title: 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: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City.
authors.forename: Nirav
authors.initials: N
authors.lastname: Dhanesha
authors.affiliation: From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City.
authors.forename: Prem
authors.initials: P
authors.lastname: Prakash
authors.affiliation: From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City.
authors.forename: Prakash
authors.initials: P
authors.lastname: Doddapattar
authors.affiliation: From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City.
authors.forename: Ira
authors.initials: I
authors.lastname: Khanna
authors.affiliation: From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City.
authors.forename: Molly J
authors.initials: MJ
authors.lastname: Pollpeter
authors.affiliation: From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City.
authors.forename: Manasa K
authors.initials: MK
authors.lastname: Nayak
authors.affiliation: From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City.
authors.forename: Janice M
authors.initials: JM
authors.lastname: Staber
authors.affiliation: From the Department of Internal Medicine (N.D., P.P., P.D., I.K., M.K.N., A.K.C.) and Stead Family Department of Pediatrics (M.J.P., J.M.S.), University of Iowa, Iowa City. anil-chauhan@uiowa.edu.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Chauhan
mesh_terms: D000071120:ADAMTS13 Protein / Q000172:deficiency / Q000235:genetics; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D016026:Bone Marrow Transplantation; D002340:Carotid Artery Diseases / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002712:Chlorides; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism*; D005290:Ferric Compounds; D020022:Genetic Predisposition to Disease; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007834:Lasers; D008297:Male; D008641:Mesenteric Vascular Occlusion / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D010641:Phenotype; D017713:Platelet Transfusion; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D013927:Thrombosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
chemical_list: D002712:Chlorides; D005290:Ferric Compounds; D018836:Inflammation Mediators; D014841:von Willebrand Factor; C502939:ADAMTS13 protein, mouse; D000071120:ADAMTS13 Protein; C024555:ferric chloride
keywords: brain ischemia/reperfusion injury; platelets; thrombosis; von Willebrand factor