A Review of the Mechanisms of Blood-Brain Barrier Permeability by Tissue-Type Plasminogen Activator Treatment for Cerebral Ischemia

Abstract

Cerebrovascular homeostasis is maintained by the blood-brain barrier (BBB), which forms a mechanical and functional barrier between systemic circulation and the central nervous system (CNS). In patients with ischemic stroke, the recombinant tissue-type plasminogen activator (rt-PA) is used to accelerate recanalization of the occluded vessels. However, rt-PA is associated with a risk of increasing intracranial bleeding (ICB). This effect is thought to be caused by the increase in cerebrovascular permeability though various factors such as ischemic reperfusion injury and the activation of matrix metalloproteinases (MMPs), but the detailed mechanisms are unknown. It was recently found that rt-PA treatment enhances BBB permeability not by disrupting the BBB, but by activating the vascular endothelial growth factor (VEGF) system. The VEGF regulates both the dissociation of endothelial cell (EC) junctions and endothelial endocytosis, and causes a subsequent increase in vessel permeability through the VEGF receptor-2 (VEGFR-2) activation in ECs. Here, we review the possibility that rt-PA increases the penetration of toxic molecules derived from the bloodstream including rt-PA itself, without disrupting the BBB, and contributes to these detrimental processes in the cerebral parenchyma.

Keywords: blood-brain barrier permeability; brain ischemia; endothelial endocytosis; intracranial bleeding; tissue-type plasminogen activator; vascular endothelial growth factor.

Figure 1

Paracellular transport in the blood-brain barrier (BBB) by the vascular endothelial growth factor (VEGF) under ischemic condition. The binding of VEGF to the VEGF receptor-2 (VEGFR-2) induces the activation of tyrosine kinase (Tyr), which leads to a decrease in the expression of zonula occludens (ZO)-1. The changes in ZO-1 correlate with small changes in action distribution, which induce disassembly of the tight junction (TJ).

Figure 2

Schematic of the mechanisms of the increase in BBB permeability by recombinant tissue-type plasminogen activator (rt-PA) treatment after ischemic stroke. rt-PA activates the low-density lipoprotein receptor-related protein (LRP), which is upregulated in endothelial cells (ECs) by ischemic stress (1). The activation of LRP induces the transcriptional upregulation of VEGF. Secreted VEGF binds to VEGFR-2 on the surface of ECs through an autocrine mechanism and induces its phosphorylation (3). The activation of VEGFR-2 leads to an increase in endocytosis and to the activation of LRP, resulting in enhanced BBB permeability by endocytosis and subsequent transcellular transport of proteins into cerebroparenchyma (4). Tyr, TJ.