title: Recombinant tissue-type plasminogen activator transiently enhances blood-brain barrier permeability during cerebral ischemia through vascular endothelial growth factor-mediated endothelial endocytosis in mice.
abstract: Recombinant tissue-type plasminogen activator (rt-PA) modulates cerebrovascular permeability and exacerbates brain injury in ischemic stroke, but its mechanisms remain unclear. We studied the involvement of vascular endothelial growth factor (VEGF)-mediated endocytosis in the increase of blood-brain barrier (BBB) permeability potentiated by rt-PA after ischemic stroke. The rt-PA treatment at 4 hours after middle cerebral artery occlusion induced a transient increase in BBB permeability after ischemic stroke in mice, which was suppressed by antagonists of either low-density lipoprotein receptor families (LDLRs) or VEGF receptor-2 (VEGFR-2). In immortalized bEnd.3 endothelial cells, rt-PA treatment upregulated VEGF expression and VEGFR-2 phosphorylation under ischemic conditions in an LDLR-dependent manner. In addition, rt-PA treatment increased endocytosis and transcellular transport in bEnd.3 monolayers under ischemic conditions, which were suppressed by the inhibition of LDLRs, VEGF, or VEGFR-2. The rt-PA treatment also increased the endocytosis of endothelial cells in the ischemic brain region after stroke in mice. These findings indicate that rt-PA increased BBB permeability via induction of VEGF, which at least partially mediates subsequent increase in endothelial endocytosis. Therefore, inhibition of VEGF induction may have beneficial effects after thrombolytic therapy with rt-PA treatment after stroke.
authors.affiliation: School of Pharmaceutical Sciences, Ohu University, Koriyama, Japan.|Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Animal Bioscience, Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama, Japan.
authors.forename: Nobuo
authors.initials: N
authors.lastname: Nagai
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kasumi
authors.initials: K
authors.lastname: Yamakawa
authors.affiliation: Ultrastructure Laboratory, Research Equipment Center, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Muranaka
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hokamura
authors.affiliation: Department of Pharmacology, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Umemura
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy / Q000473:pathology*; D002460:Cell Line; D004705:Endocytosis / Q000187:drug effects*; D042783:Endothelial Cells / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020768:Middle Cerebral Artery / Q000473:pathology; D018110:Receptors, Lipoprotein / Q000187:drug effects; D011994:Recombinant Proteins; D012710:Serum Albumin, Bovine / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000187:drug effects
chemical_list: D005343:Fibrinolytic Agents; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018110:Receptors, Lipoprotein; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D012710:Serum Albumin, Bovine; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D010959:Tissue Plasminogen Activator