Plasmalemmal Vesicle Associated Protein-1 (PV-1) is a marker of blood-brain barrier disruption in rodent models

Eveline H Shue,Yang Liu,Zarina S Ali,Jun Chen,Kevin A Walter,Bethany N Winans,Eleanor B Carson-Walter

doi:10.1186/1471-2202-9-29

Eveline H Shue, Yang Liu + Show 5 more

Open Access

https://doi.org/10.1186/1471-2202-9-29

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Abstract

BackgroundPlasmalemmal vesicle associated protein-1 (PV-1) is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS) diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state.ResultsWe demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated.ConclusionOur results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.

Highlights

Plasmalemmal vesicle associated protein-1 (PV-1) is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS) diseases associated with blood-brain barrier breakdown
Cytokines secreted by the growing tumor such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and scatter factor/hepatocyte growth factor (SF/HGF) increase the permeability of the blood-brain barrier (BBB) causing extracellular fluid accumulation
reverse transcriptase polymerase chain reaction (RT-PCR) for PV-1 was performed on reverse-transcribed RNA harvested from U87MG tumors (T1) and U87:U87/ VEGF tumors grown in mice (T2, T3) and compared to PV-1 expression levels in normal mouse brain (NL)

Summary

Introduction

Plasmalemmal vesicle associated protein-1 (PV-1) is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS) diseases associated with blood-brain barrier breakdown. Vasogenic cerebral edema causes significant morbidity and mortality in patients with malignant brain tumors. Cytokines secreted by the growing tumor such as VEGF, PDGF, and SF/HGF increase the permeability of the blood-brain barrier (BBB) causing extracellular fluid accumulation. The increase in extracellular fluid, in turn, raises intracranial pressure leading eventually to brain ischemia, herniation, and death. Clinical attempts to block these cascades have focused on inhibiting signal transduction by the circulating cytokines, including monoclonal antibodies targeted to VEGF and selective receptor tyrosine kinase inhibitors. An attractive approach may be to identify selective (page number not for citation purposes)

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