@article{KraftBenzAustinatetal.2010,
  author    = {Kraft, Peter and Benz, Peter Michael and Austinat, Madeleine and Brede, Marc Elmar and Schuh, Kai and Walter, Ulrich and Stoll, Guido and Kleinschnitz, Christoph},
  title     = {Deficiency of Vasodilator-Stimulated Phosphoprotein (VASP) Increases Blood-Brain-Barrier Damage and Edema Formation after Ischemic Stroke in Mice},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-68522},
  year      = {2010},
  abstract  = {Background: Stroke-induced brain edema formation is a frequent cause of secondary infarct growth and deterioration of neurological function. The molecular mechanisms underlying edema formation after stroke are largely unknown. Vasodilator-stimulated phosphoprotein (VASP) is an important regulator of actin dynamics and stabilizes endothelial barriers through interaction with cell-cell contacts and focal adhesion sites. Hypoxia has been shown to foster vascular leakage by downregulation of VASP in vitro but the significance of VASP for regulating vascular permeability in the hypoxic brain in vivo awaits clarification. Methodology/Principal Findings: Focal cerebral ischemia was induced in Vasp2/2 mice and wild-type (WT) littermates by transient middle cerebral artery occlusion (tMCAO). Evan's Blue tracer was applied to visualize the extent of blood-brainbarrier (BBB) damage. Brain edema formation and infarct volumes were calculated from 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain slices. Both mouse groups were carefully controlled for anatomical and physiological parameters relevant for edema formation and stroke outcome. BBB damage (p,0.05) and edema volumes (1.7 mm360.5 mm3 versus 0.8 mm360.4 mm3; p,0.0001) were significantly enhanced in Vasp2/2 mice compared to controls on day 1 after tMCAO. This was accompanied by a significant increase in infarct size (56.1 mm3617.3 mm3 versus 39.3 mm3610.7 mm3, respectively; p,0.01) and a non significant trend (p.0.05) towards worse neurological outcomes. Conclusion: Our study identifies VASP as critical regulator of BBB maintenance during acute ischemic stroke. Therapeutic modulation of VASP or VASP-dependent signalling pathways could become a novel strategy to combat excessive edema formation in ischemic brain damage.},
  subject      = {Vasodilatator-stimuliertes Phosphoprotein},
  language  = {en}
}
@phdthesis{Benz2007,
  author    = {Benz, Peter Michael},
  title     = {Cytoskeleton assembly at endothelial cell-cell contacts is regulated by Alpha-II-spectrin/vasp complexes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-23802},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Directed cortical actin assembly is the driving force for intercellular adhesion. Vasodilator-stimulated phosphoprotein (VASP) participates in actin-fiber formation and VASP activity is regulated by phosphorylations. We screened for endothelial cell proteins, which bind to VASP dependent on its phosphorylation status. Differential proteomics identified \&\#945;II-spectrin as novel VASP-interacting protein. \&\#945;II-spectrin binds to the triple GP5-motif in VASP via its SH3 domain. cAMP-dependent protein kinase-mediated VASP phosphorylation at Ser157 inhibits \&\#945;II-spectrin/VASP complex formation. VASP becomes dephosphorylated upon formation of cell-cell contacts and in confluent but not in sparse endothelial cells \&\#945;II-spectrin colocalizes with non-phosphorylated VASP at cell-cell junctions. Ectopic expression of the \&\#945;II-spectrin SH3 domain fused to claudin-5 translocates VASP to cell-cell contacts and is sufficient to initiate the formation of cortical actin cytoskeletons. \&\#945;II-spectrin SH3 domain overexpression stabilizes cell-cell contacts and decreases endothelial permeability. Conversely, permeability of VASP-deficient endothelial cells is elevated. In a skin edema model, microvascular leakage is increased in VASP-deficient over wild-type mice. We propose that \&\#945;II-spectrin/VASP complexes regulate cortical actin cytoskeleton assembly with implications for formation of endothelial cell-cell contacts and regulation of vascular permeability.},
  language  = {en}
}