title: Deficiency of vasodilator-stimulated phosphoprotein (VASP) increases blood-brain-barrier damage and edema formation after ischemic stroke in mice.
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.
  
  
  RESULTS
  Focal cerebral ischemia was induced in Vasp(-/-) 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-brain-barrier (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 mm(3)±0.5 mm(3) versus 0.8 mm(3)±0.4 mm(3); p<0.0001) were significantly enhanced in Vasp(-/-) mice compared to controls on day 1 after tMCAO. This was accompanied by a significant increase in infarct size (56.1 mm(3)±17.3 mm(3) versus 39.3 mm(3)±10.7 mm(3), respectively; p<0.01) and a non significant trend (p>0.05) towards worse neurological outcomes.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Kraft
authors.forename: Peter Michael
authors.initials: PM
authors.lastname: Benz
authors.forename: Madeleine
authors.initials: M
authors.lastname: Austinat
authors.forename: Marc Elmar
authors.initials: ME
authors.lastname: Brede
authors.forename: Kai
authors.initials: K
authors.lastname: Schuh
authors.forename: Ulrich
authors.initials: U
authors.lastname: Walter
authors.forename: Guido
authors.initials: G
authors.lastname: Stoll
authors.forename: Christoph
authors.initials: C
authors.lastname: Kleinschnitz
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D020520:Brain Infarction; D015815:Cell Adhesion Molecules / Q000172:deficiency*; D004487:Edema / Q000473:pathology; D005260:Female; D006439:Hemodynamics; D000860:Hypoxia; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins / Q000172:deficiency*; D010750:Phosphoproteins / Q000172:deficiency*; D020521:Stroke / Q000503:physiopathology*; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000199:Actins; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein