von Willebrand factor contributes to poor outcome in a mouse model of intracerebral haemorrhage

Abstract

Spontaneous intracerebral haemorrhage (ICH) is the most devastating stroke subtype and has no proven treatment. von Willebrand factor (VWF) has recently been demonstrated to promote inflammation processes. The present study investigated the pathophysiological role of VWF after experimental ICH. Functional outcomes, brain edema, blood-brain barrier (BBB) permeability, cerebral inflammation and levels of intercellular adhesion molecule-1 (ICAM-1) and matrix metalloproteinase-9 (MMP-9) were measured in a mouse model of ICH induced by autologous blood injection. We show that VWF were increased in the plasma and was accumulated in the perihematomal regions of mice subjected to ICH. Injection of VWF resulted in incerased expression of proinflammatory mediators and activation of ICAM-1 and MMP-9, associated with elevated myeloperoxidase, recruitment of neutrophils and microglia. Moreover, mice treated with VWF showed dramatically decreased pericyte coverage, more severe BBB damage and edema formation, and neuronal injury was increased compared with controls. In contrast, blocking antibodies against VWF reduced BBB damage and edema formation and improved neurological function. Together, these data identify a critical role for VWF in cerebral inflammation and BBB damage after ICH. The therapeutic interventions targeting VWF may be a novel strategy to reduce ICH-related injury.

RETRACTED: ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery

“…To examine the effects of a combined rADAMTS13 and VWF approach on neovascularization and BBB permeability, human VWF (5 mg/mouse; Haematologic Technologies, Essex Junction, VT) was administrated IV with rADAMTS13 into mice once per day for 1 week. 25 Because the half-life of human VWF is very short in mice, 26,27 daily administration was performed. VEGFR-2 antagonist Su1498 (250 ng in 2 mL PBS containing 1% dimethyl sulfoxide; Abcam, Cambridge, MA), recombinant human galectin-3 (rGal-3; 5 mg/mouse; Peprotech, Rocky Hill, NJ) or rabbit anti-VWF antibody (6 mg/g body weight; Dako, Carpinteria, CA) was administered for 1 week.…”

Biomarkers of Vascular Integrity in Traumatic Brain Injury and Correlation with Cerebrovascular Reactivity

“…Our preclinical studies have further confirmed that baseline CVR positively correlated with plasma levels of VEGF, VEGF-C, and P-selectin. Our results are consistent with other investigators' reports that elevated levels of IL-8 and sICAM-1 in the CSF may correlate with blood-brain barrier (BBB) dysfunction after TBI; sICAM-1 and TNF-α can induce macrophage inflammatory protein MIP-2 in astrocytes and microvascular endothelial cells; sICAM-1, selectins, and vWF were proposed as biomarkers of vascular endothelial damage and dysfunction [5,[11][12][13]; TBI upregulated VEGF, Flt-1, and Flk-1 [14].…”

von Willebrand factor and inflammation

“…In that regard, a common point in the studies described in the previous paragraph was that VWF deficiency or antibody‐mediated inhibition of VWF was associated with a significant decrease in vascular permeability (Fig. ) , whereas the addition of extra VWF resulted in increased vascular permeability in the experimental ICH‐model . Permeability has been differentially measured via the use of Evan's blue leakage, skin biopsy weight, or brain water content.…”