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 is biochemically different from the endothelial cell-derived 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 platelet derived-VWF mice (Plt-VWF), platelet derived-VWF mice that lack ADAMTS13 in platelets and plasma (Plt-VWF/Adamts13−/−), and endothelial cell derived-VWF mice (EC-VWF) to determine relative contribution of different pools of VWF in stroke. In brain ischemia/reperfusion injury model, we found that infarct size, post-ischemic intracerebral thrombo-inflammation (fibrin(ogen) deposition, neutrophil infiltration, IL-1β and TNF-α levels) within lesions were comparable between EC-VWF and WT mice. Infarct size and post-ischemic thrombo-inflammation were comparable between Plt-VWF and Plt-VWF/Adamts13−/− mice, but decreased compared to EC-VWF and/or WT mice (P<0.05) and increased compared to Vwf −/− mice (P<0.05). Susceptibility to FeCl3 injury-induced carotid artery thrombosis was comparable between WT 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 to Vwf −/− mice (P<0.05), but decreased compared to WT or EC-VWF mice. Conclusions Platelet-derived VWF, either in presence or absence of ADAMTS13, partially contributes to VWF-dependent injury and post-ischemic thrombo-inflammation following stroke. Endothelial cell-derived VWF is the major determinant that mediates VWF-dependent ischemic stroke by promoting post-ischemic thrombo-inflammation.

von Willebrand factor and inflammation

“…Apparently, ADAMTS‐13 mediates its anti‐inflammatory effect by preventing the persistence of ultralarge VWF multimers. The possibility that ADAMTS‐13 reduces VWF‐dependent exaggeration of the inflammatory response has also been confirmed in models for acute ischemic stroke , acute myocardial ischemia/reperfusion injury , and leukocyte recruitment to atherosclerotic plaques .…”

Thrombotic Regulation From the Endothelial Cell Perspectives

“…12 Although numerous studies have revealed the roles of VWF on hemostasis and coagulation, the differences between the endothelial VWF and the platelet VWF in thrombotic and thrombosis-related diseases are unclear. Dhanesha et al 13 examined the roles of endothelial and platelet VWF in thrombosis in vivo. Using bone marrow transplantation, they generated the platelet (Plt)-VWF mice that express VWF in hemocytes but not in ECs and the EC-VWF mice in which VWF were only expressed in ECs.…”

Endothelial Cell von Willebrand Factor Secretion in Health and Cardiovascular Disease

“…It is well known that circulating vWF originates primarily from the endothelium, with a minor contribution from platelets [20]. Our current understanding of the role of different pools of vWF in the pathophysiology of acute stroke is based on mouse models [176]. EC-vWF mice are chimeric mice that express vWF only in ECs.…”

“…Irradiated mice transplanted with bone marrow from vWFÀ/À mice to repopulate myeloid cells lack vWF in platelets but express vWF in ECs. Plt-mice are chimeric vWF À/À mice transplanted with normal bone marrow, and therefore have vWF in platelets [176]. The wildtype (WT), vWF À/À , Plt-vWF and EC-vWF mice were subjected to 1 h ischemia followed by 23 h reperfusion and the outcome was compared [176].…”

“…Plt-mice are chimeric vWF À/À mice transplanted with normal bone marrow, and therefore have vWF in platelets [176]. The wildtype (WT), vWF À/À , Plt-vWF and EC-vWF mice were subjected to 1 h ischemia followed by 23 h reperfusion and the outcome was compared [176]. The infarct volume and neurological outcome were comparable in WT and EC-vWF mice and decreased in vWF À/À mice.…”