title: Preserved vascular integrity and enhanced survival following neuropilin-1 inhibition in a mouse model of CD8 T cell-initiated CNS vascular permeability.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Neuroscience Graduate Program, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Georgette L
authors.initials: GL
authors.lastname: Suidan
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Dickerson
authors.forename: Holly L
authors.initials: HL
authors.lastname: Johnson
authors.forename: Theresa W
authors.initials: TW
authors.lastname: Chan
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Pavelko
authors.forename: Istvan
authors.initials: I
authors.lastname: Pirko
authors.forename: Kim B
authors.initials: KB
authors.lastname: Seroogy
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002199:Capillary Permeability / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002490:Central Nervous System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism
chemical_list: D010455:Peptides; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D039942:Neuropilin-1; C501163:Flt1 protein, mouse; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2