Recombinant Tissue-Type Plasminogen Activator Transiently Enhances Blood–Brain Barrier Permeability During Cerebral Ischemia through Vascular Endothelial Growth Factor-Mediated Endothelial Endocytosis in Mice

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...

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Bibliographic Details
Published in:Journal of cerebral blood flow and metabolism 2015-12, Vol.35 (12), p.2021-2031
Main Authors: Suzuki, Yasuhiro, Nagai, Nobuo, Yamakawa, Kasumi, Muranaka, Yoshinori, Hokamura, Kazuya, Umemura, Kazuo
Format: Article
Language:English
Subjects:
Animals
Blood-Brain Barrier - drug effects
Brain Ischemia - drug therapy
Brain Ischemia - pathology
Cell Line
Endocytosis - drug effects
Endothelial Cells - drug effects
Fibrinolytic Agents - pharmacology
Hypoxia-Inducible Factor 1, alpha Subunit - metabolism
Male
Mice
Mice, Inbred C57BL
Middle Cerebral Artery - pathology
Original
Receptors, Lipoprotein - drug effects
Recombinant Proteins
Serum Albumin, Bovine - metabolism
Stroke - drug therapy
Stroke - pathology
Tissue Plasminogen Activator - pharmacology
Vascular Endothelial Growth Factor A - pharmacology
Vascular Endothelial Growth Factor Receptor-2 - drug effects
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Summary: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.
ISSN:0271-678X
1559-7016
DOI:10.1038/jcbfm.2015.167