronal nuclei (NeuN)-positive cells in the CA1 area was significantly lower in the sham+SI group than in the IPC+SI group. Interestingly, we found that sublethal IPC treatment induced prominent VEGF-C expression in the CA1 pyramidal neurons and VEGFR-3 expression in the stratum radiatum and stratum lacunosum moleculare after 3 days of reperfusion that were sustained for 7 days. Moreover, VEGF-C immunoreactivity was also markedly increased, whereas VEGFR-3 expression was sustained in tolerance-acquired CA1 neurons after SI. Application of a VEGFR-3 inhibitor, SAR131675, abolished the IPC-induced neuroprotection in a dose-dependent manner in the mouse hippocampus. These results suggest that VEGF-C/VEGFR-3 signaling is associated with IPC-induced hippocampal tolerance to lethal ischemia.
authors: Department of Pharmacology, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea; Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea.
authors: M I H
authors: MI
authors: Bhuiyan
authors: Department of Pharmacology, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea; Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea.
authors: J-C
authors: JC
authors: Kim
authors: Department of Pharmacology, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea; Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea.
authors: S-N
authors: SN
authors: Hwang
authors: Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea; Department of Anatomy, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea.
authors: M-Y
authors: MY
authors: Lee
authors: Department of Pharmacology, Cell Death Disease Research Center, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea; Catholic Neuroscience Institute, College of Medicine, The Catholic University of Korea, 505 Banpo-dong, Socho-gu, Seoul 137-701, South Korea. Electronic address: syk@catholic.ac.kr.
authors: S Y
authors: SY
authors: Kim
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism* / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002340:Carotid Artery Diseases; D002452:Cell Count; D002491:Central Nervous System Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005452:Fluoresceins; D005455:Fluorescent Antibody Technique; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008810:Mice, Inbred C57BL; D009287:Naphthyridines / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002491:Central Nervous System Agents; D004268:DNA-Binding Proteins; D005452:Fluoresceins; D009287:Naphthyridines; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; C576806:SAR131675; D042582:Vascular Endothelial Growth Factor C; C435731:fluoro jade; C467483:vascular endothelial growth factor C, mouse; D040321:Vascular Endothelial Growth Factor Receptor-3
keywords: VEGF-C; VEGFR-3; cerebral ischemia; ischemic preconditioning; ischemic tolerance