Recombinant Tissue-type Plasminogen Activator Transiently Enhances Blood-brain Barrier Permeability During Cerebral Ischemia Through Vascular Endothelial Growth Factor-mediated Endothelial Endocytosis in Mice

Overview

Journal J Cereb Blood Flow Metab

Publisher Sage Publications

Specialties Cardiology & Vascular Diseases
Endocrinology
Neurology

Date 2015 Jul 30

PMID 26219596

Citations 16

Authors

Yasuhiro Suzuki

Nobuo Nagai

Kasumi Yamakawa

Yoshinori Muranaka

Kazuya Hokamura

Kazuo Umemura

Affiliations

Soon will be listed here.

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.

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