Endothelial cell-derived von willebrand factor is the major determinant that mediates von willebrand factor-dependent acute Ischemic Stroke by promoting postischemic thrombo-inflammation

Abstract

Objective-von Willebrand factor (VWF), which is synthesized in endothelial cells and megakaryocytes, is known to worsen stroke outcome. In vitro studies suggest that platelet-derived VWF (Plt-VWF) is biochemically different from the endothelial cell-derived VWF (EC-VWF). However, little is known about relative contribution of different pools of VWF in stroke. Approach and Results-Using bone marrow transplantation, we generated chimeric Plt-VWF mice, Plt-VWF mice that lack ADAMTS13 in platelets and plasma (Plt-VWF/Adamts13-/-), and EC-VWF mice to determine relative contribution of different pools of VWF in stroke. In brain ischemia/reperfusion injury model, we found that infarct size and postischemic intracerebral thrombo-inflammation (fibrin(ogen) deposition, neutrophil infiltration, interleukin-1β, and tumor necrosis factor-α levels) within lesions were comparable between EC-VWF and wild-Type mice. Infarct size and postischemic thrombo-inflammation were comparable between Plt-VWF and Plt-VWF/Adamts13-/- mice, but decreased compared with EC-VWF and wild-Type mice (P<0.05) and increased compared with Vwf-/- mice (P<0.05). Susceptibility to FeCl3 injury-induced carotid artery thrombosis was comparable between wild-Type and EC-VWF mice, whereas Plt-VWF and Plt-VWF/Adamts13-/- mice exhibited defective thrombosis. Although most of the injured vessels did not occlude, slope over time showed that thrombus growth rate was increased in both Plt-VWF and Plt-VWF/Adamts13-/- mice compared with Vwf-/- mice (P<0.05), but decreased compared with wild-Type or EC-VWF mice. Conclusions-Plt-VWF, either in presence or absence of ADAMTS13, partially contributes to VWF-dependent injury and postischemic thrombo-inflammation after stroke. EC-VWF is the major determinant that mediates VWF-dependent ischemic stroke by promoting postischemic thrombo-inflammation.