Endothelial Cell–Derived von Willebrand Factor Is the Major Determinant That Mediates von Willebrand Factor–Dependent Acute Ischemic Stroke by Promoting Postischemic Thrombo-Inflammation

• DOI: 10.1161/atvbaha.116.307660
• Publication Date: 2016-07-22T02:54:06Z
• Authors: Nirav Dhanesha; Prem Prakash; Prakash Doddapattar; Ira Khanna; Molly J. Pollpeter; Manasa K. Nayak; Janice M. Staber; Anil K. Chauhan
• Keywords: Blood Platelets; Carotid Artery Diseases; Inflammation; Male; Mice, Knockout; Lasers; ADAMTS13 Protein; Endothelial Cells; Infarction, Middle Cerebral Artery; Ferric Compounds; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; 03 medical and health sciences; Phenotype; 0302 clinical medicine; Chlorides; Neutrophil Infiltration; Mesenteric Vascular Occlusion; Animals; Genetic Predisposition to Disease; Inflammation Mediators; Bone Marrow Transplantation

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/ Adamts 13 −/− ), 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/ Adamts 13 −/− 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 FeCl 3 injury–induced carotid artery thrombosis was comparable between wild-type and EC-VWF mice, whereas Plt-VWF and Plt-VWF/ Adamts 13 −/− 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/ Adamts 13 −/− 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.