TY - JOUR
T1 - Preserved vascular integrity and enhanced survival following neuropilin-1 inhibition in a mouse model of CD8 T cell-initiated CNS vascular permeability
AU - Suidan, Georgette L.
AU - Dickerson, Jonathan W.
AU - Johnson, Holly L.
AU - Chan, Theresa W.
AU - Pavelko, Kevin D.
AU - Pirko, Istvan
AU - Seroogy, Kim B.
AU - Johnson, Aaron J.
N1 - Funding Information:
We would like to thank Dr. Lawrence Brown of Harvard for providing the flk-1 and flt-1 plasmids required to perform the in situ hybridization analysis. We would also like to thank Mike Bell of Mayo Clinic Immunology for technical assistance with quantitative RT-PCR for detection of virus loads. The authors have no conflicting financial interests. This work is supported by the National Institutes of Health grant NS060881 (AJJ), the Selma Schottenstein Harris Laboratory for Research in Parkinson’s (KBS), and a Scottish Rite Schizophrenia Foundation Fellowship (JWD).
PY - 2012/9/18
Y1 - 2012/9/18
N2 - Background: Altered permeability of the blood-brain barrier (BBB) is a feature of numerous neurological conditions including multiple sclerosis, cerebral malaria, viral hemorrhagic fevers and acute hemorrhagic leukoencephalitis. Our laboratory has developed a murine model of CD8 T cell-initiated central nervous system (CNS) vascular permeability in which vascular endothelial growth factor (VEGF) signaling plays a prominent role in BBB disruption.Findings: In this study, we addressed the hypothesis that in vivo blockade of VEGF signal transduction through administration of peptide (ATWLPPR) to inhibit neuropilin-1 (NRP-1) would have a therapeutic effect following induction of CD8 T cell-initiated BBB disruption. We report that inhibition of NRP-1, a co-receptor that enhances VEGFR2 (flk-1) receptor activation, decreases vascular permeability, brain hemorrhage, and mortality in this model of CD8 T cell-initiated BBB disruption. We also examine the expression pattern of VEGFR2 (flk-1) and VEGFR1 (flt-1) mRNA expression during a time course of this condition. We find that viral infection of the brain leads to increased expression of flk-1 mRNA. In addition, flk-1 and flt-1 expression levels decrease in the striatum and hippocampus in later time points following induction of CD8 T cell-mediated BBB disruption.Conclusion: This study demonstrates that NRP-1 is a potential therapeutic target in neuro-inflammatory diseases involving BBB disruption and brain hemorrhage. Additionally, the reduction in VEGF receptors subsequent to BBB disruption could be involved in compensatory negative feedback as an attempt to reduce vascular permeability.
AB - Background: Altered permeability of the blood-brain barrier (BBB) is a feature of numerous neurological conditions including multiple sclerosis, cerebral malaria, viral hemorrhagic fevers and acute hemorrhagic leukoencephalitis. Our laboratory has developed a murine model of CD8 T cell-initiated central nervous system (CNS) vascular permeability in which vascular endothelial growth factor (VEGF) signaling plays a prominent role in BBB disruption.Findings: In this study, we addressed the hypothesis that in vivo blockade of VEGF signal transduction through administration of peptide (ATWLPPR) to inhibit neuropilin-1 (NRP-1) would have a therapeutic effect following induction of CD8 T cell-initiated BBB disruption. We report that inhibition of NRP-1, a co-receptor that enhances VEGFR2 (flk-1) receptor activation, decreases vascular permeability, brain hemorrhage, and mortality in this model of CD8 T cell-initiated BBB disruption. We also examine the expression pattern of VEGFR2 (flk-1) and VEGFR1 (flt-1) mRNA expression during a time course of this condition. We find that viral infection of the brain leads to increased expression of flk-1 mRNA. In addition, flk-1 and flt-1 expression levels decrease in the striatum and hippocampus in later time points following induction of CD8 T cell-mediated BBB disruption.Conclusion: This study demonstrates that NRP-1 is a potential therapeutic target in neuro-inflammatory diseases involving BBB disruption and brain hemorrhage. Additionally, the reduction in VEGF receptors subsequent to BBB disruption could be involved in compensatory negative feedback as an attempt to reduce vascular permeability.
KW - Blood-brain barrier (BBB)
KW - CD8 T cell
KW - CNS vascular permeability
KW - FMS-related tyrosine kinase-1 (flt-1)
KW - Fetal liver kinase 1 (flk-1)
KW - Neuropilin-1 (NRP-1)
KW - Vascular endothelial growth factor (VEGF)
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U2 - 10.1186/1742-2094-9-218
DO - 10.1186/1742-2094-9-218
M3 - Article
C2 - 22985494
AN - SCOPUS:84866274602
SN - 1742-2094
VL - 9
JO - Journal of Neuroinflammation
JF - Journal of Neuroinflammation
M1 - 713
ER -